SPINAL MUSCULAR ATROPHY

SPINAL MUSCULAR ATROPHY
A Project
On
“SPINAL MUSCULAR ATROPHY”
Submitted to
Jayoti Vidyapeeth Women’s University, Jaipur, Rajasthan,
in partial fulfillment of the requirement for

the award of the degree of
Bachelor of Pharmacy
By:
JV’n KHUSHBU
Enrollment No. : JV-I/14/7438
FACULTY OF PHARMACEUTICAL SCIENCE

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY
JAIPUR-303007, RAJASTHAN, INDIA
JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 1

Dedicated to My Beloved Parents
When we were young,

they taught us to walk.
When we grew older,
guided us on right path.
Always with us they are,
they are two shining stars,
like a shadow, they follow,
like our gods they are so ᴉᴉᴉ

DECLARATION
I hereby declare that project entitled “SPINAL MUSCULAR ATROPHY” is based on

the original work carried out at Jayoti Vidyapeeth Women’s University, Jaipur,
Rajasthan, and to the best of my knowledge it has not been submitted elsewhere by me
for the award of any degree or diploma.
Supervised by: Submitted by:
Mr. Praveen Kumar (Assistant Professor), JV’N KHUSHBU
Faculty of Pharmaceutical Science, JV-I/14/7438
Jayoti Vidyapeeth Women’s University,
Jaipur, Rajasthan

ACKNOWLEDGEMENT:
Research is a continuous process by an individual or team of persons probing into never
ending newer prospects of science. The field of pharmacy is a highly innovative field.
Every pharmaceutical product requires being stable, biologically effective, possessing
good aesthetic appeal and a development process which must be feasible for industrial
scale production. Development of each product requires sound knowledge and wide
range of experimentation. At this juncture, I consider my privilege to express my
gratitude and thanks to all those persons without whose whole hearted encouragement,
support and co-operation, this dissertation work would not have been possible.
I would like to thank Mrs. Vidushi Garg, (Hon’ble Chairperson) and Dr. Panckaj
Garg (Founder and Advisor), Jayoti Vidyapeeth Women’s University, Jaipur,
Rajasthan,for providing facilities so that we can able to complete our research work in
due course of time.
I would like to extend my deep and sincere thanks to Prof(Dr.) Dharmendra Ahuja
(Director), Faculty of Pharmaceutical Science , Jayoti Vidyapeeth Women’s
University, Jaipur, Rajasthan, whose able guidance has helped me to complete this
project work. The incredible encouragement, candid co-operation and perfect guidance
are my greatest privilege their constant encouragement and eminent guidance helped me
to complete the task to best of my ability.
I am grateful to Prof.(Dr). Anurekha Jain, (Dean) and JV’n Mr. Deepak Mittal
(Associate Professor), JV’n Mr. Praveen Kumar, (Assistant Professor), JV’n Miss
Preeti Singh, Assistant Professor, JV’n Miss Bhagyashree Goswami”, Assistant
Professor, Faculty of Pharmaceutical Science, Jayoti Vidyapeeth Women’s
University, Jaipur , Rajasthan, providing me with necessary support to complete this
project work successfully.
I would also like to express my acknowledgement to all my friends in Jayoti Vidyapeeth
Women’s University, Jaipur , Rajasthan, who all had stood for and with me in all
situations.
Date :
Place : JV’n Khushbu

CONTENTS
S.NO. CHAPTERS Page No.
1 INTRODUCTION 6-7
2 CLASSIFICATION 8-10
3 CAUSES 10-11
4 SYMPTOMS 11-12
5 GENETIC CHANGES 12-14
6 DIAGNOSIS 14-15
7 TREATMENT 15-16
8 MANAGEMENT 16-19
9 PROGNOSIS 19
10 RESEARCH DIRECTION 19-23
11 OTHER RESEARCHES 23-35
12 STRATEGY 35-40
13 RESULT 40
14 CONCLUSION 40
15 REFERENCES 41-43

INTRODUCTION:
Spinal muscular atrophy is a genetic disorder that affects the control of muscle
movement. It is caused by a loss of specialized nerve cells, called motor neurons, in the
spinal cord and the part of the brain that is connected to the spinal cord (the brainstem).
The loss of motor neurons leads to weakness and wasting (atrophy) of muscles used for
activities such as crawling, walking, sitting up, and controlling head movement. In severe
cases of spinal muscular atrophy, the muscles used for breathing and swallowing are
affected.[1]
Spinal muscular atrophy
Synonyms Autosomal recessive proximal spinal muscular atrophy,

5q spinal muscular atrophy
Location of neurons affected by spinal muscular atrophy in the spinal

cord
There are many types of spinal muscular atrophy distinguished by the pattern of features,
severity of muscle weakness, and age when the muscle problems begin. The disorder is

caused by a genetic defect in the SMN1 gene, which encodes SMN, a protein widely
expressed in all eukaryoticcells (that is, cells with nuclei, including human cells) and
necessary for survival of motor neurons. Lower levels of the protein results in loss of
function of neuronal cells in the anterior horn of the spinal cord and subsequent system-
wide atrophy of skeletal muscles. Spinal muscular atrophy manifests in various degrees
of severity, which all have in common progressive muscle wasting and mobility
impairment. Proximal muscles, arm and leg muscles that are closer to the torso
and respiratory muscles are affected first. Other body systems may be affected as well,
particularly in early-onset forms of the disorder. SMA is the most common genetic cause
of infant death.[1,2]
Spinal muscular atrophy is an inherited disorder and is passed on in an autosomal
recessive manner (see video explanation of autosomal recessive inheritance). In
December 2016, nusinersen became the first approved drug to treat SMA while several
other compounds remain in clinical trials. In the most common form of SMA
(chromosome 5 SMA, or SMN-related SMA), there is wide variability in age of onset,
symptoms and rate of progression. In order to account for these differences, the
chromosome 5 SMA often is classified into types 1 through 4.The age at which SMA
symptoms begin roughly correlates with the degree to which motor function is affected:
The earlier the age of onset, the greater the impact on motor function. Children who
display symptoms at birth or in infancy typically have the lowest level of functioning
(type 1). SMA onset in children (types 2 and 3), teens or adults (type 4) generally
correlates with increasingly higher levels of motor function.[2]
Spinal Muscular Atrophy (SMA) Types I, II, and III belong to a group of hereditary
diseases that cause weakness and wasting of the voluntary muscles in the arms and legs
of infants and children. The disorders are caused by an abnormal or missing gene known
as the survival motor neuron gene 1 (SMN1), which is responsible for the production of a
protein essential to motor neurons. Without this protein, lower motor neurons in the
spinal cord degenerate and die. The type of SMA (I, II, or III) is determined by the age of
onset and the severity of symptoms. Type I (also known as Werdnig-Hoffman disease, or
infantile-onset SMA) is evident at birth or within the first few months. Symptoms include
floppy limbs and trunk, feeble movements of the arms and legs, swallowing and feeding
difficulties, and impaired breathing. Type II (the intermediate form) usually begins 6 and
18 months of age. Legs tend to be more impaired than arms. Children with Type II may
able to sit and some may be able to stand or walk with help. Symptoms of Type III (also

called Kugelberg-Welander disease) appear between 2 and 17 years of age and include
difficulty running, climbing steps, or rising from a chair. The lower extremities are most
often affected. Complications include scoliosis and chronic shortening of muscles or
tendons around joints.[2]
Classification:
SMA manifests over a wide range of severity, affecting infants through adults. The
disease spectrum is variously divided into 3–5 types, in accordance either with the age of
onset of symptoms or with the highest attained milestone of motor development.[2,3]
The most commonly used classification is as follows:

SMA type 1 (Infantile)
Spinal muscular atrophy affects physical function but not necessarily intellectual ability.
Eponym :-Werdnig-Hoffman disease.
Usual age of onset :- 0-6 months.
Characteristics:- SMA type I is a serious condition. Children with this disorder never
manage to sit or stand. It is usually fatal before the age of 2 years.It can be detected
before birth, as there may be a reduction in fetal movement during the final months of
pregnancy.

If not, it will become evident within the first few months of life.Infants with SMA type I
never sit or stand, and they do not usually survive to the age of two years.
The severe form manifests in the first months of life, usually with a quick and unexpected
onset ("floppy baby syndrome"). Rapid motor neuron death causes inefficiency of the
major bodily organs - especially of the respiratory system - and pneumonia-induced
respiratory failure is the most frequent cause of death. Unless placed on mechanical
ventilation, babies diagnosed with SMA type 1 do not generally live past two years of
age, with death occurring as early as within weeks in the most severe cases (sometimes
termed SMA type 0). With proper respiratory support, those with milder SMA type I
phenotypes, which account for around 10% of SMA1 cases, are known to live into
adolescence and adulthood.
SMA type 2 (Intermediate)
Eponym:-Dubowitz disease
Usual age of onset:- 6-18 months
Characteristics:- SMA type II usually appears between the ages of 6 and 18 months. The
infant may learn to sit, but will never be able to stand or walk.Life expectancy depends
on whether or not the patient develops breathing problems. Most people with SMA type
II survive into adulthood.The intermediate form affects children who are never able to
stand and walk but who are able to maintain a sitting position at least some time in their
life. The onset of weakness is usually noticed some time between 6 and 18 months. The
progress is known to vary greatly, some people gradually grow weaker over time while
others through careful maintenance avoid any progression. Scoliosis may be present in
these children, and correction with a brace may help improve respiration. Body muscles
are weakened, and the respiratory system is a major concern. Life expectancy is reduced
but most people with SMA2 live well into adulthood.[2,3]
SMA type 3 (Juvenile)
Eponym :-Kugelberg-Welander disease
Usual age of onset :- >12months

Characteristics :- SMA type III, or Kugelberg-Welander disease, appears between 2 and

17 years of age.Symptoms include an unusual gait and difficulty running, climbing steps,
or rising from a chair. There may be a slight tremor of the fingers. Some people may lose
the ability to walk, and they may also develop scoliosis. Complications
include obesity and osteoporosis.[2,3]
SMA type 4 (Adult-onset)
Usual age of onset:- Adulthood
Characteristics :- The adult-onset form (sometimes classified as a late-onset SMA type 3)

usually manifests after the third decade of life with gradual weakening of muscles –
mainly affects proximal muscles of the extremities – frequently requiring the person to
use a wheelchair for mobility. Other complications are rare, and life expectancy is
unaffected.[2,3]
CAUSES:
Spinal muscular atrophy has an autosomal recessive pattern of inheritance.Chromosome

5 SMA is caused by a deficiency of a motor neuron protein called SMN, for “survival of
motor neuron.” This protein, as its name implies, seems to be necessary for normal motor
neuron function. Its deficiency is caused by genetic flaws (mutations) on chromosome 5
in a gene called SMN1. Neighboring SMN2 genes can in part compensate for
nonfunctional SMN1 genes. Other rare forms of SMA (non-chromosome 5) are caused
by mutations in genes besides SMN. SMA happens when motor neurons in the spinal
cord and the brainstem either do not work or stop working, because of genetic changes.
Motor neurons are the nerve cells that control movement.[4]
Every human cell contains a part that receives instructions from genes, and when the
instructions contain a mistake, this is called a deletion. The part that receives the
instructions is normally a protein. In SMA, the instructions that are given to the motor
neurons, or nerves that control motion, contain a deletion that causes a protein deficiency.
The gene responsible for the instruction to motor neurons is a survival motor neuron,
normally SMN 1. Each person has 2 pairs of genes for each instruction given. One gene
is inherited from the mother and one from the father. Some diseases will appear if only

one of the inherited genes contains an instruction error. Other diseases, such as SMA,
will only emerge if there is a mistake in both the mother's and the father's inherited genes.
For a child to have SMA, both parents must contribute an SMN 1 with faulty instructions.
However, even if both parents have the faulty gene, the child will not always inherit it.
Even among this population, the chance is only 1 in 4 per pregnancy that the child will
have SMA. One in 40 adults are carriers of the gene that causes SMA. Types I, II, III, and
IV spinal muscular atrophy are inherited in an autosomal recessive pattern, which means
both copies of the SMN1 gene in each cell have mutations. The parents of an individual
with an autosomal recessive condition each carry one copy of the mutated gene, but they
typically do not show signs and symptoms of the condition. Extra copies of
the SMN2 gene are due to a random error when making new copies of DNA (replication)
in an egg or sperm cell or just after fertilization. SMA-LED and the late-onset form
of spinal muscular atrophy caused by VAPB gene mutations are inherited in an autosomal
dominant pattern, which means one copy of the altered gene in each cell is sufficient to
cause the disorder.[4]
X-linked spinal muscular atrophy is inherited in an X-linked pattern. The UBA1 gene is
located on the X chromosome, which is one of the two sex chromosomes. In males (who
have only one X chromosome), one altered copy of the gene in each cell is sufficient to
cause the condition. In females (who have two X chromosomes), a mutation would have
to occur in both copies of the gene to cause the disorder. Because it is unlikely that
females will have two altered copies of this gene, males are affected by X-linked
disorders much more frequently than females. A characteristic of X-linked inheritance is
that fathers cannot pass X-linked traits to their sons.[4]
SYMPTOMS:
The symptoms of SMA depend on its severity and the person's age when it starts. Infants
with SMA type I are born with very little muscle tone, weak muscles, and feeding and
breathing problems. With SMA type III, symptoms may not appear until the second year
of life. In all of its forms, the primary feature of SMA is muscle weakness, accompanied
by atrophy of muscle. This is the result of denervation, or loss of the signal to contract,
that is transmitted from the spinal cord.[4]

This signal is normally transmitted from motor neurons in the spinal cord to muscle via
the motor neuron's axon. In SMA, either the motor neuron with its axon, or the axon
itself, becomes non-functioning. It stops working. Many of the symptoms of SMA relate
to secondary complications of muscle weakness. These can be relieved partly by therapy.
SMA symptoms cover a broad spectrum ranging from mild to severe. The primary
symptom of chromosome 5-related (SMN-related) SMA is weakness of the voluntary
muscles. The muscles most affected are those closest to the center of the body, such as
those of the shoulders, hips, thighs and upper back. Special complications occur if the
muscles used for breathing and swallowing are affected, resulting in abnormalities in
these functions. If the muscles of the back weaken, spinal curvatures can develop.[4]
There's a great deal of variation in the age of onset and level of motor function achieved
in chromosome 5-related SMA. These are roughly correlated with how much functional
SMN protein is present in the motor neurons, which in turn is correlated with how many
SMN2 genes a person has. Sensory, mental and emotional functioning are entirely normal
in chromosome-5 SMA. Some forms of SMA are not linked to chromosome 5 or SMN
deficiency. These forms vary greatly in severity and in the muscles most affected. While
most forms, like the chromosome 5-related form, affect mostly the proximal muscles,
other forms exist that affect mostly the distal muscles (those farther away from the
body’s center) — at least in the beginning.[4]
GENETIC CHANGES:
Mutations in the SMN1, UBA1, DYNC1H1, and VAPB genes cause spinal muscular
atrophy. Extra copies of the SMN2 gene modify the severity of spinal muscular atrophy.
The SMN1 and SMN2 genes provide instructions for making a protein called the survival
motor neuron (SMN) protein. The SMN protein is important for the maintenance of
specialized nerve cells called motor neurons. Motor neurons are located in the spinal cord
and the brainstem; they control muscle movement. Most functional SMN protein is
produced from the SMN1 gene, with a small amount produced from the SMN2 gene.
Several different versions of the SMN protein are produced from the SMN2 gene, but
only one version is full size and functional.[5]
Mutations in the SMN1 gene cause spinal muscular atrophy types I, II, III, and
IV. SMN1 gene mutations lead to a shortage of the SMN protein. Without SMN protein,

motor neurons die, and nerve impulses are not passed between the brain and muscles. As
a result, some muscles cannot perform their normal functions, leading to weakness and
impaired movement.[5]
Some people with type I, III, or IV spinal muscular atrophy have three or more copies of
the SMN2gene in each cell. Having multiple copies of the SMN2 gene can modify the
course of spinal muscular atrophy. The additional SMN proteins produced from the extra
copies of the SMN2 gene can help replace some of the SMN protein that is lost due to
mutations in the SMN1 gene. In general, symptoms are less severe and begin later in life
as the number of copies of the SMN2 gene increases.
Mutations in the UBA1 gene cause X-linked spinal muscular atrophy. The UBA1 gene
provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is
involved in a process that targets proteins to be broken down (degraded) within
cells. UBA1 gene mutations lead to reduced or absent levels of functional enzyme, which
disrupts the process of protein degradation. A buildup of proteins in the cell can cause it
to die; motor neurons are particularly susceptible to damage from protein buildup.
The DYNC1H1 gene provides instructions for making a protein that is part of a group
(complex) of proteins called dynein. This complex is found in the fluid inside cells
(cytoplasm), where it is part of a network that moves proteins and other materials. In
neurons, dynein moves cellular materials away from the junctions between neurons
(synapses) to the center of the cell. This process helps transmit chemical messages from
one neuron to another. DYNC1H1 gene mutations that cause SMA-LED disrupt the
function of the dynein complex. As a result, the movement of proteins, cellular structures,
and other materials within cells are impaired. A decrease in chemical messaging between
neurons that control muscle movement is thought to contribute to the muscle weakness
experienced by people with SMA-LED. It is unclear why this condition affects only the
lower extremities.[5,6]
The adult-onset form of spinal muscular atrophy is caused by a mutation in
the VAPB gene. The VAPB gene provides instructions for making a protein that is found
in cells throughout the body. Researchers suggest that this protein may play a role in
preventing the buildup of unfolded or misfolded proteins within cells. It is unclear how
a VAPB gene mutation leads to the loss of motor neurons. An impaired VAPB protein
might cause misfolded and unfolded proteins to accumulate and impair the normal
function of motor neurons. Other types of spinal muscular atrophy that primarily affect

the lower legs and feet and the lower arms and hands are caused by the dysfunction of
neurons in the spinal cord. When spinal muscular atrophy shows this pattern of signs and
symptoms, it is also known as distal hereditary motor neuropathy. The various types of
this condition are caused by mutations in other genes.[5,6]
DIAGNOSIS:
The most severe manifestation on the SMA spectrum can be noticeable to mothers late in
their pregnancy by reduced or absent fetal movements. Symptoms are critical (including
respiratory distress and poor feeding) which usually result in death within weeks. In
comparison to the mildest phenotype of SMA (adult-onset), where muscle weakness may
present after decades and progress to the use of a wheelchair but life expectancy is
unchanged.[1]
The more common clinical manifestations of the SMA spectrum that prompt diagnostic
genetic testing:
• Progressive bilateral muscle weakness (Usually upper arms & legs more so than
hands and feet) preceded by an asymptomatic period (all but most severe type 0)[1]
• Flattening of the chest wall when taking a breath and belly protrusion when taking a
breath in.
• hypotonia associated with absent reflexes.
While the above symptoms point towards SMA, the diagnosis can only be confirmed
with absolute certainty through genetic testing for bi-allelic deletion of exon 7 of
the SMN1 gene which is the cause in over 95% of cases.[7] Genetic testing is usually
carried out using a blood sample, and MLPA is one of more frequently used gene
sequencing techniques, as it also allows establishing the number of SMN2 gene copies.
Preimplantation testing
Preimplantation genetic diagnosis can be used to screen for SMA-
affected embryos during in-vitro fertilisation.[1,2]
Prenatal testing
Prenatal testing for SMA is possible through chorionic villus sampling, cell-free fetal
DNA analysis and other methods.[1,2]

Carrier testing
Those at risk of being carriers of SMN1 deletion, and thus at risk of having offspring
affected by SMA, can undergo carrier analysis using a blood or saliva sample.
The American College of Obstetricians and Gynecologists recommends all people
thinking of becoming pregnant be tested to see if they are a carrier.[1,2]
Routine screening
Routine prenatal or neonatal screening for SMA is controversial, because of the cost, and
because of the severity of the disease. Some researchers have concluded that population
screening for SMA is not cost-effective, at a cost of $5 million per case averted in the
United States as of 2009. Others conclude that SMA meets the criteria for screening
programs and relevant testing should be offered to all couples. The major argument for
neonatal screening is that in SMA type I, there is a critical time period in which to initiate
therapies to reduce loss of muscle function and proactive treatment in regards to
nutrition.[1,2]
TREATMENT:
There is no cure for SMA. Treatment consists of managing the symptoms and preventing
complications.
In December 2016 the U.S. Food and Drug Administration approved nusinersen
(Spinraza ™) as the first drug approved to treat children and adults with spinal muscular
atrophy. The drug is administered by intrathecal injection into the fluid surrounding the
spinal cord. It is designed to increase production of the full-length SMN protein, which is
critical for the maintenance of motor neurons.[7]
Muscle relaxants such as baclofen, tizanidine, and the benzodiazepines may reduce
spasticity. Botulinum toxin may be used to treat jaw spasms or drooling. Excessive
saliva can be treated with amitriptyline, glycopyolate, and atropine or by botulinum
injections into the salivary glands. Antidepressants may be helpful in treating
depression. Physical therapy, occupational therapy, and rehabilitation may help to
improve posture, prevent joint immobility, and slow muscle weakness and atrophy.
Stretching and strengthening exercises may help reduce spasticity, increase range of
motion, and keeps circulation flowing. Some individuals require additional therapy for
speech, chewing, and swallowing difficulties. Applying heat may relieve muscle pain.
Assistive devices such as supports or braces, orthotics, speech synthesizers, and
wheelchairs may help some people retain independence. Proper nutrition and a balanced
diet are essential to maintaining weight and strength. People who cannot chew or
swallow may require insertion of a feeding tube. Non-invasive ventilation at night can
prevent apnea in sleep, and some individuals may also require assisted ventilation due to
muscle weakness in the neck, throat, and chest during daytime.[7]
Spinraza
In December 2016, the United States (U.S.) Food and Drug Administration (FDA)
approved a drug, nusinersen (Spinraza) to treat SMA. It is the first drug to be approved
for this condition. It is given by injection, the first three doses at 14-day intervals, the
fourth after 30 days, and then every 4 months. Spinraza targets the underlying defect in
SMA, so it may help delay, prevent, or even reverse the symptoms. Common side
effects include a higher risk of respiratory tract infection and constipation. There may
also be a risk of bleeding and kidney problems.[7]
Assistive devices
Assistive technology such as ventilators, power wheelchairs, and modified access to

computers are enabling individuals with SMA to live longer, be more active, and to
participate in the community. Ventilation is especially important. The severity of the
individual's weakness directly affects the course of the disease. Infants with severe SMA
may experience respiratory disease, because the muscles that support breathing are weak.
Children with milder forms of SMA can expect to have a longer lifespan, although they
may need extensive medical support. Molecular biology has improved our understanding
of SMA. Many experimental treatments are being tested, including gene replacement,
stem-cell replacement of motor neurons, and therapies to increase the expression of the
SMN 2 gene. SMA is genetic, and there is no way to prevent it. Parents with a family
history of SMA are encouraged to seek genetic counseling before starting a family.[7]
Management
The clinical management of an individual with SMA varies based upon the severity/type.
Management of individual patients with the same type of SMA can vary. In the most
severe forms (types 0/1), individuals have the greatest muscle weakness requiring prompt
intervention. Whereas the least severe form (type 4/adult onset), individuals may not seek

the certain aspects of care until later (decades) in life. While types of SMA and
individuals among each type may differ, therefore specific aspects of an individual's care
can differ.[7,8]
Respiratory care
The respiratory system is the most common system to be affected and the complications
are the leading cause of death in SMA types 0/1 and 2. SMA type 3 can have similar
respiratory problems, but it is more rare. The complications that arise due to weakened
intercostal muscles because of the lack of stimulation from the nerve. The diaphragm is
less affected than the intercostal muscles. Once weakened, the muscles never fully
recover the same functional capacity to help in breathing and coughing as well as other
functions. Therefore, breathing is more difficult and pose a risk of not getting enough
oxygen/shallow breathing and insufficient clearance of airway secretions. These issues
more commonly occurs while asleep, when muscles are more relaxed. Swallowing
muscles in the pharynx can be affected, leading to aspiration coupled with a poor
coughing mechanism increases the likelihood of infection/pneumonia. Mobilizing and
clearing secretions involve manual or mechanical chest physiotherapy with postural
drainage, and manual or mechanical cough assistance device. To assist in breathing, Non-
invasive ventilation (BiPAP) is frequently used and tracheostomy may be sometimes
performed in more severe cases; both methods of ventilation prolong survival to a
comparable degree, although tracheostomy prevents speech development.[7,8]
Nutrition
The more severe the type of SMA, the more likely to have nutrition related health issues.
Health issues can include difficulty in feeding, jaw opening, chewing and swallowing.
Individuals with such difficulties can be at increase risk of over or undernutrition, failure
to thrive and aspiration. Other nutritional issues, especially in individuals that are non-
ambulatory (more severe types of SMA), include food not passing through the stomach
quickly enough, gastric reflux, constipation, vomiting and bloating. Therein, it could be
necessary in SMA type I and people with more severe type II to have a feeding
tube or gastrostomy. Additionally, metabolic abnormalities resulting from SMA impair β-
oxidation of fatty acids in muscles and can lead to organic acidemia and consequent
muscle damage, especially when fasting. It is suggested that people with SMA, especially
those with more severe forms of the disease, reduce intake of fat and avoid prolonged
fasting (i.e., eat more frequently than healthy people) as well as choosing softer foods to
avoid aspiration. During an acute illness, especially in children, nutritional problems may
first present or can exacerbate an existing problem (example: aspiration) as well as cause
other health issues such as electrolyte and blood sugar disturbances.[7,8]
Orthopaedics
Skeletal problems associated with weak muscles in SMA include tight joints with limited
range of movement, hip dislocations, spinal deformity, osteopenia, an increase risk of
fractures and pain. Weak muscles that normally stabilize joints such as the vertebral
column lead to development of kyphosis and/or scoliosis and joint contracture. Spine
fusion is sometimes performed in people with SMA I/II once they reach the age of 8–10
to relieve the pressure of a deformed spine on the lungs. Furthermore, immobile
individuals, posture and position on mobility devices as well as range of motion
exercises, and bone strengthening can be important to prevent complications. People with
SMA might also benefit greatly from various forms of physiotherapy, occupational
therapy and physical therapy.[1,2]
Mobility support
Orthotic devices can be used to support the body and to aid walking. For example,
orthotics such as AFOs (ankle foot orthoses) are used to stabilise the foot and to aid gait,
TLSOs (thoracic lumbar sacral orthoses) are used to stabilise the torso. Assistive
technologies may help in managing movement and daily activity and greatly increase the
quality of life.[2]
Cardiology
Although the heart is not a matter of routine concern, a link between SMA and certain
heart conditions has been suggested.[2]
Mental health
SMA children do not differ from the general population in their behaviour;
their cognitive development can be slightly faster, and certain aspects of
their intelligence are above the average. Despite their disability, SMA-affected people
report high degree of satisfaction from life.
Palliative care in SMA has been standardised in the Consensus Statement for Standard of
Care in Spinal Muscular Atrophy which has been recommended for standard adoption
worldwide.[8]
Medication
Nusinersen is the only approved medication to treat spinal muscular atrophy. It is

administered directly to the central nervous system using an intrathecal injection. It was
approved by the European Commission in centralised procedure in June 2017.[8]
Prognosis
The prognosis is poor for babies with SMA Type I. Most die within the first two years.
For children with SMA Type II, the prognosis for life expectancy or for independent
standing or walking roughly correlates with how old they are when they first begin to
experience symptoms - older children tend to have less severe symptoms Life
expectancy is reduced but some individuals live into adolescence or young adulthood.
Individuals with SMA type III may be prone to respiratory infections but with care may
have a normal lifespan.[9,10]
In lack of pharmacological treatment, people with SMA tend to deteriorate over time.
Recently, survival has increased in severe SMA patients with aggressive and proactive
supportive respiratory and nutritional support.
The majority of children diagnosed with SMA type 0 and I do not reach the age of 4,
recurrent respiratory problems being the primary cause of death. With proper care, milder
SMA type I cases (which account for approx. 10% of all SMA1 cases) live into
adulthood. Long-term survival in SMA type I is not sufficiently evidenced; however,
recent advances in respiratory support seem to have brought down mortality.
In SMA type II, the course of the disease is slower to progress and life expectancy is less
than the healthy population. Death before the age of 20 is frequent, although many people
with SMA live to become parents and grandparents. SMA type III has normal or near-
normal life expectancy if standards of care are followed. Type IV, adult-onset SMA
usually means only mobility impairment and does not affect life expectancy. [9,10]
In all SMA types, physiotherapy has been shown to delay the progress of disease.
Research Directions
Since the underlying genetic cause of SMA was identified in 1995,[42] several therapeutic
approaches have been proposed and investigated that primarily focus on increasing the
availability of SMN protein in motor neurons. The main research directions are as
follows:

SMN1 gene replacement

Gene therapy in SMA aims at restoring the SMN1 gene function through inserting
specially crafted nucleotide sequence (a SMN1 transgene) into the cell nucleus using
a viral vector; scAAV-9 and scAAV-10 are the primary viral vectors under
investigation.[11,12,13]
Only one programme has reached the clinical stage:
• AVXS-101 – a proprietary biologic under development by Avexis which uses self-

complementary adeno-associated virus type 9 (scAAV-9) as a vector to deliver
the SMN1transgene. As of June 2016, a phase I clinical trial was under way, with
published early results showing marked improvement in treated infants compared to
the natural course of the disorder. As of February 2017, two pivotal trials in SMA1
infants have been announced to start during 2017. Work on developing gene therapy
for SMA is also conducted at the Institut de Myologie in Paris and at the University of
Oxford.
SMN2 alternative splicing modulation
This approach aims at modifying the alternative splicing of the SMN2 gene so that to
force it to code for higher percentage of full-length SMN protein. Sometimes it is also
called gene conversion, because it attempts to convert the SMN2 gene functionally
into SMN1 gene.
The following splicing modulators have reached clinical stage development:
• Branaplam (LMI070, NVS-SM1) is a proprietary small-molecule experimental drug

administered orally and being developed by Novartis. As of October 2017 the
compound remains in phase-II clinical trial in infants with SMA type 1 while trials in
other patient categories are under development.
• RG7916 is a proprietary small-molecule drug administered orally and developed
by PTC Therapeutics in collaboration with Hoffmann-La Roche and SMA
Foundation. As of October 2016, RG7916 has advanced to phase II trials across all
ages and SMA types.
Of discontinued clinical-stage molecules, RG3039, also known as Quinazoline495, was a
proprietary quinazoline derivative developed by Repligen and licensed to Pfizer in March
2014 which was discontinued shortly after, having only completed phase I trials. PTK-

SMA1 was a proprietary small-molecule splicing modulator of the tetracyclines group

developed by Paratek Pharmaceutical and about to enter clinical development in 2010
which however never happened. RG7800 was a molecule akin to RG7916, developed by
Hoffmann-La Roche and trialled on SMA patients in 2015, whose development was put
on hold indefinitely due to long-term animal toxicity.[12,13]
Basic research has also identified other compounds which modified SMN2 splicing in
vitro, like sodium orthovanadate and aclarubicin. Morpholino-type antisense
oligonucleotides, with the same cellular target as nusinersen, remain a subject of intense
research, including at the University College London and at the University of Oxford.
SMN2 gene activation
This approach aims at increasing expression (activity) of the SMN2 gene, thus increasing
the amount of full-length SMN protein available.
• Oral salbutamol (albuterol), a popular asthma medicine, showed therapeutic potential

in SMA both in vitro and in three small-scale clinical trials involving patients with
SMA types 2 and 3, besides offering respiratory benefits.[12,13]
A few compounds initially showed promise but failed to demonstrate efficacy in clinical
trials:
• Butyrates (sodium butyrate and sodium phenylbutyrate) held some promise in in

vitro studies but a clinical trial in symptomatic people did not confirm their efficacy.
Another clinical trial in pre-symptomatic types 1–2 infants was completed in 2015 but
no results have been published.[13]
• Valproic acid was widely used in SMA on experimental basis in the 1990s and 2000s
because in vitro research suggested its moderate effectiveness. However, it
demonstrated no efficacy in achievable concentrations when subjected to a large
clinical trial. It has also been proposed that it may be effective in a subset of people
with SMA but its action may be suppressed by fatty acid translocase in others. Others
argue it may actually aggravate SMA symptoms.
• Hydroxycarbamide (hydroxyurea) was shown effective in mouse models and
subsequently commercially researched by Novo Nordisk, Denmark, but demonstrated
no effect on people with SMA in subsequent clinical trials.[13]
Compounds which increased SMN2 activity in vitro but did not make it to the clinical
stage include growth hormone, various histone deacetylase inhibitors, benzamide M344,
hydroxamic acids (CBHA, SBHA, entinostat, panobinostat, trichostatin A, vorinostat ) ,

prolactin natural polyphenol compounds like resveratrol and curcumin. Celecoxib, a p38
pathway activator, is sometimes used off-label by people with SMA based on a single
animal study but such use is not backed by clinical-stage research.[13]
SMN stabilisation
SMN stabilisation aims at stabilising the SMNΔ7 protein, the short-lived defective
protein coded by the SMN2 gene, so that it is able to sustain neuronal cells. No
compounds have been taken forward to the clinical stage. Aminoglycosides showed
capability to increase SMN protein availability in two studies. Indoprofen offered some
promise in vitro.[13,14]
Neuroprotection
Neuroprotective drugs aim at enabling the survival of motor neurons even with low levels
of SMN protein.
• Olesoxime is a proprietary neuroprotective compound developed by the French

company Trophos which showed stabilising effect in a phase-II clinical trial involving
people with SMA types 2 and 3. The drug is being developed by Hoffmann-La
Roche since its acquisition of Trophos in early 2015.
Of clinically studied compounds which did not show efficacy, thyrotropin-releasing
hormone (TRH) held some promise in an open-label uncontrolled clinical trial but did not
prove effective in a subsequent double-blind placebo-controlled trial. Riluzole, a drug
that has mild clinical benefit in amyotrophic lateral sclerosis, was proposed to be
similarly tested in SMA, however a 2008–2010 trial in SMA types 2 and 3 was stopped
early due to lack of satisfactory results. Compounds that had some neuroprotective effect
in in vitro research but never moved to in vivo studies include β-lactam
antibiotics (e.g., ceftriaxone) and follistatin.[13,14]
Muscle restoration:
This approach aims to counter the effect of SMA by targeting the muscle tissue instead of
neurons.
• CK-2127107 (CK-107) is a skeletal troponin activator developed by Cytokinetics in

cooperation with Astellas. The drug aims at increasing muscle reactivity despite

lowered neural signalling. As of October 2016, the molecule is in a phase II clinical

trial in adolescent and adults with SMA types 2, 3, and 4.[14]
Stem cells
As of 2016, there has been no significant breakthrough in stem cell therapy in SMA. An
experimental programme to develop a stem cell based therapeutic product for SMA was
run, with financial support from the SMA community, by a US company California Stem
Cell starting from 2005. It was discontinued in 2010, unable to enter the clinical stage,
and the company ceased to exist shortly after. In 2013–2014, a small number of SMA1
children in Italy received court-mandated stem cell injections following the Stamina
scam, but the treatment was reported having no effect.[14]
Whilst stem cells never form a part of any recognised therapy for SMA, a number of
private companies, usually located in countries with lax regulatory oversight, take
advantage of media hype and market stem cell injections as a "cure" for a vast range of
disorders, including SMA. The medical consensus is that such procedures offer no
clinical benefit whilst carrying significant risk, therefore people with SMA are advised
against them.[14]
Other SMA Researches
This decade, for the first time, scientific research in spinal muscular atrophy (SMA) has
yielded enough information to allow the pursuit of several avenues of disease treatment
and prevention. Most are centered around increasing cellular levels of a protein called
SMN (survival of motor neuron), first identified in the mid-1990s as the root cause of
almost all cases of SMA. A few scientists are studying exactly what SMN does to see if
its absence might be compensated for via some other gene or protein. During the 1990s,
investigators, many of whom had MDA support, uncovered a fundamental clue about
SMA that would have profound implications for its treatment: While everyone with SMA
lacked or had mutations in genes known as SMN1, located on chromosome 5, everyone
with the disease also had at least one functional copy of a gene called SMN2 located
nearby. Researchers soon learned the difference between SMN1 and SMN2: Most of the
protein produced from the DNA instructions carried by the SMN1 gene is so-called “full-
length” SMN, a protein whose functions are incompletely understood but apparently

necessary to the health of motor neurons. By contrast, most of the protein produced from
neighboring SMN2 genes is a short form of SMN, which is not functional.[15,16]
The key word in that sentence is “most.” About 20 percent of the protein molecules
produced from the SMN2 gene are in fact full-length, fully functional SMN. And the
more SMN2 activity there is, the better an organism tolerates the loss of SMN1.
Researchers quickly learned that the number of SMN2 “backup gene” copies varies in the
population in general. In people with SMA, who lack functional SMN1 genes, the more
SMN2 copies someone has, the better he or she is likely to fare.[15,16]
Babies born with no SMN1 genes and one or two SMN2 genes usually have the very
severe form of the disease known as type 1 SMA, in which severe weakness and
respiratory muscle impairment usually lead to early death. Type 2 SMA is less severe and
allows for a longer life span, albeit with disabilities, and people with this form of the
disease generally have about three copies of SMN2.[17]
Type 2 SMA is less severe and allows for a longer life span, albeit with disabilities, and
people with this form of the disease generally have about three copies of SMN2. The
least severe SMA cases, known as type 3 (with some physicians adding a type 4)
generally occur when there are at least three SMN2 genes present. The correlation
between number of SMN2 genes and severity of SMA, however, is only approximate.
Research to identify other factors is under way.[1,2,17]
Just what SMN does in nerve or other cells, and whether its presence is required during
development of the nervous system to prevent permanent damage, remain incompletely
answered questions.[17]

Augmenting SMN by modifying SMN2 gene instructions
For Adrian Krainer at Cold Spring Harbor Laboratory on New York’s Long Island, the
preferred strategy to find a cure for SMA involves changing the SMN2 gene’s
instructions by altering a process called splicing, a kind of molecular cutting and pasting
that cells perform. “Changing the splicing that underlies the defect has a certain
elegance,” says Krainer, who has MDA funding for this work and is collaborating
with Isis, a drug development company in Carlsbad, Calif. However, he says, “there are
different ways of solving the SMA problem, many approaches to pursue in parallel.”
Since 1983, Krainer has been working on RNA splicing, a method cells use to refine a
genetic message as it moves from its permanent form as DNA to a “rough draft” RNA
molecule and then to one or more “final” RNA versions, known as messenger RNAs, that
provide direct instructions for the cell to make protein molecules. One way to change
how a cell splices the RNA on its way to becoming a final copy is by hiding parts of the
RNA strand from the cell’s processing mechanism, thereby changing the final structure
of the messenger RNA. Krainer and others accomplish this sleight of hand by using
synthetic material called “antisense,” which specifically targets, sticks to and prevents a
cell from “seeing” an RNA section. Without treatment, the section of the SMN2 gene
called exon 6 is spliced directly to the section called exon 8, and exon 7 is left out of the
final RNA. But using antisense to block a “clip out exon 7” signal on the RNA coaxes the
cell to include this critical exon and ultimately make full-length SMN protein. Krainer is
now testing the various antisense molecules in two strains of laboratory mice with a
disease closely resembling human SMA. Before proceeding toward human testing, which
Krainer hopes will be within the next few years, he and his colleagues want to find out in
the laboratory how important the timing of SMN treatment is and determine whether an
increase in SMN after the onset of SMA can stop disease progression, or even reverse the
disease process.[18,19]
Christian Lorson, an MDA grantee at the University of Missouri-Columbia, is also

pursuing strategies to get more full-length SMN out of the SMN2 gene, although that’s
not the only approach to SMA that intrigues him. Lorson says he’s working on several
experimental approaches to treating SMA. Two of them, both aimed at changing splicing,
are known as “trans-splicing” and “bifunctional” RNAs. Rather than just masking part of
the SMN2 RNA with antisense and hoping the cell will include exon 7, Lorson says he

prefers to take a firmer approach to “persuading” the cell to include exon 7 by providing
that piece of RNA along with blocking the original instructions. He and graduate student
Tristan Coady developed an antisense molecule that overlaps the place where exon 6
would be spliced to exon 8, preventing that from happening. The cell then has to
“choose” between no splicing at all and splicing in the new exon 7 provided by the
scientists, Lorson says. “When faced with that choice,” Lorson says, the cell considers
splicing in the newly supplied exon 7 RNA (“trans-splicing”) the better option.Lorson’s
lab group is also working on a variation of this strategy, using what he calls
“bifunctional” RNAs. A bifunctional RNA molecule is a combination of a piece of
antisense that targets the SMN2 gene at the point where exon 7 normally would be
spliced out, tethered to another piece of RNA that specifically attracts cellular proteins
normally involved in splicing that encourage exon 7 inclusion. Lorson’s lab group is also
working on a variation of this strategy, using what he calls “bifunctional” RNAs. A
bifunctional RNA molecule is a combination of a piece of antisense that targets the
SMN2 gene at the point where exon 7 normally would be spliced out.[19,20]
About 80 percent of the time, an RNA section called exon 7 is spliced out of the final
instructions for the SMN2 gene, resulting in production of a short version of the SMN
protein. Many strategies to treat SMA are based on coaxing cells to include exon 7 in the
instructions for SMN.[19,20]
Stabilizing short SMN

Lorson, who has fingers in almost every part of the SMA research pie, also is working on
a unique strategy that he says isn’t widely endorsed but is gaining adherents: improving
the stability of the short protein made from the SMN2 gene. In collaboration with Cheng-
Wei Tom Chang, a chemist at Utah State University in Logan, Lorson and Virginia
Mattis, another graduate student, are experimenting with antibiotics known as

aminoglycosides, which cause cells to ignore, or “read through,” stop signals in RNA and
make longer protein molecules.[20]
An alternative to encouraging exon 7 inclusion in the final instructions for SMN would
be lengthening the short form of SMN by adding a “tail” to it. The “read-through”
product made from the SMN2 gene still lacks exon 7, but it has a longer tail after exon 7
than it normally would have.
“It may be that the read-through protein is not by itself intrinsically more functional,”
Lorson says, “but in combination with full-length SMN, it enhances and stabilizes the
normally low SMN levels. At the end of the day, we want more SMN protein, regardless
of mechanism. That would be great.” His hypothesis, now being studied, is that the read-
through SMN protein forms a two-part molecule with whatever full-length SMN is
available, which improves its stability and function. Normally, he says, full-length SMN
molecules associate with each other and form this type of two-part structure, but short
SMN that lacks both exon 7 and a longer tail can’t participate in this interaction.[20]
He says that if the benefit they’re seeing in cells “is coming about because of full-length
SMN” rather than directly from short SMN, “that’s fine.”The next step will be to see if it
helps SMN-deficient mice.Raising SMN levels by increasing total output from the SMN2
gene.Because some percentage of output from the SMN2 gene is full-length SMN
protein, it stands to reason that increasing the total output from the gene would raise
levels of both compounds.One way to increase the activity of a gene is with compounds
known as histone deacetylase inhibitors, or HDAC inhibitors, which keep DNA messages
open for transcription into RNA and ultimately cause more protein molecules to be made.
Several ongoing drug trials in people with SMA are making use of this phenomenon.
Sodium phenylbutyrate and valproic acid are in this category and are being tested in
patients. The Boston pharmaceutical company Paratek is investigating whether antibiotics
in the tetracycline family have HDAC inhibitory activity and can increase SMN
production. According to a 2008 press release, the company has been encouraged by
early evidence.[20,21]

Elliot Androphy, who has MDA supportfor SMA research at the University of
Massachusetts-Worcester, believes HDAC inhibitors “hold promise” but that they also
come with some caveats. “It’s an idea with potential and some experiments suggest these
may be of benefit,” he says. “But we really don’t know how they may be working.”
Androphy and others are concerned about the lack of specificity of HDAC inhibitors,
which are likely to increase output from a number of genes, not just the SMA target
gene.[20.21]
Transferring genes or stem cells

Another strategy for raising full-length SMN levels is to deliver the compound via genes
that make it, using stem cells or other delivery vehicles. California Stem Cell in Irvine is
developing cell transplant therapies and has named SMA and ALS (amyotrophic lateral
sclerosis) as its first targets. According to Chief Operating Officer Chris Airriess, the
company hopes to test stem cells in type 1 SMA patients later this year. At the U.S. Food
and Drug Administration, Jakob Reiser has MDA support to study the delivery of the
SMN1 gene via gene therapy. Reiser, a molecular biologist who specializes in developing
viral gene delivery vehicles, is working closely with neurosurgeon Nicholas Boulis at
Emory University in Atlanta. Reiser says they’ll inject the SMN1 gene at various time
points into mice that have an SMA-like disease that allows them to survive for six to
seven months with a fair percentage of their motor neurons intact. The investigators will
deliver the gene, encased in a viral transporter, into mouse muscles, with the expectation
that it will be transported from muscle fibers to motor neurons via connecting nerve
fibers. The viral transporter carrying the SMN1 gene is an altered lentivirus, which has a
good reputation for reaching the nervous system. Reiser and Boulis also plan to use a
molecular “on switch” (“promoter”) called Hb9, which should cause the gene to be
activated and the SMN1 protein produced in motor neurons and probably not in other
types of cells. Either gene therapy or stem cells also could be used to deliver other
therapeutic agents, such as “neurotrophic” (nerve-nourishing) proteins. Reiser and Boulis
plan to study the effects of transferring the gene for one such protein, called insulin-like
growth factor 1 (IGF1), alone and in combination with the SMN1 gene, in their SMA
mice.[20,21]

In addition, stem cells are expected to provide a valuable research tool. In December
2008, Lorson was part of a scientific team coordinated by Clive Svendsen at the
University of Wisconsin-Madison, that showed SMA-affected motor neurons can be
developed in the laboratory from skin cells taken from an SMA patient. These, he says,
will provide a valuable environment in which to “ask biological questions” about the
SMA disease process as well as develop therapeutics in a human disease context. Using
stem cells as therapeutic agents themselves, Lorson says, is not as simple as it’s
sometimes depicted, although truly exciting breakthroughs seem to be developing at an
unprecedented rate. “There are biological barriers designed to keep the central nervous
system protected and isolated,” he notes, and these would have to be breached for new
motor neurons to grow and activate muscle fibers at significant distances from the spinal
cord.[20,21]
Beyond boosting SMN

Umrao Monani, who has received MDA funding for SMA studies at Columbia
University’s Motor Neuron Center in New York, wants to know more about what SMN
does and when it does it. “I am convinced that SMN is multifunctional,” he says, “and
that the level of SMN you have may determine how many functions of SMN you can
maintain.”
One role of full-length SMN that’s universally agreed upon is its participation in building
the so-called spliceosomes in the cell nucleus. Spliceosomes are the structures where
RNA splicing, in which draft RNA becomes messenger RNA, is conducted. With so
much emphasis on changing the splicing of SMN2 RNA so that full-length SMN is made,
it’s confusing to think of SMN itself as part of the splicing machinery that affects the
manufacturing of various proteins, but that’s a crucial concept. So far, it’s not clear which
RNAs are most affected by a lack of SMN and therefore deficient spliceosome activity,
but it’s certain that some are. If any of those affected are needed during development of
the nervous system, their absence early in life could take a heavy toll. Monani is among
those who believe SMN’s role is not limited to spliceosome formation. He’s particularly
interested in SMN’s potential involvement in transporting RNA molecules down the long
fibers (axons) from motor neurons in the spinal cord to muscles, especially during the
development of the axons. “One scenario is that SMN transports a particular molecule to
the neuromuscular junction [where nerve fibers and muscle fibers intersect],” Monani
says.[20,21]
He and his colleagues published a paper last summer supporting this idea by showing that
mice with insufficient functional SMN early in life don’t form normal neuromuscular
junctions and have impaired transmission of signals from nerve to muscle. Monani and
colleagues, however, draw a positive conclusion from this otherwise concerning finding,
suggesting that maintaining function at the neuromuscular connection might be a
promising treatment avenue for SMA. Livio Pellizzoni, who’s also part of Columbia’s
Motor Neuron Center, believes it’s important to understand more about SMN function
and the time period during which the protein is essential before relying on SMN-based
therapies as treatments for SMA. He says, SMA can be prevented by increasing SMN
levels before birth, but it’s unclear whether it can be effectively treated or cured by
increasing them later on.[20,21]
He cites a landmark MDA-supported study published in 2000 that shows positive

outcomes for mice bred so as not to have any copies of the mouse SMN genes and eight
copies of the human SMN2 gene. Although the researchers achieved full rescue of the
mice by increasing SMN protein levels, Pellizzoni notes that they only prevented the
disease; they didn’t reverse it. Likewise, humans lacking SMN1 genes benefit from
having multiple SMN2 genes. But, like the mice, they have these genes from birth; they
don’t acquire them later on. Pellizzoni, who had MDA funding from 2004 to 2006 to
study SMN in mice, says the protein appears to have many roles in nerve cells, most of
which are incompletely understood. Studying all of SMN’s functions “gives you an

opportunity to understand the mechanisms of this disease, so that you have additional
ways to identify targets and develop therapies.” While he’s in favor of pursuing strategies
to change SMN2 gene splicing or increase its total output, he says identification of
additional targets alsoneeds to be pursued. “We need to see if there’s a gene X that might
influence the SMA phenotype [clinical picture] and be amenable as a drug target.” And,
he says, “It would be great to have an animal model showing the time window for
intervention.”[20,21]
Newborn screening would allow earlier treatment

If it becomes clear that very early treatment, either with SMN augmentation strategies or
other measures, can improve survival and quality of life for people with SMA, the case
for newborn screening to detect the disease becomes a strong one.
“We ought to consider newborn screening,” says Tom Prior, who directs the Molecular
Pathology Laboratory at Ohio State University in Columbus. Prior, who received MDA
funding from 1996 to 2001 to develop diagnostic testing for SMA, advocates screening
newborns for SMA so that babies can be enrolled in a clinical trial or receive whatever
treatments are developed as early as possible. He also advocates screening for carriers of
the disease so that parents can make informed reproductive decisions.[22]
Carrier and prenatal testing can decrease disease incidence

“We have to hit SMA at both ends,” Prior says. “We need newborn screening for the
betterment of the child and the ability to enroll in clinical trials immediately, and we need
carrier testing to decrease the incidence of the disease.” (Carrier testing is available
through several clinical laboratories, including the one at Ohio State.)
In an article in the November 2008 issue of Genetics in Medicine, Prior recommends that
SMA carrier testing be offered to all couples; that formal genetic counseling services be
made available to anyone requesting this testing; that all identified carriers be referred for
follow-up genetic counseling; and that parents be informed that negative carrier test
results reduce but don’t completely eliminate the possibility of having an affected child,
and that carrier testing can’t predict disease severity.[22]

Prenatal testing to identify SMA affected fetuses and preimplantation genetic diagnosis to
identify SMA affected embryos also are available at some centers.
Non-chromosome 5 SMA
In 2008, Lisa Baumbach-Reardon at the University of Miami (Fla.) and colleagues
announced the culmination of their decade-long search for the cause of a severe,
infantile-onset form of SMA that isn’t caused by SMN deficiency but arises from a
mutation in an X-chromosome gene. Baumbach-Reardon, who received three MDA
grants for this search between 1999 and 2005, led a study team with Alfons Meindl at
Technical University Munich (Germany) that identified this gene last year. The gene,
known as UBE1, carries instructions for ubiquitin-activating enzyme 1, which normally
helps attach a molecular tag to proteins to mark themfor destruction by a cell. Altered
function of this protein disposal system is the likely mechanism by which X-linked SMA
occurs. In addition to helping the small number of families affected by this rare form of
SMA, understanding how UBE1 defects cause the disease may lead to further insights
about motor neurons that will prove useful with respect to chromosome-5 SMA as
well.[22]
Biomarkers for SMA

For many diseases, there are indicators in the body that change when a person has a
disease or when the disease gets worse or better. These indicators are called “biomarkers”
and can be found by testing the blood or urine, or by using other more sophisticated types
of testing, such as nerve conduction tests commonly used to diagnose motor neuron
disorders. One area of active research within the SMA field is to identify biomarkers
which could be used to tell how SMA patients are progressing and whether they are
responding to a potential treatment. Since motor function tests can be variable and
difficult to conduct, especially in young infants, identification of biomarkers would be
useful in the efforts to find treatments for SMA. SMA biomarkers are currently being
evaluated in the NIH NeuroNEXT clinical trial, titled “SMA Biomarkers in the
Immediate Postnatal Period of Development.” In this trial, infants with SMA and healthy
controls are being followed over time, and a variety of testing is being conducted to
determine whether any reliable biomarkers can be identified for SMA.[22,23]

Targeting muscle
Motor neurons are a specialized type of nerve cell that dies in people with SMA. These
motor neurons are the wires that connect the brain and spinal cord to the muscles, and
their death leads to muscle weakness and paralysis in SMA. One approach researchers are
pursuing for SMA focuses on protecting muscles from paralysis and increasing their
strength. Although this approach does not fix the underlying genetic problem in SMA,
drugs that enhance muscle function could likely be used in combination with other
therapies that act on the SMN genes. Cytokinetics is developing drugs that increase the
ability of the muscle to contract. These drugs have shown early promise in patients with a
similar motor neuron disease called amyotrophic lateral sclerosis (ALS). Together with
Astellas, Cytokinetics is developing a similar drug called CK-2127107 for SMA. This
drug has been tested in a phase 1 clinical trial of healthy volunteers, where it proved to be
safe and able to increase muscle force. Cytokinetics is planning to test CK-2127107 in a
phase 2 clinical trial in SMA patients.[22,23]
Stasimon: A study recently found that increasing the activity of a gene

called stasimon improved motor function in SMA disease models. The findings suggest
that the stasimon gene could be a new therapeutic target.
Zinc finger protein 1 (ZPR1): Researchers found that adequate levels of a protein called
zinc finger protein 1 (ZPR1) is associated with a milder form of the disease in a research
mouse model of SMA. If the findings are corroborated, ZPR1 potentially could serve as a
target for SMA therapy development; in addition, genetic testing to determine ZPR1
protein levels could help inform physicians and families about the likely disease course in
affected individuals. Although a great deal of SMA research is aimed at increasing SMN
levels, investigators don’t yet know whether doing so after the onset of the disease will
rescue nerve cells. Therefore, some MDA-supported research is focused not on
increasing SMN, but on improving muscle strength and function through other means.
These non-SMN-based strategies hold promise for all forms of SMA, including X-linked
SMA and SMA-LED.[23]
Fasudil: A Canada-based research team has found that a drug called fasudil extended life
span, improved function and increased the size of muscle fibers in mice with an SMA-
like disorder. Fasudil did not increase levels of SMN protein, and the research team

suggests that the effects may be the result of restoration of the typical development
process of skeletal muscle.[23]
CLINICAL TRIALS: MDA is funding research that identifies, develops and tests
strategies that restore sufficient levels of the needed SMN protein. Two of the most
exciting projects are potential therapies now being evaluated in human trials. The U.S.
Food and Drug Administration (FDA) has granted both therapies fast track and orphan
drug designations. A fast track designation allows for faster review of drugs that treat
serious diseases and fill an unmet need, while orphan drug status provides economic
incentives to companies developing treatments for rare diseases.[24]
RG3039: RG3039 is a small-molecule compound designed to increase production of

functional SMN protein using the instructions carried in SMN2. The drug, which
currently is being evaluated in a phase 1b clinical trial, is in development through
a collaboration between biotechnology firm Repligen and the global pharmaceutical
company Pfizer. Launched in late 2012, the safety trial is testing multiple doses of
RG3039 in 24 healthy adult volunteers. Previous encouraging results for RG3039 were
reported in April 2012, with findings showing that the drug was safe and well-tolerated in
an earlier MDA-supported phase 1 clinical trial, also conducted in healthy volunteers.
Data from the trial suggests that the drug reached and worked on its biological target, an
enzyme called DcpS. A $1.4 million grant from MDA is helping to support the phase 1b
trial of RG3039; the grant also supported the earlier phase 1 trial and laboratory research
required for advancing the compound to human testing. MDA's support builds on funding
for this therapy by Families of SMA.[24,25]
ISIS-SMNRx: This experimental antisense drug is being developed by biotechnology

company Isis Pharmaceuticals. Antisense-based therapies block specific sections of
genetic instructions, changing the way a cell constructs a protein; in SMA, the goal of
antisense therapy is to change the way instructions from the SMN2 gene are interpreted
so that full-length, functional SMN protein can be made. MDA-supported lab research
contributed to development of ISIS-SMNRx.
A trial to test the safety and tolerability of multiple doses of the drug in children with
SMA is ongoing, and a phase 2 clinical trial to test multiple doses of the drug in infants

with SMA has opened in the United States and Canada. These ongoing trials
follow encouraging results from an earlier phase 1 trial, reported in March 2013, showing
that ISIS-SMNRx was safe and well-tolerated in children between the ages of 2 and 14
years with SMA. Although the trial was not designed to test efficacy, indications of
improved muscle function were observed in trial participants who received the highest
dose level of the drug.[24]
STRATEGIES:
Basic Research
Basic research is the first step in developing a treatment and cure for SMA. Basic
research projects investigate the biology and cause of SMA in order to identify the most
effective strategies for drug discovery. Cure SMA has been investing in basic research for
three decades. Since 2004 nearly 100 basic research grants for more than $11 million.
Drug Discovery
Drug discovery converts what we have learned about the causes and biology of SMA
through basic research into new drug candidates that can be tested in clinical trials.
It can be a long and difficult process. Failures happen often, so it’s difficult to predict
which drugs will be successful. An estimated 80% to 90% of experimental drugs starting
human clinical trials never gain FDA approval.[24,25]
Achievements in Drug Discovery
• In December 2016, the FDA announced that it had approved Spinraza, a treatment
developed by Biogen and Ionis, making it the first-ever approved therapy for SMA. Cure
SMA provided the very first research funding for this program beginning in 2003.
• The approval of Spinraza is just the leading edge of a robust drug pipeline, with a breadth
and depth that reflects the goal of treatments for all ages and types. Fifteen years ago,
there was just two potential drugs in the beginning stages of preclinical discovery. Today
the first-ever approved treatment, plus another 17 programs in development, including
five in clinical trials.

• Important biotech and pharmaceutical partners are committed to SMA research. Today,
14 companies are engaged in SMA research, including some of the biggest
pharmaceutical companies in the world.[24,25]
Drug Discovery Funding
Cure SMA has funded over $20 million in drug discovery grants, converting basic
research seed ideas into candidates that can be tested in the next stage of research.
Clinical Trial Phases
A drug must pass each individual phase of a clinical trial before advancing. The number
of participants in each phase can vary. The numbers given below are typical of trials for
an orphan disease such as SMA.
• Phase 1 tests safety and dosage levels, usually on 10-20 individuals. Sometimes, these
volunteers are healthy individuals. However, for an orphan disease like SMA, some or all
may be patients with the condition being studied.
• Phase 2 tests a slightly larger group, usually 20-40 individuals, all of whom have the
condition being studied.
• Phase 3 increases the number of people tested—up to 100-200 including the control or
placebo group. A drug that passes these three phases can be approved and marketed to the
general public.
• Phase 4 primarily involves ongoing evaluation and monitoring, even after a drug is
approved for the general public.
The First Steps
Researchers test new therapies in the laboratory and in animal studies, and those with the
most promising results are moved into clinical trials.
Funding for clinical trials can come from physicians, medical institutions, foundations,
voluntary groups, pharmaceutical companies, or federal agencies such as the National
Institutes of Health (NIH), the Department of Defense (DOD), and the Department of
Veteran's Affairs (VA).[25]

Regulating Clinical Trials
The clinical trial process is regulated in a number of ways, both before it begins and
while it’s in progress.
• FDA Approval: The Food and Drug Administration (FDA) must approve the drugs used
in clinical trials, so that they can be distributed across state lines (clinical trials are
usually conducted in multiple cities and states to ensure the most comprehensive and
most accurate results). To get FDA approval, clinical trial sponsors submit an
Investigational New Drug (IND) application to the FDA. Once approved, the IND allows
them to distribute the drug for the duration of the trial.[25]
• IRB Review: Clinical trials must also be approved by an institutional review board
(IRB). This independent committee ensures that the trial is conducted ethically, that the
potential benefits justify any risks, and that the rights of participants are protected. The
IRB continues to review the trial as it progresses.[25]
• Informed Consent: Trial participants must receive all key facts about a trial before it
starts and sign an informed consent document. Informed consent is not a contract, and the
participant can still withdraw from the trial.[25]
Clinical Trial Protocols
A protocol is a study plan for a clinical trial. It covers important details like:
• Who can participate These rules, called "inclusion and exclusion criteria," typically
include age, stage or type of disease, previous treatment history, and other medical
conditions.
• What procedures, medications, and dosages will be given, and how often.
• When the participants must see a study doctor, and what tests or measurements the
doctor will use to evaluate them.
• How the control group (if any) will be set up. Participants assigned to a control group
will receive a placebo—an inactive pill, liquid, or powder—or a standard treatment. The
other group is given the experimental treatment. Participants are often not told which

group they are in, and the researchers may not know either. This "double-blind" format
keeps participant or researcher bias from affecting the results.
Clinical Care
The fourth prong in Cure SMA’s research strategy is clinical care research. The clinical
care research is to understand the issues that affect daily life for people with SMA, from
breathing to nutrition, and to improve their quality of life today.[25]
Clinical Care Standards
In 2007, the Journal of Child Neurology published the “Consensus Statement for
Standard of Care in Spinal Muscular Atrophy” and the “Family Guide to Consensus
Statement for Standard of Care in Spinal Muscular Atrophy.” These documents
established general guidelines for the management of SMA.
Cure SMA’s clinical care research builds on these consensus statements, with evidence-
based projects that demonstrate positive results for those currently living with SMA.
Clinical Care Improvements
The outcomes of Cure SMA-funded clinical care projects may include:
• Pilot studies which then serve as the basis for larger, multi-center studies in SMA.
• New family-focused care publications, including Cure SMA care series booklets.
• Peer-reviewed journal publications to influence insurance coverage.
Clinical Care Funding
Periodically, Cure SMA issues a request for clinical care proposals. All applications are
reviewed by our Medical Advisory Council, using an NIH-like scoring system based on
both scientific quality and relevance to the Cure SMA mission of improving care for all
those affected by SMA.
In 2016, an RFP will not be issued while we focus on other clinical care projects,
including the development of a network of clinical care centers that will collaboratively

collect patient care data to answer questions and develop strategies for optimal clinical
management of SMA.[25]
Key Measurements
The pipeline measures the progress of the research in two key ways. First, by tracking
each individual program all the way to FDA approval.Second, by tracking how these
programs are spread among the different therapeutic approaches.
Progress of Individual Drug Programs
Cure SMA's research model funds drug programs at all stages of development. The basic
research program studies the biology and causes of SMA, often revealing new and more
effective ways of making drugs. These basic research ideas are then converted into
practical drug candidates through drug discovery. Finally, those drug candidates move
through the clinical trial process. The drug pipeline monitors each individual program as
it moves through these stages.[25]
First-Ever Approved Therapy for SMA
On December 23, 2016, the FDA announced that it had approved Spinraza, a treatment
developed by Biogen and Ionis, making it the first-ever approved therapy for SMA. Cure
SMA provided the very first research funding for this program beginning in 2003. The
drug pipeline also tracks the implementation of this and other therapies as they are
approve.
Balance of Therapeutic Approaches
In order to find a treatment and cure for SMA, we know it's crucial to attack SMA from
all sides. As with all scientific research, it's difficult to predict which SMA drug
programs might be successful.
By investing in a diversity of approaches, maximize the chances for success. If one drug
candidate or one approach fails, the others has to take its place.[25,26]

The Cure SMA drug pipeline identifies four possible treatment targets:
• Replacement or correction of the faulty SMN1 gene.
• Modulation of the low functioning SMN2 “back-up gene.”
• Neuroprotection of the motor neurons affected by loss of SMN protein.
• Muscle protection to prevent or restore the loss of muscle function in SMA. [26,27]
RESULTS:
During the study period 67 children had a discharge diagnosis of SMA. Werdnig
Hoffman disease (SMA type I) was the commonest variant seen in 37 (56%) children.
Overall 68% were infants. High parental consanguinity was observed in 68% of the study
cohort. The history of delayed development and undiagnosed early death was observed in
the families of 19 children. Genetic testing was performed in 22 (33%) children. Survival
motor neuron (SMN) 1 gene deletion was found in 19 (86%) of the 22 patients in whom
the gene analysis was done and 13 (68%) were also positive for neuronal apoptosis
inhibitory proteins (NAIP) deletion.[27]
CONCLUSION:
SMA is a difficult to diagnose disorder, because it is little known, and treatment is

uncertain. Pharmacological treatments and supportive therapies are not yet able to
recover motor neurons or muscle cells that have already been lost, but are aimed at
delaying disease progression and improving patients’ residual muscle function.[28]

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21;371(9630):2120-33. doi: 10.1016/S0140-6736(08)60921-6. Review.
2. Prior TW, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [updated 2016 Dec
22]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH,
Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors.
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3. Prior TW, Swoboda KJ, Scott HD, Hejmanowski AQ. Homozygous SMN1
deletions in unaffected family members and modification of the phenotype by
SMN2. Am J Med Genet A. 2004 Oct 15;130A(3):307-10
4. Wirth B, Brichta L, Schrank B, Lochmüller H, Blick S, Baasner A, Heller R.
Mildly affected patients with spinal muscular atrophy are partially protected by an
increased SMN2 copy number. Hum Genet. 2006 May;119(4):422-8. Epub 2006
Mar 1.
5. Ottesen, Eric W. (2017-01-01). "ISS-N1 makes the first FDA-approved drug for
spinal muscular atrophy". Translational Neuroscience. 8 (1): 1–
6. doi:10.1515/tnsci-2017-0001. ISSN 2081-6936. PMC 5382937 
. PMID 28400976.
6. Main, M.; Kairon, H.; Mercuri, E.; Muntoni, F. (2003). "The Hammersmith
Functional Motor Scale for Children with Spinal Muscular Atrophy: A Scale to
Test Ability and Monitor Progress in Children with Limited
Ambulation". European Journal of Paediatric Neurology. 7(4): 155–
159. doi:10.1016/S1090-3798(03)00060-6. PMID 12865054.
7. Krosschell, K. J.; Maczulski, J. A.; Crawford, T. O.; Scott, C.; Swoboda, K. J.
(2006). "A modified Hammersmith functional motor scale for use in multi-center
research on spinal muscular atrophy". Neuromuscular Disorders. 16 (7): 417–426.

8. Dubowitz, V. (2009). "Ramblings in the history of spinal muscular

atrophy". Neuromuscular Disorders. 19 (1): 69–
73. doi:10.1016/j.nmd.2008.10.004. PMID 18951794.
9. Wang, Ching (Summer 2007). "Consensus Statement for Standard of Care in
Spinal Muscular Atrophy". Journal of Child Neurology. 22 – via PubMed.
10. Carrier Screening in the Age of Genomic Medicine - ACOG". www.acog.org.
Retrieved 24 February 2017.
11. Little, S. E.; Janakiraman, V.; Kaimal, A.; Musci, T.; Ecker, J.; Caughey, A. B.
(2010). "The cost-effectiveness of prenatal screening for spinal muscular
atrophy". American Journal of Obstetrics and Gynecology. 202 (3):
253.2e1. doi:10.1016/j.ajog.2010.01.032. PMID 20207244.
12. Prior, T. W.; Professional Practice Guidelines Committee (2008). "Carrier
screening for spinal muscular atrophy". Genetics in Medicine. 10 (11): 840–
842. doi:10.1097/GIM.0b013e318188d069. PMC 3110347  . PMID 18941424.
13. Bodamer, olaf (November 2017). "Spinal Muscular Atrophy". uptodate.com.
Retrieved December 1, 2017.
14. Bach, J. R.; Niranjan, V.; Weaver, B. (2000). "Spinal Muscular Atrophy Type 1: A
Noninvasive Respiratory Management Approach". Chest. 117 (4): 1100–
1105. doi:10.1378/chest.117.4.1100. PMID 10767247.
15. Chen, Y. S.; Shih, H. H.; Chen, T. H.; Kuo, C. H.; Jong, Y. J. (2011). "Prevalence
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19. Rudnik-Schoneborn, S.; Heller, R.; Berg, C.; Betzler, C.; Grimm, T.; Eggermann,
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21. . Feldkötter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses
of SMN1 and SMN2 based on real-time lightCycler PCR: fast and reliable carrier
testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet.
2002;70:358-68.
22. Chang JG, Hsieh-Li HM, Jong YJ, Wang NM, Tsai CH, Li H. Treatment of spinal
muscular atrophy by sodium butyrate. ProcNatlAcadSci U S A. 2001;98:9808-13.
23. Campbell L, Potter A, Ignatius J, Dubowitz V, Davies K. Genomic variation and
gene conversion in spinal muscular atrophy: implications for disease process and
clinical phenotype. Am J Hum Genet. 1997;61:40-50.
24. Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, Blumcke I, et al.
Valproic acid increases the SMN2 protein level: a well-known drug as a potential
therapy for spinal muscular atrophy. Hum Mol Genet. 2003;12:2481-9.
25. Burnett, B. G.; Munoz, E.; Tandon, A.; Kwon, D. Y.; Sumner, C. J.; Fischbeck, K.
H. (2008). "Regulation of SMN Protein Stability". Molecular and Cellular
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. PMID 19103745.
26. Mattis, V. B.; Rai, R.; Wang, J.; Chang, C. W. T.; Coady, T.; Lorson, C. L.
(2006). "Novel aminoglycosides increase SMN levels in spinal muscular atrophy
fibroblasts". Human Genetics. 120 (4): 589-601.
27. Tsai LK, Tsai MS, Ting CH, Li H. Multiple therapeutic effects of valproic acid in
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Jayoti Vidyapeeth Women’s University, Jaipur, Rajasthan,

in partial fulfillment of the requirement for

Enrollment No. : JV-I/14/7438

FACULTY OF PHARMACEUTICAL SCIENCE

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 1

Dedicated to My Beloved Parents

When we were young,

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 2

I hereby declare that project entitled “SPINAL MUSCULAR ATROPHY” is based on

Supervised by: Submitted by:

Mr. Praveen Kumar (Assistant Professor), JV’N KHUSHBU

Faculty of Pharmaceutical Science, JV-I/14/7438

Jayoti Vidyapeeth Women’s University,

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 3

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 4

S.NO. CHAPTERS Page No.

5 GENETIC CHANGES 12-14

10 RESEARCH DIRECTION 19-23

11 OTHER RESEARCHES 23-35

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 5

SPINAL MUSCULAR ATROPHY

Spinal muscular atrophy

Synonyms Autosomal recessive proximal spinal muscular atrophy,

Location of neurons affected by spinal muscular atrophy in the spinal

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 6

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 7

The most commonly used classification is as follows:

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 8

SMA type 3 (Juvenile)

Eponym :-Kugelberg-Welander disease

Usual age of onset :- >12months

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 9

Characteristics :- SMA type III, or Kugelberg-Welander disease, appears between 2 and

SMA type 4 (Adult-onset)

Usual age of onset:- Adulthood

Characteristics :- The adult-onset form (sometimes classified as a late-onset SMA type 3)

Spinal muscular atrophy has an autosomal recessive pattern of inheritance.Chromosome

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 10

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 11

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 12

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 13

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 14

Assistive technology such as ventilators, power wheelchairs, and modified access to

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 16

Nusinersen is the only approved medication to treat spinal muscular atrophy. It is

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 19

SMN1 gene replacement

• AVXS-101 – a proprietary biologic under development by Avexis which uses self-

• Branaplam (LMI070, NVS-SM1) is a proprietary small-molecule experimental drug

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 20

SMA1 was a proprietary small-molecule splicing modulator of the tetracyclines group

• Oral salbutamol (albuterol), a popular asthma medicine, showed therapeutic potential

• Butyrates (sodium butyrate and sodium phenylbutyrate) held some promise in in

hydroxamic acids (CBHA, SBHA, entinostat, panobinostat, trichostatin A, vorinostat ) ,

• Olesoxime is a proprietary neuroprotective compound developed by the French

• CK-2127107 (CK-107) is a skeletal troponin activator developed by Cytokinetics in

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 22

lowered neural signalling. As of October 2016, the molecule is in a phase II clinical

Other SMA Researches

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 23

JAYOTI VIDYAPEETH WOMEN’S UNIVERSITY, JAIPUR Page 24

Augmenting SMN by modifying SMN2 gene instructions