Development of gene

therapy for Cockayne

syndrome – type B
Dr Nejc Jelen, PhD
Viljem Julijan Association for Children with Rare Diseases
 Cockayne syndrome type B (CSB)
A very rare and devastating genetic disorder. It is a progressive
disease characterized by the early and severe progression of
symptoms that display multiorgan dysfunction. CSB causes
premature aging (progeria), neurological abnormalities (with
progressive mental and sensorial retardation), growth failure,
and photosensitivity. Individuals with CSB may also experience
hearing loss, vision problems, dental abnormalities, and
skeletal abnormalities.
Average lifespan of children with CSB is 12 years.
Development of gene therapy for CSB -> research groups:
• Dr. Clévio Nóbrega, head of the Molecular
Neuroscience and Gene Therapy Group at the Algarve
Biomedical Center Research Institute at the University of
Algarve in Portugal
• Dr. Christina Pacak, head of the Pacak Laboratory
research group at the University of Minnesota, Medical
School, USA and
Prof. Peter B. Kang, MD, physician, professor at the
University of Minnesota Medical School
 Cockayne syndrome type B

Mutations in ERCC6 gene -> codes for CSB protein

 Cockayne syndrome type B

ERCC6 gene -> chromosome 10 (q11)

 Gene therapy for CSB

• Viral vectors, RNAi (antisense

oligonucleotides), CRISPR (gene
editing)…

• in vivo or ex vivo
 Gene therapy for CSB
»Classical« gene therapy (in
vivo)

AAV vectors remains within the

cell as separate, free-floating
elements.

Vector -> Adeno Associated

Virus (AAV)
+
„healthy/normal“ ERCC6 gene
 Gene therapy for CSB
I. step
Construction of
functional AAV-ERCC6
vector
+ identification of the
most optimal construct

Selection/testing
for the most
optimal AAV
serotype
 Gene therapy for CSB
II. step
Testing efficiency of ERCC6-AAV vector in
laboratory models of CSB
 Gene therapy for CSB
II. step
Testing efficiency of ERCC6-AAV vector in
laboratory models of CSB

a) CSB iPSC cell line

derived from CSB patient
 Gene therapy for CSB
II. step
Testing efficiency of ERCC6-AAV vector in
laboratory models of CSB

b) CSB brain organoids

derived from CSB patient
 Gene therapy for CSB
II. step
Testing efficiency of ERCC6-AAV vector in
laboratory models of CSB

c) CSB mouse model

double knockout -> Csb(-/-) or Csb(-/-)/Xpc(-/-)
(Csb(-/-)/Xpc(-/-) mice have a lifespan of 3 weeks)
-> survival of the animals (extension of the lifespan)
-> expression in different organs and tissues
 Gene therapy for CSB
II. step
Testing efficiency of ERCC6-AAV vector in
laboratory models of CSB

d) CSB swine model

double knockout -> Csb(-/-)
-> survival of the animals (extension of the lifespan)
-> expression in different organs and tissues
 Gene therapy for CSB
III. step
Testing efficiency in human patients – clinical trials