Current ALD therapeutic options

It is important to understand at the outset that there is presently no complete curative therapy for X -ALD. A variety of symptomatic therapeutic treatments for affected individuals are present however. Men with AMN and symptomatic women carriers will often benefit from physiotherapy and agents that address: Spasticity Neuropathic pain Bladder disruption

Boys and men with cerebral disease will require monitoring of nutrition and when appropriate a gastrostomy tube. Their function may deteriorate quickly and there are often severe and painful muscle spasms associated with progression. This will require antispasmodic medications (such as dicyclomine and hyoscyamine ) and Analgesia. Families will often benefit from palliative care services too. Adrenal replacement Adrenal hormone therapy is mandatory and life saving for patients with adrenal insufficiency. Individuals and their families should receive proper instruction and management of adrenal replacement, requirements for medical alert bracelets, and the recognition and rapid treatment of impending crisis. Unfortunately, adrenal replacement does not alter neurologic progression. (Additional info: http://marrow.org/Patient/Disease_and_Treatment/About_Your_ Disease/Metabolic_Disorders/Cerebral_X Linked_ALD.aspx#HormoneReplacementTherapy ) Hematopoietic stem cell transplant This therapy can be useful for patients with MRI and clinical evidence of mild cerebral involvement, though its use is limited by several factors. It is recommended only for boys or adolescents who have evidence of active inflammatory cerebral demyelination that is still in i ts early stages. Because of its multiple risks the procedure is not recommended for young patients who have no evidence of cerebral involvement. The basis of the procedure is described in figure one on the following page.

Current ALD therapeutic options

Figure one: The basis of HSC Tr ansplant. (Additional info: http://www.x-ald.nl/treatment-options/hsct/) Dietary restriction and inhibition of endogenous synthesis of VLCFAs The demonstration that the abnormal accumulation of VLCFAs is the principle biochemical abnormality in X -ALD led to the introduction of dietary therapy aimed to reduce VLCFA levels. The first attempts involved the stringent reduction of VLCFA intake via diet, however, plasma C26:0 levels remained unalter ed and there was no effect on clinical progression. This led to scientists and clinicians to believe that VLCFAs were not only taken in via diet, but also produced via enzymatic reactions i n the body, termed biosynthesis (See figure two).

Current ALD therapeutic options

Figure two: Normal individual and a patient with ALD supplemented with Lorenzos Oil. Note that both diet and biosynthesis are reduced, as displayed by the red crosses. Lorenzos Oil Therapy Upon the numerous trials, including one by Rizzo et al. (1984), diminishing the synthesis of saturated VLCFAs by overloading the body with unsaturated VLCFAs such as oleic acid (C18:1) , it was then determined that erucic acid (C22:1) offered additional efficacy. This led to the development of a 4:1 mixture of glyceryl trioleat e and glyceryl trierucate, subsequently named Lorenzos Oil; after a boys parents who worked with scientists to develop the oil. The administration of this mixture was reported to normalize plasma C26:0 levels within four weeks. This led to a series of clinical trails, which had various outcomes. On the basis of the data achieved from the numerous trials, still occurring today, it is hypothesized that lowering plasma C26:0 levels lowers the risk of childhood cerebral X -ALD, but the prevention is not absol ute. The mechanism of the preventative effect is incompletely understood owing to our inability to measure C26:0 levels in vivo (in the body, rather than in vitro; in test tube) (Moser, et al., 2007). (Additional info: http://rarediseases.about.com/cs/ald/a/041301.htm )

Current ALD therapeutic options

Other potential therapy options for Adrenoleukodystrophy A variety of other potential therapies for X -ALD have been suggested. 4-Phenylbutyrate, a prodrug, activated only once metabolized in the liver into phenylacetate, which actively inhibits an enzyme (mevalonate pyrophosphate decarboxylase), has been of interest because of the studies by Kemp et al. (1998). They showed that 4Phenylbutyrate increases the capacity of cultured skin fibroblasts of X-ALD patients to metabolize VLCFAs via other enzymes inhibited in the presence of mevalonate pyrophosphate decarboxylase, resulting in the normalization of VLCFA levels within these cultures. However, the mechanism of action is not yet clear. Research continues. Lovastatin, a type of Statin often used to treat dyslipidaemia, has been administered because of its favourable effect on VLCFA metabolism in X-ALD fibroblasts combined with its antiinflammatory action (Kwak et al., 2000). A study by Pai et al. (2000) reported that lovastatin is able to lower VLCFA levels in patients, however Cartier et al. (2000) did not denote such findings within X-ALD mouse models. Enzyme replacement therapy (ERT). R. Brady speculated in 1966 that if an enzyme were insufficiently active, one might attempt to purify it and inject it into patients to see if it would provide therapeutic benefit (Brady, 1966, 1967). The first investigation along this line was the intravenous injection of hexosaminidase A into an infant with Tay-Sachs disease, such patients accumulate the gnaglioside, GM2, in the brain and globoside in peripheral tissues and the blood. (Johnson et al., 1973). A significant reduction of globoside occurred in the circulation shortly after infusing the enzyme. However, none of the enzyme reached the brain, failing to pass the blood-brain barrier. The patient also experienced Pyrexia (high temperature) following infusion, and there was no change to the patients clinical condition. To date, ERT has provided no reported clear benefits in patients who have Leukodystrophy. However, given its promise, ERT is currently under investigation in metachromatic and globoid cell Leukodystrophies. Future development It is crucial to mention that advancement in therapeutics will depend upon international multicentre collaborations, an idea that was strongly promulgated by Hugo Moser. This requires the establishment of a complex infrastructure, which includ es electronic databases for clinical, genetic, laboratory, and neuroimaging data. Moser and collaborators showed that structures could be established with modern, next -generation Internet

Current ALD therapeutic options

technology and enhance information between institutions. It is expected that with the advancement of computer technology these types of multicentre databases will become feasible and allow the conduct of multiple therapeutic trials. REFERENCES: Brady (1966) The sphingolipidoses. N Engl J Med. 275:312-318. Brady (1967) Enzymatic abnormalities in diseases of sphingolipid metabolism. Clin Chem. 13:565-577. Cartier, et al. (2000) Simvastatin does not normalize very long chain fatty acids in Adrenoleukodystrophy mice. FEBS Letter. 478(3):205-208. Johnson, et al. (1973) Intravenous injection of purified hexosaminidase A into a patient with Tay -Sachs disease. Birth Defects Orig Artic Ser. 9:120-124. Kemp, et al. (1998) Gene redundancy and pharmacological gene therapy: implications for X-linked Adrenoleukodystrophy . Nat. Med. 4(11): 1261-1268. Kwak, et al. (2000) Statins as a newly recognised immunomodulator. Nat. Med. 6(12):1399-1402. type of

Moser, et al. (2007) Lorenzos oil therapy for X -linked Adrenoleukodystrophy: rationale and current assessment of efficacy. J Mol Neurosci. 33:105-113. Pai, et al. (2000) Lovastatin therapy for X -linked Adrenoleukodystrophy: clinical and biochemical observations on 12 patients. Mol. Genet. Metab. 69(4): 312-322. Raymond, et al. (eds) (2011) Leukodystrophies. International Review of Child Neurology Series. Mac Keith Press: London, UK. Rizzo, et al. (1984) Adrenoleukodystrophy very long-chain fattyacid metabolism in fibroblasts. Neurology. 34(2): 163-169. ADDITIONAL WEBSITES: Stop ALD foundation: http://www.stopald.org/ald/TreatingALD .asp NINDS ALD info page: http://www.ninds.nih.gov/disorders/adrenoleukodystrophy/adreno leukodystrophy.htm#Is_there_any_treatment

Current ALD therapeutic options

Science Daily: http://www.sciencedaily.com/releases/2007/02/070220182857.htm Mayo Clinic: http://www.mayoclinic.org/adrenoleukodystrophy/