14800-DvRappard

169 Discussion, summary and future perspectives 10 Melatonine is recommend as first step, other options are alimemazine and gabapentine. Gabapentine is a calcium channel modulator and is typically used to treat chronic pain or epilepsy. 15 Apart from its regular indication, we used gabapentine in three patients suffering from irritability accompanied by increasedmuscle tone not sufficiently treated by ITB, with positive effect. FUTURE PERSPECTIVES Novel treatments It is likely that in the future, therapy for MLD will be multimodal, including HCT-GT and enzyme replacement therapy. We learned from patients in whom HCT was successful that there are still obstacles to overcome such as the previously mentioned cognitive decline and the continuing peripheral neuropathy. Hematopoietic Stem Cell- Gene Therapy (HSC-GT) In HSC-GT, HSCs culture and manipulation are essential steps to achieve gene transfer. Vectors integrate into the host genome, thereby expressing the corrective gene in their progeny. 17 Preliminary results of a lentiviral mediated HSC-GT clinical trial of 9 patients with presymptomatic late-infantile and early symptomatic early juvenile patients report safety of the procedure. 18 At a median follow-up of 3 years after treatment, all patients were alive with halted disease progression or prevention of disease onset. One patient, who did have disease progression between enrollment and treatment initiation, did not benefit from the treatment. Remarkably, peripheral neuropathy (already present at diagnosis) improved in one third of patients 2 years after HSC-GT. This suggests that the above normal enzyme expression reached by HSC-GT has an advantage in correcting MLD. 18 Remyelination, by local Schwann cell precursors, is thought to take place after removal of sulfatides from nerve tissue. 18 Intrathecal GT with viral vectors encoding ARSA has the advantage of more rapid and significant expression of ARSA in the brain over lentiviral mediated HSC-GT. Disadvantages are the invasiveness of the procedure and the risk of an immune reaction against the transgene. 17 Intrathecal GT is thought to target mostly neurons, but the lysosomal enzyme could be secreted by transduced neurons and recaptured by other cells and thereby also correct the enzyme deficiency in oligodendrocytes. A phase 1/2 clinical trial to assess the safety of and efficacy of intrathecal GT with AAVrh.10hARSA into the white matter of both hemispheres (NCT01801709; clinicaltrials.gov) was stopped because of lack of efficacy (P. Aubourg, personal communication).