14800-DvRappard

39 Metachromatic leukodystrophy: disease spectrum and approaches for treatment 2 this limitation. (http://www.clinicaltrial.gov/NCT01510028 ). The patients receive intracerebral injections of recombinant human arylsulfatase A every other week for 40 weeks. This trial is open for patients with the late infantile form who are still able to ambulate with help. In this selected group, the effectiveness of the treatment can be evaluated quickly due to the rapid progression of the disease. Moreover, no other treatment option is available for this group of patients . Even if the enzyme reaches the brain, this remains an intensive procedure with the risk of complications. Gene therapy In gene therapy, the goal is to genetically modify autologous hematopoietic stem cells (HSC) to express the ARSA gene. 1 Cells can also be modified to overexpress ARSA leading to a supraphysiological amount of enzyme. Animal studies This method has successfully been tested in experiments using the knock out animal model of MLD. 24 Through the use of retroviruses new genes can be integrated into the host cell genome. Various viral vectors, such as adeno-associated viral (AAV), lentiviral (LV) and retroviral (RV) vectors, have been used and have been found suitable for clinical trials of gene therapy. 24 In MLD, lentiviral vectors were successful in generating overexpression of the ARSA gene. 2 Efficient gene marking of mouse and human HSC is possible, with full maintenance of stem cell properties and transgene expression. 1 Biffi et al 37 transplanted HSCs transduced with a lentiviral vector carrying the ARSA cDNA in MLD mice. They report that enzyme activity was reconstituted in the hematopoietic system and development of central nervous system and peripheral nervous system disease manifestations was prevented and corrected. Another approach is introducing the normal gene directly in the CNS. Colle et al 38 demonstrate the safety of intracerebral injection of AAV2-5 vector encoding human ARSA, which results in expression and activity of recombinant ASA enzyme in the brain of non-human primates. Piguet et al 39 compared the intracerebral injection of AAVrh.10cu ARSA vector with AAV5-PGK- ARSA vector and found the AAVrh.10vector to both result in a more robust and diffuse expression of ASA enzyme as well as in a correction of sulfatide accumulation in brain. Clinical studies Biffiet al 40 performed a phase I/II clinical trial inwhich they treated threepresymptomatic infantile MLD patients with HSC-gene therapy. The autologous HSCs were transduced ex vivo with ARSA encoding LVs and reinfused after the patients had been treated with a myeloablative regimen. One year after HSC-GT, functional ASA was isolated from cerebrospinal fluid from all three patients; levels and activity were comparable