14800-DvRappard

40 Chapter 2 to healthy donors. Moreover, disease manifestation was halted for the follow up times, ranging from 18-24 months. This was based on findings on MRI and evaluation of cognitive and motor skills. No evidence for activation of a nearby oncogene by an insertion was found. An advantage of this autologous gene-transduced HSCT is that supra –normal levels of the enzyme can be reached. In the future, better predictable gene-transduction efficacy and better predictable engraftment of transduced cells may further optimize treatment. At the moment a clinical trial of intracerebral gene therapy is performed in Paris by Aubourg et al. AAVhr.10 is used to transfer the ARSA cDNA coding for the ASA enzyme. Patients with an early onset MLD type are eligible, aged between 6 months and 4 years. The interval between the first symptoms and inclusion must be 12 months or less. Advantages of these approaches, when compared to allogeneic HSCT, are less transplant related morbidity and no risk of GVHD, 40 limitations the uncertainty about the risk of mutagenesis of cancer. 2 When vectors are integrated genome wide, they risk being integrated in the vicinity of proto-oncogenes, triggering their expression and thereby neoplasia. Another point of caution is the possible effect that the overexpression of the ASA enzyme may have on the other sulfatases and the closely regulated sulfatide levels. 37 Table 1 provides a summary of the results of clinical studies regarding HSCT and HSC gene therapy. Other forms of therapy Small molecule based therapies Small molecules can cross the blood brain barrier. 2 Specific small molecules are able to rescue misfolded proteins. This could possibly enhance the level of the available mutant ASA, thereby increasing residual ASA enzymatic activity. 2 Pharmacological chaperones (PCs) are small molecules that can enhance the level of the misfolded-prone mutant enzymes. Proteostasis regulators (PRs) are small molecules that improve the protein folding capacity of cells. When these two classes of small molecules are used together, the misfolded enzyme can be guided to a folded state, maintaining its structural ability. 2 Through high throughput screening (HTS) assays the small molecules that function as PCs or PRs can be identified. Small molecules for mutant ASAs have been identified by HTS assays using patient derived cells. This might allow the identification of potential drugs for MLD. 41 Another way in which small molecules can be used is by manipulating downstream pathways that are initiated or disturbed by the enzyme defect; the so called pathogenic cascades. 2