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In vivo gene therapy for Mucopolysaccharidosis type III (Sanfilippo syndrome): A new treatment horizon.

For most lysosomal storage diseases (LSDs) there is no cure. Gene therapy is an attractive tool for the treatment of LSDs caused by deficiencies in secretable lysosomal enzymes in which neither full restoration of normal enzymatic activity nor transduction of all cells of the affected organ are necessary. However, some LSD, such as Mucopolysaccharidosis type III (MPSIII) diseases or Sanfilippo syndrome, represent a difficult challenge because patients suffer severe neurodegeneration with mild somatic alterations. The disease's main target is the central nervous system (CNS) and enzymes do not efficiently cross the blood-brain barrier (BBB) even if present at very high concentration in circulation. No specific treatment has been approved for MPSIII. Here we discuss the adeno-associated viral (AAV) vector-mediated gene transfer strategies currently being developed for MPSIII disease. These strategies rely on the local delivery of AAV vectors to the CNS, either through direct intraparenchymal injection at several sites or through delivery to the Cerebrospinal Fluid (CSF), which bathes the whole CNS, or exploit the properties of certain AAV serotypes capable of crossing the BBB upon systemic administration. Although studies in small and large animal models of MPSIII diseases have provided evidence supporting the efficacy and safety of all of these strategies, there are considerable differences between the different routes of administration in terms of procedure-associated risks, vector dose requirements, sensitivity to the effect of circulating neutralizing antibodies that block AAV transduction, and potential toxicity. Ongoing clinical studies should shed light on which gene transfer strategy leads to highest clinical benefits while minimizing risks. The development of all these strategies opens a new horizon for the treatment of not only MPSIII and other LSD, but also of a wide range of neurological diseases.