Gene Therapy for Metabolic NeuroDevelopmental Disorders

Several diseases affecting the nervous system are caused by mutation in a gene whose product functions in the conversion of molecules within a metabolic pathway.  When a non-functional copy of the gene is inherited from each parent, the gene product is absent in the offspring.  In the absence of the gene product, precursor molecules are not processed rapidly enough, accumulate, and cause neuronal dysfunction and neuronal death. A treatment strategy for these disorders is to replace the missing enzyme. 

Tay-Sachs Disease and Sandoff Disease are “GM2 Gangliosidoses,” meaning the disease is caused by the accumulation of gangliosides in the brain.  These diseases manifest in childhood and they severely impact neuronal function and lifespan. The causative mutations are in the HexA and HexB genes. When either gene carries an inactivating mutation, the active enzyme cannot be formed because the active enzyme consists of a dimer, a 1:1 ratio of the two gene products.   Drs. Miguel Sena-Esteves, Heather Gray-Edwards and colleagues have been investigating a gene replacement therapy for Sandhoff and Tay-Sachs Diseases.  This approach has been successful in cat and sheep models of the diseases, and is being developed for clinical trials.

Canavan Disease is a rare, fatal disorder that also results from accumulation of a toxic metabolite in the brain.  In this case, mutations in the ASPA gene lead to deficiency in the enzyme aspartoacylase (ASPA), allowing accumulation of N-acetylaspartic acid (NAA) in the brain. This leads to damage to myelin sheaths, the insulative wrapper that protect axons and speed conduction of electrical impulses through them. Dr. Guangping Gao and colleagues have developed a gene therapy approach to treat Canavan Disease that is currently being tested in affected children.