Chapter 23 - Clinical Trials of Gene Therapy for Canavan Disease

Abstract

This chapter discusses the canavan disease (CD) treatment options using gene therapy, especially focusing on the latest results in the context of aspartoacylase (ASPA) gene transfer in human, mouse, and rat. CD is an autosomal-recessive early-onset leukodystrophy, caused by loss of function mutations in the gene for ASPA. ASPA deficiency results in severe psychomotor retardation, seizures and premature death. Under normal conditions, ASPA hydrolyzes N-acetyl aspartate (NAA) into aspartate and acetate, the latter representing the building block for lipid synthesis required for myelination. The NAA metabolism is highly segmented in that NAA production occurs in neurons, while its degradation is restricted to myelinating glia. The etiology of CD is thought to relate to cytotoxic and osmotic effects of excess NAA, but also to potential hypomyelination due to an undersupply with acetate. CD is a monogenic disease with a pathology confined to the brain, and no treatment exists. Therefore, CD has been a candidate for gene replacement utilizing ASPA gene transfer to the CNS and human experimentation started even before animal models of CD became available, and an ongoing phase 1 trial is the most advanced gene therapy for a non-malignant CNS disorder. ASPA deficiency in the mouse or the rat causes a CD-like pathology and these models have been used for gene therapy approaches, and to study disease mechanisms.