Gene therapy for amyotrophic lateral sclerosis

Abstract

The development of better viral vectors, in particular those based on adeno–associated viruses (AAV), have led to successful results of clinical studies for hemophilia, congenital retinal blindness, aromatic l–amino acid deficiency, and Parkinson's disease. We recently developed tyrosine–mutant AAV9/3 vectors that can cross the blood– or meningeal–brain barriers. These vectors are expected to be utilized in treating neurodegenerative diseases, in which broad areas of brain must be transduced. In patients with sporadic amyotrophic lateral sclerosis (ALS), considerable proportions of spinal cord motoneurons express abnormal unedited GluA2 (a subunit of the AMPA receptor) at the glutamine/arginine site. This is primarily due to the downregulation of adenosine deaminase acting on RNA 2 (ADAR2). The excessive Ca²⁺ permeability of the AMPA receptors leads to motoneuron death. Gene delivery of ADAR2 using tyrosine–mutant AAV9/3 vectors in conditional ADAR2 knockout mice has significantly delayed the onset of the disease, extended the life span of the mice, abated their behavioral impairments, and promoted survival of the motoneurons without inducing any adverse effects. Based on these favorable outcomes in this proof–of–principle investigation in an ALS mouse model, we are planning a phase I/II clinical study. We have already initiated large–scale production of GMP–grade AAV vectors that express ADAR2 using the baculovirus system.