Multifactorial Gene Therapy as a Novel Approach for the Treatment of Mutant Superoxide Dismutase-1 Linked Familial Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis is a rapidly progressing disease characterized by the degeneration and death of upper and lower motor neurons, and it is associated with a lifetime risk of 1 in 1000. The disease not only involves damage to the motor neurons themselves but also to neighboring glial cells. Since the characterization of the disease roughly a century and a half ago, few successes have been seen in the development of a treatment plan that yields viable results and prevents neurodegeneration. The shortcomings of past therapies have been attributed to the narrow focus of treatment plans, targeting a single aspect of the disease pathology. The pathophysiology is complex and multifactorial, integrating aspects such as aberrant reactive oxygen species formation, excitotoxicty, a reduced antioxidant response, and dysfunction of the endoplasmic reticulum and mitochondria. Recent research employing a multifactorial approach to treatment has yielded success in mice engineered with the mutant SOD1 gene, a mutation which mimics the disease progression and pathophysiology seen in ALS patients. Current clinical research for ALS has focused on using gene therapy techniques to introduce therapeutic genes coding functional proteins into affected cells in the hopes of addressing several of the pathological aspects of the neurodegenerative disease.