Laying the Foundation for Neuromuscular Disease Gene Therapy

Abstract

NEUROMUSCULAR DISEASES ARE inherited disorders that primarily affect the nervous system and muscle. Most neuromuscular diseases have no effective therapy. Advances in adeno-associated virus (AAV)-mediated gene therapy are now bringing hopes to alleviating these diseases at the genetic root. 1,2 An outstanding example is the approval of Zolgensma, an AAV drug that changes the disease course of type I spinal muscular atrophy (SMA) patients by one-time intravenous administration, on May 24, 2019 by the U.S. Food and Drug Administration. 3 Despite the promise, there are still enormous challenges ahead due to the inherent complexity of individual neuromuscular disease, the scarcity of animal models, the difficulty in crossing the blood-brain barrier, the necessity for bodywide therapy, the immune toxicity associated with high-dose systemic delivery, and the small packaging capacity of the AAV vector. Preclinical animal studies are essential to establish the proof-of-principle and refine the gene therapy protocol before conducting human trials. In this issue of Human Gene Therapy, a collection of articles is presented to highlight some of the effort in addressing various barriers in neuromuscular disease gene therapy. 4-6 Friedreich's ataxia (FRDA) affects 1 in 20,000 to 50,000 people. It is caused by frataxin deficiency due to pathological expansion of guanine-adenine-adenine (GAA) trinucleotides in the intron 1 of the frataxin gene. Late-onset heart failure is a prominent cause of mortality. Yet, there is no good model that can reproduce the subclinical nature of the heart disease in human patients. The Ronald Crystal laboratory developed a cardiac-specific FRDA model that exhibited stress-induced cardiac manifestations reminiscent of the patient phenotype. 4 The authors then tested an AAVrh10 frataxin vector in the new model. Intravenous injection of 1 • 10 10 viral genome particles of the vector effectively attenuated the heart disease. 4 The new FRDA