Translational Medicine: Evolution, Fulfillment, and Belief in Gene Therapy

MY LIFETIME GOAL IN TRANSLATIONAL medicine began five decades ago, directed toward making a difference for patients with devastating neurological diseases. The terminology ‘‘translational medicine’’ as we use it today was not part of our vocabulary. Since the millennium, clinical gene therapy is better recognized as a subspecialty of translational medicine. A brief review of this innovation of gene delivery to patients makes us aware of how recently this was brought to the clinical world. The first successful gene therapy trial was ex vivo delivery for adenosine deaminase severe combined immunodeficiency (ADASCID) published in 1995. The uniqueness of clinical gene therapy can be further appreciated, considering there were only two publications in the Journal of Translational Medicine in its inaugural year, 2003. The novelty and freshness of gene transfer as a tool for translational medicine is further emphasized by the small number of approved gene therapy products for commercial use at the time of this writing. These include Luxturna (voretigene neparvovec/AAV2-hRPE65v2; Spark Therapeutics, Philadelphia, PA) for autosomal recessive retinitis pigmentosa caused by mutations of the RPE65 gene, and systemic delivery of Zolgensma (onasemnogene abeparvovec/AAV9.CB.SMN; Novartis, Basel, Switzerland) for the rapidly fatal disease, spinal muscular atrophy type 1 (SMA1). My own career enabled an experience in bench to bedside medicine because of political events taking place in the 1960s. My first exposure to the translational world came at the expense of 60,000 American deaths and more than 3.3 million Vietnamese in one of the costliest wars in the history of the United States. Many of the young investigators reading this essay probably don’t know that during the Vietnam war, the military draft was mandatory for every medical school graduate. The mandate for conscription (called the Doctor’s Draft) suddenly changed one’s destiny after internship, including the possibility of carrying a rifle under the overcast sky of Vietnam through green mountainous terrain or through hot and humid, insect-infested jungles. Circumventing this fate was a gift from heaven for the few selected to serve in the Public Health Service, in the branch that came to be known as ‘‘Yellow Beret’’ at the National Institutes of Health (NIH). Many of us who were selected had some research background in medical school (University of Texas Southwestern Medical Center). My further good fortune came through acceptance to the Medical Neurology Branch at the National Institute of Neurological Disorders and Stroke as a research fellow. This acceptance was a eureka moment for me and defined the remainder of my career, even up to the present. Chosen for this position was fate because I had only two formal years of neurology training (Columbia University) rather than the three ‘‘required.’’ This branch had a vivid history pioneering neuromuscular disease. Milton Shy, the first Director and his successor, W.K. Engel, clinically described new diseases and concepts in muscle diseases, including nemaline myopathy, central core disease, mitochondrial diseases, and myotubular and centronuclear myopathy. For young researchers like me, the traditional residency/fellowship regulatory guidelines that restrict research participation had not been established. My Branch Chief at the NIH strongly encouraged research involvement in a neuromuscular disease of interest to the individual. At 27 years of age, I saw my first Duchenne muscular dystrophy (DMD) patient. He was 7 years old and on the threshold of losing ambulation; there was no treatment, and I was firmly committed to making a difference. Molecular-based tools were limited, and uncovering the genetic basis of the disease was not on the horizon. Insight was gained by understanding the pathological findings. This led to my first major translational paper