News : 2017 : October

Richard Alan Smith, M.D.,‘65 and Treating ALS

Richard Alan Smith, M.D.,’65 is a renowned neurologist who played a crucial role in in discovering one of the most promising therapeutic means of treating Amyotrophic Lateral Sclerosis, or ALS. He is the Director of the Center for Neurologic Study in La Jolla, California, where he is continuing to pursue drug discovery and the development of treatments for incurable neurodegenerative diseases.

1. You played a significant role in discovering one of the most promising therapeutic means of treating ALS- antisense therapy – a DNA based therapy that can modulate the synthesis of malfunctioning proteins. What led you to pursue research in ALS?

During my medical training, it was apparent that ALS patients were modern day lepers: nobody wanted to help them. Patients were told there was no hope and they should put their affairs in order and accept their fate. Within a short time, I demonstrated that palliative care could improve their lives. Later, most of my effort was focused on experimental treatments, such as the use of growth factors and antivirals. In retrospect, I am not sure if I chose to work on ALS or the disease chose me. Either way, I was never tempted to change my emphasis on ALS.

With the discovery in the 90s of genes responsible for Huntington’s disease and ALS, etc. the focus was primarily on figuring out the basis for the toxicity associated with the mutant protein that results from these mutations with the intent of designing therapies to counter these effects. This had not been notably successful. With this background, I came up with the idea of down-regulating the expression of mutant genes, reasoning that if patients lived seemingly healthy lives for years before becoming ill, they would likely benefit from the reduction of the amount of mutant protein that cells needed to process. After considering several strategies to accomplish this, I settled on the use of ASOs (antisense oligonucleotide therapy).

2) Your research was funded by the ALS Association in 2004. Can you tell us how your collaboration with them came to be?

For a number reasons, my ALS treatment strategies were always considered long shots. But ultimately, several biotech companies became interested in them. In the instance of antisense therapy, Ionis Pharmaceutical Corporation agreed to synthesize oligonucleotides for me, Don Cleveland, Ph.D., at the University of California San Diego decided to provide the lab space that I needed, and I won a Scripps Skaggs scholar award which paid my salary for three years. By the time these essential components were in place, I was 60 years old. In time, both the ALS association and the Muscular Dystrophy Association generously funded much of what was needed to proceed to a clinical trial.

3) Antisense therapy has drastically changed the gene therapy landscape and fueled significant clinical trials. What do you see as being the next steps in the fight against ALS?

If successful, the ongoing ASO Familial ALS trial being conducted by Biogen, will be a medical first that will rapidly be followed by similar studies. In fact, the drug currently being evaluated may well end up being tested in patients who have “sporadic ALS,” which accounts for the majority of patients. As for the future, complimentary approaches, such as gene therapy are in the development stage, and one suspects that the reluctance to edit human genes, currently on hold, will be irresistible in the instance of familial neurologic diseases.

4) You credit UM’s Department of Neurology with helping to shape your career. Can you explain how?

The clinical training I received at UM was superior to the training I received anywhere else. In this regard, it would be remiss not to mention the UM faculty that influenced my decision to become a neurologist: Sherif Shafey, M.D., Peritz Scheinberg, M.D., Noble David, M.D., and Lawton Smith M.D. My research roots go back to the time I spent in the laboratory of Sheldon Greer, Ph.D. For a while, he redirected his lab based on my attempt to transfer a gene from one bacterial species to another.

5) What’s been your proudest achievement in medicine?

As a clinician-researcher, I am pleased with the choices I made: the decision to work with patients afflicted with the incurable disease and the decision to focus on the development of palliative and experimental treatment for these maladies. Whereas clinical neurology had mostly been a descriptive discipline that was anchored in the application of clinical physiology, the field changed dramatically with the advent of imaging technology, the ability to clone genes, and, ultimately, the emergence of biotechnology. In retrospect, I can’t imagine a better time to have become a neurologist.

As for personal achievement, I believe my early work on interferon and my later work leading to the development of Nuedexta, and the use of ASOs as treatment modalities for CNS disorders are the most notable.

6) What do you like to do in your spare time?

My favorites are the time spent with family, friends, and colleagues and time spent sailing, collecting American art, and renovating historic buildings.