A pioneer in the field of orphan diseases and gene therapy, James M. Wilson, MD, PhD, reflects on 10 years of leading Penn’s Orphan Disease Center.
In many ways, rare – or orphan – diseases are the simplest of all to treat, because many are caused by a single defect in a gene, notes James M. Wilson, MD, PhD. Yet orphan diseases have a long history of receiving little interest or funding. In his nearly 40 years of focusing on orphan diseases, progress hasn’t happened at the pace Wilson had expected at the outset.
About a decade ago, things began to change, with the opening of the Orphan Disease Center (ODC) at Penn, a first-of-its-kind center dedicated entirely to rare diseases, which Wilson directs and serves as Rose H. Weiss Professor, and which he says has served as a capstone to his experience at Penn. He is also director of Penn’s Gene Therapy Program and professor in Medicine and Pediatrics at the Perelman School of Medicine.
Wilson’s groundbreaking research equips adeno-associated virus vectors (AAVs) with the ability to carry healthy DNA into specific cells – work that has changed the field. It has significantly progressed rare disease treatment and delivered hope: However spectacularly rare or even unique the genetic mutation that gives rise to an individual’s orphan disease, gene therapy could potentially provide a mutation-specific solution.
As the ODC rounds the 10-year mark, those hopes are only rising further. Its anniversary symposium, held virtually in February, was studded with keynotes from luminaries including NIH Director Francis S. Collins, MD, PhD. Scientific interest in rare diseases has grown as the potential for gene therapy to treat them becomes clear, Wilson notes. At the same time, newer industry business models have changed the investment math on developing therapies to treat tiny populations of patients. In the Q&A below, Wilson reflects on this progress and the exciting time in the field.
What is it about orphan diseases that drew you in?
Many patients and their families embark on a long journey, in spite of the fact that their lives are often relatively short. Many physicians don’t have experience with these rare diseases, so it takes a long time for diagnosis. Frequently, once diagnosed, they are left with little hope in treatment options. It’s often when they reach this point that they contact us. Frequently, they’re just delighted that someone is even answering the phone. We have a tremendous opportunity and responsibility to these patients, and it’s rewarding to watch their despair become hope. That’s the part of my job that I really enjoy.
When you reflect on the ODC’s decade of research, what stands out the most?
We’ve made consistent progress with treatments for more than 40 diseases. I’m proud of the fact that we’ve accomplished that at scale and at a high level of scientific quality. I’m pleased that the staff and faculty has remained true to our mission, which is to address the needs of patients regardless of where they live or with what disease they have.
Traditionally, big pharma has largely steered clear of orphan diseases. How is that changing and what strategies have you employed to get around the lack of interest?
For gene therapy, you’re looking at a curative, one-and-done treatment, which is disruptive and different. Much of my 38 years of working in this space, big pharmacy hasn’t been interested. But over time, they realized it might be a better way to treat patients. Biotech has been more receptive and willing to take on risk, so we started there, and eventually, big pharma signed on, too.
Now that the technology of gene therapy has come of age and been applied successfully in commercial products, interest in supporting gene therapy has skyrocketed. Because of the history and capabilities in our lab, we’re in a position to help support development of these products for many diseases and through many companies. We actually ran out of research and office space and couldn’t find any available in Philadelphia, so we’ve expanded our research operations to a Discovery Labs site in (nearby) King of Prussia. We will have the ability to support research all the way through submission of new drugs for clinical trials.
It’s part of a new ecosystem in life science research in our region. Ten years ago we had five companies incorporating our approach in gene therapy. Today it’s 90, and over half are using techniques that came out of Penn.
You recently co-founded biotech company Passage Bio to fund other start-ups interested in gene therapy coming out of Penn, and another startup, iEcure, to develop therapies based on Penn gene-editing technologies. What do you hope to accomplish?
The ODC has about eight different alliances now. I feel strongly that academia, when possible, should do everything it can to assure the translation of research and discovery into treatments that will help people. Yet, academic institutions are not in the business of developing drugs, so we need strong partnerships in the pharmaceutical industry in order to accomplish that. Penn is a real leader in partnering with the pharmaceutical industry, which is appropriate, and allows physicians and scientists to see their research evolve into treatments.
How are you applying your gene therapy knowledge and techniques to develop treatments for COVID-19?
We have engineered a protein that is a soluble form of the receptor COVID uses, which can interfere with the uptake of the virus. It works as a decoy: The virus binds to it and the protein neutralizes the virus so that it can’t infect people. We’ve engineered it so that, no matter what variant is involved, it won’t be able to avoid the decoys. We’re experimenting with nasal delivery and have many sponsors interested in supporting us. We’ve started manufacturing for clinical trials so that we can begin formal safety testing with larger animals. We’re moving as fast as we can given the newer variants.
— Interview by Amanda Loudin
Editor’s note: Wilson is a Penn faculty member, scientific collaborator, key advisor, and co-founder of numerous gene therapy companies spun out of Penn, including Passage Bio and iEcure. As such, he holds equity stakes in these companies, his laboratory at Penn receives sponsored research funding from them, and as an inventor of the licensed technology he may receive additional future financial benefits under licenses granted by Penn to these companies. The University of Pennsylvania also holds equity and/or licensing interests in these same companies.