How Gene Therapy Became The Future Of Modern Medicine | Dr. William Kelley

In the world of 21st century medicine, gene – based medicines and vaccines (AKA gene  therapy) is thought to be the future, and physicians like William Kelley are among those who  were involved at the beginning of this new field of medicine which is now revolutionizing  the way we prevent, cure and/or treat many human diseases.

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THE BEGINNING OF THE FUTURE OF MEDICINE:

The field of gene-based medicines and vaccines (aka gene therapy) has been evolving since the 1980’s, and progress has been impressive throughout many  academic centers and companies worldwide. Several important life saving drugs  which lead to cures of fatal or chronic illnesses have already been  approved by the FDA for human use.  

However, it was the recent development of mRNA technology to produce an  effective vaccine against Covid-19, as part of this discipline, that has recently accelerated this revolution. These vaccines will probably save millions of lives in  the US alone. The future of medicine has clearly changed and the rate of future changes will  be dramatic. 

The key inventors of this new vaccine technology were Doctors Katalin Kariko and Drew Weissman who did their basic research at Penn Medicine. Dr. Kariko had come to Penn in 1989, driven by an absolute commitment to make mRNA translate into effective drugs or vaccines. She teamed up with Dr. Weissman, a highly successful infectious disease expert  interested in vaccine development, after he joined the faculty at Penn in 1998. 

This mRNA technology was licensed by Penn to Moderna and BioNTech/Pfizer and this  became the basis of the new mRNA vaccines to prevent Covid-19. In addition  to its usefulness for vaccines (and literally dozens will follow for other infectious  diseases), this approach may well prove useful for the prevention or cure of a wide  range of other diseases. Truly, the revolution is well on its way.

“The advancements that we are currently witnessing with mRNA vaccines is one of the  biggest breakthroughs in the history of medicine. There may not ever be another new vaccine produced without using the mRNA technology because of how fantastically successful it has proven to be.”

THE BEGINNING OF THE BEGINNING:

As impressive advances in molecular biology proceeded in the 1970s, the concept of gene therapy began to attract attention with the first of several reviews of the topic in Science magazine by Dr. Ted Friedman. In the early to mid 1980’s, Dr. French Anderson proposed several genetic diseases which he believed would be appropriate candidates for gene-based cellular therapy. Dr. Anderson proposed a form of gene therapy where cells from the body would be grown in tissue culture, the gene of interest would be put into an RNA virus and the modified virus would then be put into the cultured cells. These modified cells could then be given to the animal or patient to correct the genetic defect. This form of gene therapy, where the gene of interest actually infects the cells outside of the body (ex vivo) and the modified cells are administered to the patient is now referred to as cellular (or ex vivo) gene therapy. This attracted the attention of Dr. William Kelley then at the University of Michigan since several of the specific diseases proposed by Dr. Anderson as candidates were diseases of special interest to him.

One of these diseases was the Lesch-Nyhan syndrome. Dr. Kelley had been directly involved in the discovery in 1967 of the molecular basis of this disease, the deficiency of the enzyme, Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) and much of the work in his  laboratory at this time related to these patients, and the specific nature of the abnormal gene and protein leading to their devastating clinical syndrome (more later on this). While Dr. Kelley was very interested in this proposal by Dr. Anderson, he did not believe this type of cellular gene therapy would work in his patients with the Lesch Nyhan Syndrome, because he believed that the gene would need to be put directly into the brain. In other words, in vivo (directly in the body) gene therapy would be required. 

Dr. Kelley had a highly talented group of trainees in his laboratory at the University of  Michigan including graduate students, James Wilson and Beverly Davidson (both now distinguished scientists in the gene therapy field and currently on the faculty at  Penn), a talented post doctoral fellow from Japan, Dr. Yugi Hidaka, an impressive junior faculty member, Dr. Tom Palella, and two experts on Herpes viruses, Dr. Myron Levine, Professor of Human Genetics and Dr. Joseph Glorioso, Professor of Microbiology, both at the University of Michigan.

By the mid to late 1980s, several in the Kelley lab began to pursue the possibility of in vivo gene therapy in an animal model of HPRT deficiency. Dr. Hidika in a series of experiments was able to directly insert a recombinant neurotropic HSV-1 vector carrying the human gene for HPRT into the brain of a  mouse deficient in this enzyme and demonstrate expression of the human gene  product in the brain. A patent application was first submitted for approval for this work in 1987, and was eventually issued by the US patent office in 1997. The research was presented for the first time to a scientific audience in May 1989, and was published in a peer reviewed scientific journal shortly thereafter. A far more highly sophisticated approach using this concept is currently being considered by others for the treatment of patients with the Lesch-Nyhan Syndrome.

Dr. Kelley was convinced that this new approach in medicine would be revolutionary and he was committed to trying to expand the concepts as rapidly as  possible; he knew it would take more than a village. He was unable to get a program expanded at the University of  Michigan as he had hoped, so in 1989, he took the position at the University of Pennsylvania  as  Dean of the  medical school and as CEO of the Hospital of the University of Pennsylvania. This gave him a position to begin, among other things, to implement a program at Penn medicine which would be attractive to outstanding scientists and physician scientists who  were interested in pursuing this new discipline of gene based medicines and vaccines. 

In order to help facilitate the research in gene therapy, Dr. Kelley established within the  University the Institute for Human Gene Therapy as well as a new basic science  department, the Department of Molecular and Cellular Engineering. In 1993, he recruited Dr. Jim Wilson, who by then had completed his post-doctoral training and joined the faculty at the University of Michigan, to become the Chair of the new  department and Director of the new Institute. 

Many new faculty came to the University of Pennsylvania medical school in the 1990s to pursue this new discipline. Indeed, by the end of the 1990’s there were a large number of faculty pursuing research in gene therapy. 

However, at the turn of the 21st century, things were to become more difficult. In October 1999, an 18-year-old patient died while participating in an approved gene therapy trial at the Hospital of the University of Pennsylvania. This death was tragic and was the first known death of a gene therapy patient enrolled in a scientific trial. It was best explained by a severe allergic reaction he had had to the adenoviral vector used in the experiment. This was assumed to be due to a previous adenoviral infection (common cold), which the patient had had.  

Following this event, the Institute for Human Gene Therapy and the Department of Molecular and Cellular Engineering were discontinued. Dr. Kelley was no longer in his position as CEO and Dean. 

Recovery of the gene therapy program at Penn Medicine at this point in time was seriously in question. It was only the superb efforts of the two academic leaders who followed Dr. Kelley, Dr. Arthur Rubenstein (2001-2011), and Dr. Larry Jameson (2011-present) that the program is not only alive and well, but perhaps the academic epicenter of the world for gene based medicines and vaccines. The gene therapy program continued with Jim Wilson in charge, but no longer identified as a separate institute. Dr. Kelley continued on the faculty at Penn Medicine as a professor of medicine where he still serves. 

 Most faculty who had come to Penn Med in the 1990s were able to continue their research and there were to be some dramatic successes. In addition to doctors Kariko and Weissman as mentioned earlier, others included (1) Dr. Jim Wilson who, stimulated by the need to replace the potentially dangerous adenoviral vector used in the fatal trial described above, went on to establish the AAV (Adeno Associated Virus) vector platform which eventually became the most commonly used DNA vector in the world for in vivo gene therapy including virtually all of these gene therapy drugs that have been FDA approved to date. (2) Dr. Carl June who was the first to create CAR -T cell therapy as a cure for patients with fatal acute lymphocytic leukemia. In 2017, this technology, which employed ex vivo gene therapy, was the first ever approved in this field by the FDA. (3) Dr. Jean Bennett, Dr. Albert Maguire, and Dr. Kathy High, who would go on to be the first individuals to receive US regulatory approval for gene therapy drugs administered in vivo, in this case for the cure of a  genetic form of human blindness. This was approved by the FDA in 2018, becoming the first in vivo gene therapy drug approved by this agency. 

Clearly many faculty at Penn Medicine were to become established as world leaders in gene therapy through the first twenty years of the 21st century. Then along came the breakthrough research using mRNA from the Penn Medicine labs of Doctors Kariko and Weissman as noted above. WOW!

“Dr. Kelley’s greatest gift to American Medicine and science lives on with the men and women whose potential he discovered at an early age, whom he trained, and on his or her career he nurtured. His contributions to medicine, science, and society continue to this day and will extend far beyond our  lifetimes.” 

Who was this at THE BEGINNING OF THE BEGINNING?

Bill Kelley grew up mostly in West Palm Beach Florida. His initial introduction to  Medicine was seeing patients with his dad as a young boy. His father was a general internist practicing in Palm Beach. In addition to his patient  population from Palm Beach, however, he used to take care of many patients who lived in  rural Palm Beach County west of West Palm Beach. On Saturdays, his father, Dr. Oscar Kelley, would take him on  house calls to see these patients.

Sometimes his father would have him meet the  patient at their bedside, sometimes he would have his son wait in the living room  while he saw the patient, sometimes he would have his son wait in the car depending  on the circumstances. What Bill Kelley remembers vividly from these trips is that  often the family would bundle up bags of oranges, grapefruit, or sometimes mangoes  from the back yard, or even eggs, to give to his Dad on his departure from the home. While Bill didn’t know for sure, he assumed this was probably the only payment his  dad would receive for this visit. 

Bill Kelley decided to attend college and medical school at Emory University where  his father and grandfather had gone. Little did he know that this would be just the  beginning of a long and accomplished career eventually participating in the early  years of this new field of gene- based medicines and vaccines.

Bill was considering internships as a senior medical student at Emory when he had an opportunity to hear a visiting professor from UT Southwestern give a lecture  on cholesterol metabolism. He was so excited by the science that he decided to do  his training in Internal Medicine at UT Southwestern in Dallas. This turned out to be  an extremely important decision for the soon to be Dr. Kelley. A few months after his arrival in Dallas, the Chairman of Medicine, Dr. Donald Seldin, with whom he had had  considerable contact at the bedside and in the conference room setting suggested that  he seek further training at the National Institutes of Health, and he offered to make it happen.

This, indeed, sounded very attractive to Dr. Kelley because not only would this be such an  exciting scientific opportunity for training, but this would also allow him and his family to spend his two years of required national service time as a Commissioned Officer in the Public Health Service in Bethesda Maryland at the NIH. 

These two years of research experience at the NIH turned out to be the most important  single professional event in his life in retrospect. He had the opportunity to work  with Dr. Jay Seegmiller, who was one of the world’s leaders in purine metabolism research. When he entered the lab, Dr. Seegmiller suggested that he work on a  disease recently discovered by faculty at Johns Hopkins, the Lesch-Nyhan  syndrome. It was a bizarre disease characterized by a high uric acid level and  excessive purine production, a bizarre behavioral disorder with self mutilation, mental retardation, and a form of cerebral palsy. 

In shortly over one year through a series of clinical and basic research experiments,  Dr. Kelley and colleagues were able to show that these patients had a deficiency of the enzyme,  HPRT, as the cause of their disease.  

In addition, they found a partial deficiency of the same enzyme in a number of  patients with a severe form of gout but without neurologic disease; this latter  syndrome is now called the Kelley Seegmiller syndrome. Importantly, it was because of Dr. Kelley’s interest in the  Lesch-Nyhan syndrome, as noted earlier, that he was driven to evaluate the possibility of gene therapy as a treatment for these patients. 

Once Dr. Kelley had completed his research experience at the NIH, he decided to complete  his final year of clinical training in internal medicine at the Massachusetts General  Hospital in Boston. Here he had a great experience and began to appreciate why this  institution was held in such high regard within the academic medical world. 

After his time at the MGH, Dr. Kelley decided to accept an offer to join the faculty at  Duke University where he was to have an amazing early career. He was provided superb  resources in a beautiful laboratory where he could begin his faculty career. After one year, he was asked to take on the position as Chief for the Division of  Rheumatic and Genetic diseases, which he did. This was a great experience and all  went well. He had a number of superb post-doctoral trainees, many of whom have continued on with highly successful careers, and have remained great friends. Within five years, the division was ranked well in the top 5 of Divisions of  Rheumatology in the country. 

In 1975, seeking more responsibility and an advance in his career, Dr. Kelley accepted the position as chairman of the Department of Internal Medicine at the  University of Michigan. This made him the youngest chair of medicine in the  country at 36-years-old, but he felt he was ready. Indeed, this turned out to be a great  decision.  

Not only did it give him an opportunity to recruit some of the most outstanding young  faculty in the country to join the department but it would allow him to have superb  students and trainees in his own laboratory. It was based on the latter, that his lab was able to  conduct the gene therapy experiment of injecting the human HPRT gene directly into the  brain of a mouse genetically deficient in that enzyme and achieve expression of the human gene product. 

In 1989, Dr. Kelley made the move to a major leadership position at PENN as described earlier. In addition to his effort to begin a program in gene therapy, Dr. Kelley had  responsibility for all other aspects of the Penn Medicine programs. He reported directly to  the president of the university and he had the opportunity to allocate the resources within Penn Medicine as appropriate. He focused on bringing the medical school back to its  previous stature as one of the top two or three in the country. This required that he recruit the best medical students, as well as the best junior faculty, and the next generation of leaders in medicine and in the medical sciences. It would be  these individuals who would be the best measures of his success.  

According to the Journal of Clinical Investigation, in just over a decade at Penn Medicine, Kelley moved the medical school from 10th place to 2nd place in NIH funding. By 1999, 14 of Penn Meds academic departments were ranked in the top five of their respective disciplines.  Overall the medical school’s national ranking as measured by US News and World Report  improved from 10th to 3rd. By the late 1990s the Hospital of the University of  Pennsylvania had moved into the honor roll of the nation’s top hospitals in the US News  and World report survey for the first time ranking tenth by the year 2000. 

Kelley and his colleagues launched and implemented a new medical curriculum – curriculum 2000. He significantly expanded the MD/PhD program and established 12 major multidisciplinary research centers and Institutes at the medical school level. 

Bill recognized that access to patients was being threatened in the early 1990s, and yet patients obviously were critical, to achieve the medical school’s tripartite mission. His leadership team conceived of, and built, the University of Pennsylvania Health System (UPHS), the nation’s first fully integrated university-based academic health system which was formally approved by the University trustees in 1993. By 2000, the health system included the school of medicine, four owned and 12 affiliated hospitals, and 850 physician multi-specialty faculty, a 270 physician primary-care regional network, and two large off-site multi-specially satellites. Over the past 28 years UPHS has continued to flourish and to grow dramatically. 

“Bill Kelley was the most effective leader of an academic medical center in several decades. His major accomplishments include the recruitment of a great faculty with a terrific leadership team. He largely rebuilt much of the medical center’s physical plant and added numerous new facilities and laboratories. He improved the care of patients. He totally overhauled and improved the education program. He raised the quality and quantity of research activity so that the University of Pennsylvania Health System was close to the top.” said Dr. Roy Vagelos, former Chairman of the University of Pennsylvania Board of Trustees, former Chairman and CEO of Merck, Inc., and currently Chairman of the Board of Regeneron. 

Dr. Kelley’s numerous accomplishments have led him to receiving a multitude of awards and  honors for his advances in medicine. He has founded and edited two major textbooks, served on 14 editorial boards, and has been a valued contributor to academia, government, and industry. 

Dr. Kelley’s contributions have been widely recognized by election to the most prestigious  academic societies and through receipt of numerous awards. He was elected to membership in the American Philosophical Society, the American Academy of Arts and Sciences, the National Academy of Medicine and others. He served as president of the American Federation for Clinical Research, American Society for Clinical Investigation, and the American College for Rheumatology. He served on the Council of the National Academy of Medicine for two elected terms in the 1990s. He is a recipient of numerous prestigious awards for academic achievement. He was chosen to receive the David Rogers Award of the Association of American Medical Colleges, the John Phillips Award of the American College of Physicians, and the gold medal from the American College of Rheumatology. He was also selected to receive recognition as a Master by both the American College of Physicians and the American College of Rheumatology. He received the prestigious Emory medal from his alma mater in 2000. 

According to Dr. Edward Holmes, a physician who worked as a post-doctoral fellow in the Kelley lab, and is himself today one of the great leaders of American medicine, Dr. Kelley’s “greatest gift to American medicine and science lives on in the men and women whose potential he discovered at an early age, whom he trained and whose careers he nurtured, and whose contributions to medicine, science, and society continue to this day and will extend far beyond.” 

Several have used the quote used to describe the success of Wayne Gretzky as a hockey great, “skate to where the puck is going to be, not to where it has been,” to describe Dr. Kelley’s success in medicine, and gene therapy is a great example of that. 

“I truly believe that in 10 years we are going to be preventing or curing diseases that human beings never  thought would even be treatable. Messenger RNA is just so exciting and it’s already  proven to save millions of lives during this pandemic.”

FINAL THOUGHTS:

Dr. Kelley concluded our interview with the following thoughts:

“The whole gene therapy revolution is clearly one of the greatest breakthroughs in the history of medicine. This has now been greatly accelerated by the use of mRNA to produce vaccines; this scientific advance is so important that there may never be another new vaccine produced without using the mRNA technology because of how fantastically successful it has proven to be.  

Many devastating diseases may also succumb to this new mRNA technology. Sickle Cell disease, for  example, is one of the most devastating genetic diseases throughout the world. If one can apply the same mRNA techniques that scientists put into creating the Covid vaccines to prevent diseases like Sickle Cell disease, this would have an immense impact on the health of  the world. There are literally hundreds of other examples that seem possible using this new technology. The full technology is not here yet, but it will be soon. 

I truly believe that in 10 years we are going to be preventing or curing diseases that human beings never  thought would even be treatable. Messenger RNA is just so exciting and it’s already  proven to save millions of lives during this pandemic. I truly think that this is just the  very beginning of how far this and related technologies will go, and mRNA is only part of the story.  We also will continue to see the advances with what are now the more traditional forms of  both in vivo and ex vivo gene therapy, using viral vectors and even using ‘free’ DNA itself. 

“I’m just happy to have been involved in this new field of gene based medicines and  vaccines where my team could make a contribution early in its development and then be able to help  some of the early pioneers be successful.”