CIGT Advances CHOP's In Vivo Gene Therapy Leadership

By Jillian Rose Lim

More clinical investigators have in vivo gene therapy clinical studies underway at Children’s Hospital of Philadelphia than ever before, with more than 20 clinical trials spanning 7 clinical divisions. Guiding this extraordinary growth is the multidisciplinary Clinical In Vivo Gene Therapy group (CIGT), which combines decades of experience to advance preclinical discoveries into clinical trial.

While ex vivo gene therapy treatments like chimeric antigen receptor (CAR) T-cell therapy extract cells from a patient to engineer them in a lab, in vivo gene therapies deliver corrective genes directly into a patient’s body through an intravenous treatment dose.

There are currently five FDA licensed in vivo vectors, Luxturna^® (retinal dystrophy), Zolgensma^® (spinal muscular atrophy), Roctavian^TM (hemophilia A), Hemgenix^® (hemophilia B) and Elevidys^® (Duchenne muscular dystrophy (DMD)). Lindsey George, MD, a CHOP hematologist with expertise in gene therapy and CIGT director, expects the number of licensed vectors, along with the number of patients who receive them, to continue to rise. With its legacy of gene therapy work, CHOP is the perfect place for in vivo gene therapy research to thrive, she said, as CIGT leans on its expertise in managing clinical trials to streamline study operations and take a multidisciplinary approach.

“We’ve been developing in vivo gene therapy for approaching three decades,” Dr. George said. “The breadth and depth of work and the longevity in this space is unparalleled. The volume of clinical trials is completely unique to CHOP. Other institutions have conducted a depth of work in X space. We’re doing a lot of work in A, B, C, through Z space. Our hospital and Research Institute have truly been seminal players in this space for decades.”

For Dr. George, this “remarkable expansion” of basic, translational, and clinical work is a “brute force” that not only prompted the creation of CIGT — it necessitated it to bring together people who have gene therapy expertise with those who have excellent disease-specific expertise.

Composed of a network of physician investigators, clinical research coordinators, regulatory specialists, and operation specialists, CIGT aims to centralize in vivo gene therapy research at CHOP. Ben Samelson-Jones, MD, PhD (hematology) and Amy Waldman, MD, MSCE, (neurology) serve as associate directors and Susan Matesanz, MD (neurology) as medical director.

Established in 2021, CIGT currently supports investigators in across CHOP, including Cardiology, Endocrinology, Hematology, Genetics and Metabolism, Neurology, Ophthalmology, and Otolaryngology. Among them, Dr. George counts more than 20 interventional trials currently enrolling at CHOP for 17 disorders.

“This work has been ongoing at CHOP for about 20 years, but when it comes to the volume and number of people involved, it’s relatively new,” Dr. George said. “There are varying levels and divisions of people approaching gene therapy in vivo, but we are united by a common theme: The remarkable potential for gene therapy to be hugely impactful to patients.”

Safe, Smart, and Successful Clinical Trials

Currently, most in vivo therapies are delivered via adeno-associated virus (AAV) vectors to treat rare single-gene diseases. AAV “infects” the patient with a life-saving gene. That gene then instructs cells to produce a protein that’s otherwise missing. For example, in one of Dr. George’s research projects, AAV vectors carry transgenes that express factor VIII, so that patients with hemophilia A can produce the clotting factor they lack.

CHOP’s hefty history of breakthroughs paves the way for investigators to adapt the successes of AAV vectors. But to do so in a safe and efficient manner that targets disorders that cross a multitude of clinical disciplines requires a structured and centralized approach. Dr. George outlined how CIGT's initiatives are evolving based on three core missions:

First: conduct and support high-quality clinical trial work. CHOP’s history in the space has created a critical mass of clinical PIs and regulatory personnel embedded within CIGT who have the expertise and logistical knowledge of how to safely conduct in vivo gene therapy trials while meeting federal and institutional regulatory requirements. By creating a cohesive AAV investigator community, Dr. George envisions an expansion of investigator-initiated trials, more efficient onboarding of industry-sponsored trials, simplified scheduling for study procedures, and expanding CHOP’s already deep institutional knowledge of gene therapy trials.

“There might be one or two people in each of the clinical divisions doing this work, but we are bringing people together so we can share information, learn from each other, and create synergy among one another,” Dr. George said.

The second core mission is safety and optimizing clinical outcomes. CIGT aims to be a central hub that streamlines communication between clinical teams and gene therapy experts to ensure increased surveillance of potential toxicities and complications and to conduct collaborative quality improvement work, leading to improved patient safety and optimal clinical outcomes.

“Some of the approved, or expected-to-be approved, therapies are targeting larger disease populations,” Dr. George said. “For example, Luxturna treats an ultra-rare disorder, whereas DMD has an incidence of one in 3,500 boys, so that’s pretty common. As more licensed vectors come on board, which is a good thing, we have to meet the need safely and efficiently.”

Finally, the third core mission is education. In vivo gene therapy had its successful start in hematology, and now CIGT is widening CHOP’s translational and clinical expertise of AAVs by providing training opportunities for any division and at all levels of the career leader, from clinical PIs, to nurses, physician trainees, and more.

“You do a clinical trial, but this will be a licensed product and people in various stages of training will be taking care of the patient,” Dr. George said.

Some CIGT education initiatives include quarterly investigator meetings, a planned AAV translational and clinical symposium, and the Cell and Gene Therapy Clinical Training program, which is an intensive gene therapy training course designed for physicians that seek to be clinical PIs or PhDs who aim to be involved in translational gene therapy. In the future, CIGT hopes to develop fellowship and research training programs for in vivo gene therapy. Ideally, this investment in education will cultivate a robust pipeline of gene therapy expertise at CHOP and allow the Research Institute to train and retain top talent in the field.

A History of In Vivo Leadership

It helps to know CIGT’s origin story, to fully understand its depth of experience and dedication to in vivo therapy research and development. Since the early 2000s, CHOP and the University of Pennsylvania have been at the forefront of developing and advancing AAV vectors.

CIGT took root within CHOP’s Raymond G. Perelman Center for Cellular and Molecular Therapeutics (CCMT). Katherine High, MD, PhD, a key collaborator with University of Pennsylvania’s Jean Bennett, MD, PhD in the development of Luxturna, founded CCMT in 2005 to advance research demonstrating the promise of therapies that correct or alter the expression of missing or defective genes in vivo.

The CCMT provided a base for researching gene therapies for children, and it precipitated the creation of the Clinical Vector Core (CVC), an in-house vector manufacturing facility that received recognition from the International Society for Pharmaceutical Engineering. This work was essential to expanding translational and clinical in vivo gene therapy.

In 2006, Dr. High and colleagues demonstrated in Nature Medicine the first safe parenteral administration of an AAV vector in adult men with severe hemophilia B; this approach to gene therapy is now used widely for a number of genetic disorders. A year later, CHOP researchers were the first to describe the human cellular immune response to AAV in Nature Medicine.

Over the next 10 years, breakthroughs at CHOP continued, including the foundational work for Luxturna. In 2017, the U.S. Food and Drug Administration (FDA) approved Luxturna to treat inherited biallelic RPE65 mutation-associated retinal dystrophy, making it the first approved AAV therapy in the U.S. and the first FDA-approved therapy for a genetic disease.

At the same time, Dr. George and Dr. High worked together on the first successful hemophilia B Padua trial. Published in the New England Journal of Medicine, they described sustained therapeutic expression of factor IX after gene transfer in 10 participants with hemophilia B. A few years later, Dr. George published another paper in NEJM showing the first durable Factor VIII (8) expression for hemophilia A following gene therapy.

Future Directions

“What I hope for in the future is a licensed gene therapy for children with hemophilia A and B; current efforts are only in adults,” Dr. George said. “We’re also seeing exciting work in DMD and several other neuromuscular disorders. There’s a large volume of work ongoing in metabolic disorders. I’m optimistic that we could start to see a growth of in vivo gene editing efforts, which is likely to be important for successful durable gene therapy in children and, conceivably, treating many genetic disorders.”

Indeed AAVs are not the only method of in vivo gene therapy that CHOP investigators are exploring, as basic work is underway for lipid nanoparticles and AAV gene editing. In fact, the first-ever in vivo delivery of an experimental CRISPR gene editing medicine to a pediatric patient occurred at CHOP in a CIGT-supported ophthalmologic trial.

Meanwhile, CHOP also is playing an important role in the Foundation for the National Institutes of Health (FNIH) Accelerating Medicines Partnership® Bespoke Gene Therapy Consortium (AMP® BGTC), which seeks to accelerate the development and delivery of customized gene therapies for rare diseases. As part of the BGTC’s portfolio, CHOP investigators Rebecca Ahrens-Nicklas, MD, PhD, and Laura Adang, MD, PhD will use gene therapy to target multiple sulfatase deficiency (MSD), paving the future for sustaining gene therapy research for ultra-rare diseases.

The number of investigational and licensed in vivo gene therapies in the pipeline is expected to continue to grow exponentially, and it’s truly an exciting time to be involved with in vivo gene therapy. With its extensive history, rich expertise, and CIGT as a supportive infrastructure, we can expect many more in vivo gene therapy firsts and breakthroughs to occur at CHOP.

Contact CIGT at cigt@chop.edu.