NATIONAL HARBOR, Maryland — The momentum in favor of cell and gene therapies has the potential to successfully treat an estimated 80% of rare diseases caused by genetic mutations, Mo Heidaran, PhD, vice president of technical and regulatory consulting at Parexel International Biotech, said at a discussion at the 2021 World Orphan Drug Congress.

The advancements in the fields of cell and gene therapy over the past few decades have been exponential, according to the panel of industry and rare disease experts who held the discussion.

Lessons have been learned from clinical trials regarding safety and the adaptation of regulatory frameworks throughout the process of expanding in vivo and ex vivo treatments and engineered cell therapies, the panelists explained. In the 1990s, gene therapy research centered on treating monogenic diseases, but with technological advancements, the thought process has changed to consider the impact gene therapy can have on more complex diseases.

Another insight that has emerged regarding treatment of rare diseases is that “no one type of approach fits all in gene and cell therapy,” according to Shephard Mpofu, MD, chief executive officer of Novartis Gene Therapies. One gene may not be suitable for the entire population within a specific disease, so understanding surrounding epigenetic factors is crucial to determining efficacy.

The foundation for success of a treatment is the collaboration with regulators to “cement understanding of the pathophysiology of disease,” Dr. Mpofu said. Awareness that animal studies may not translate into human studies must also be acknowledged and may impact translation into clinical practice.

The durability of gene therapy treatments poses a concern for the US Food and Drug Administration (FDA), panelists said. Longitudinal patient studies are required to better understand disease progression and therapeutic benefit over a length of time. One suggestion involved electronic medical record capture of data over an extended period of time and formation of patient registries for easier access to this information.

Key challenges to the advancement of cell and gene therapies include small patient populations, poorly understood disease mechanisms, lack of comprehensive natural history collection, and lack of appropriate endpoints, according to the speakers. Composite symptoms cards can report up to 10 or 15 disease symptoms per patient, as symptoms may vary from person to person within a particular rare disease. This may assist with more accurate endpoint selection and validation.

However, “what patients appreciate and what can be accurately measured may be 2 different things,” according to Sharon Hesterlee, executive vice president and chief research officer of the Muscular Dystrophy Association. Patient advocacy groups can guide this development process by conducting benefit-risk studies, gathering data, and providing a natural history on disease progression directly from the patients. When researchers are determining relevant endpoints, risk-benefit analyses within patient advocacy groups may determine the willingness of patients or parents of children with rare diseases to take risks, especially when major changes to quality of life impacting mobility or other factors are concerned.

Surrogate endpoints substitute for direct measurements of patient feelings, functionality, or survival. Although these endpoints may not reflect primary clinical interests, the benefit to the patients should also be considered, which is why natural history is critical in connecting the symptoms to biomarkers to obtain proof that a treatment is working. Subjective feelings of patients may translate into objective measurements, the panelists explained.

Patients also maintain great influence with regulators, proving “invaluable to the entire ecosystem in developing drugs and how regulatory officials are involved,” said James Mullen, CEO of Editas Medicine.


Treating rare diseases: future of innovation and development for cell and gene therapies. Presented at: World Orphan Drug Congress USA 2021; August 26, 2021; National Harbor, MD.