Realizing the Promise of Gene Therapy: Q&A With Clinical Vector Core Directors

Nov 6 2018

Realizing the Promise of Gene Therapy: Q&A With Clinical Vector Core Directors

Sometimes when looking for a new therapeutic, one just needs to turn toward nature. A group of passionate scientists in the Clinical Vector Core at the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (CCMT), directed by Beverly L. Davidson, PhD, at Children’s Hospital of Philadelphia are focused on making a difference in the field of gene therapy by tapping into how viruses efficiently infect and transfer their genes to host cells. Core Director Johannes (Han) van der Loo, PhD, and Director of Quality Olga Zelenaia, PhD, work diligently with their team to produce high quality viral vectors for numerous pre-clinical and clinical trials occurring at CHOP and elsewhere. We sat down with Drs. van der Loo and Zelenaia to find out more about the role of the Clinical Vector Core in the CCMT and about the daily challenges of continually raising the bar for the Core’s high vector production capacity. We also learned how their proven track record, consistency, and world-class expertise have set the foundation for the Core’s new state-of-the-art Clinical Manufacturing Facility located in the Colket Translational Research Building.

Tell us how the CCMT Clinical Vector Core at CHOP has evolved over the last 10 or so years.

Dr. van der Loo: The Core’s history goes back more than a decade to the formation of the Center of Cellular and Molecular Therapeutics, founded and directed by Dr. Katherine High and later directed by Dr. Beverly Davidson. The Core was one of three cores set up as part of the CCMT, and was initiated at a time when gene therapy at CHOP was just getting started, and the first few patients were being treated. That was a very exciting time. This came after more than 40 years of research envisioning that these types of single gene defect-based diseases could be treated. Approximately 12 years ago, CHOP joined several academic centers to develop methods to get products manufactured for early phase clinical trials. It’s been a long road with ups and downs in the field. Only recently have we seen a number of successes, such as a gene therapy treatment for Leber’s Congenital Amaurosis, a rare form of childhood blindness and the genetic modification of patient’s immune cells to treat life-threatening acute lymphoblastic leukemia that received approval from the Food and Drug Administration last year. Now the field is really taking off.

Dr. Zelenaia: As Han said, for the last 10 to 12 years we at CCMT were on a mission to move gene therapy forward. Now, we’re becoming progressively more and more busy with projects. In the beginning, we were making only one clinical product a year, and now it’s approximately 10 clinical products a year. We have expanded from a group that was delivering products mainly for clinical trials for CHOP and the University of Pennsylvania to a group that now has international clients. The evolution has been very fast, especially as we handle the challenges of compliance with international regulations. We have developed a hands-on, daily improvement process that is very intense and can be stressful. What has helped us along the way was that we were able to hire scientists from many different backgrounds who shared our passion about the quality of our products.

For the field of gene therapy as a whole, what do you think have been the biggest challenges?

Dr. van der Loo: One of the challenges that we encounter is the need for more and more products and the fact that both academic centers and biotech are increasingly focused on commercialization. Client expectations are much higher now than they used to be. It is a logical result of the growth of the field, with more and more trials being conducted. We are only a small group but at the same time need to comply with the same regulations that large pharmaceutical companies have to comply with. In response to the growth in gene therapy, and dramatic increase in a need for products, we decided several years ago to start work on expanding our facility and streamline our operations to be able to better meet these challenges. The new facility, expected to come online in 2019, will provide options to scale manufacturing processes, and more efficiently manage and decontaminate our cleanrooms.

Dr. Zelenaia: I think that one of the challenges is the modeling of vector effect in preclinical studies. We really don’t know how it will pan out when we start the process to prove safety and efficacy of a treatment before the FDA or any other regulatory agency will approve. I think that’s the challenge: showing that the vector is not only safe, which has to be done in animals, and then showing that it’s effective, which does not always work in animals. And then we must develop the functional testing for the vectors, which is critical to show that the drug actually can be used and will be beneficial for humans.

Dr. van der Loo: That is indeed a challenge for us. Since we continuously manufacture unique viral vector products for clients, we ourselves are unable to develop a specific potency-indicating assays for every single product. To develop and perform the potency assays, we largely depend on the investigators themselves, who are most familiar with how to measure efficacy of their vector. This was different in the beginning; when there were only one or two products a year, we were able to spend time on developing such custom assays. Today, these challenges are addressed in partnership with investigators.

Dr. Zelenaia: So it’s a slow process, if you think about it. There are timelines. There are demands. But we have to practice due diligence — our equipment has to be certified and maintained, we have to have proper stickers on every piece of equipment, and make sure that it’s functional, so we have to run standards. When we provide investigators with a signed certificate of analysis for the product they can have a high level of confidence that the vector was manufactured in compliance with applicable standards and meets the agreed upon specifications. Vector manufacturing is a multi-component process that people who work in a research setting may not always fully appreciate.

Now that we’re seeing products that are becoming licensed and available to the general population, with more vectors going into clinical trials, where do you see the field going?

Dr. van der Loo: The original approach that was used for gene therapy is gene addition, in which genes are added to cells. Over the past years technologies have been developed that go far beyond simply gene addition, including for instance gene editing or inhibitory RNA technology. I believe we will see a variety of different applications in different diseases being developed in the future that will use these newer technologies.


Dr. Zelenaia: About five years ago, nobody even knew about gene editing, and now gene editing is a common approach. The combination of stem cell technology, which takes part in another Core housed in CCMT, with gene therapy represents the next new level. At international meetings such as the annual meetings of the American Society of Gene and Cell Therapy or European Society of Gene and Cell Therapy, scientists are presenting work in which stem cells are programmed to develop into certain tissues. It’s individualized medicine in a way because they’re stem cells from a patient treated with viral vectors. It’s just fascinating.

Dr. van der Loo: The field of gene therapy may ultimately not be limited to the use of viral vectors. However, until now, viral vectors provide a very efficient way of getting genes or RNAi into cells. It is the delivery mechanism nature invented. Where we go from here, time will tell. We feel that enormous credit should be given to CHOP, and to CHOP’s vision in continuing to support the CCMT and the Clinical Vector Core to help advance these novel technologies.


We all know that the field hasn’t been without risks. For an institution like CHOP, a world leader in child health, to push this program and to provide resources for a new and expanded state-of-the-art vector manufacturing facility is commendable. Personally, it is humbling to have a chance to contribute to the field in this way, and I think we’re all very proud to be part of it.