Next week, Los Angeles hosts what is likely to be the largest gene therapy conference in history as the American Society of Gene and Cell Therapy (ASGCT) arrives. More than 6,000 attendees are expected to gather to discuss the latest advances in the booming field.

For a preview of ASGCT, we caught up with Terry Flotte, MD, a pioneer in the gene therapy space since the early 1990s. Flotte is the provost/dean and Celia Isaac Haidak Professor at the University of Massachusetts Chan Medical School and the Editor-in-Chief of GEN’s sister journal, Human Gene Therapy. He has also just been announced as the Society’s incoming Vice President (and future president). We asked Flotte to share his thoughts on the state of gene therapy and to preview next week’s event.

[This interview has been edited for length and clarity.]

GEN: Terry, how would you sum up the state of gene therapy in 2023? 

FLOTTE: We’re continuing to have great dissemination of the technology to more patient populations. New therapies are being approved by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) as clinical trials are advancing. For example, we’re very excited about the FDA gene therapy advisory committee later this month to recommend approval for Sarepta’s Duchenne Muscular Dystrophy product, which is one of the tougher targets for gene therapy—the entirety of a patient’s muscle mass, including cardiac and skeletal muscle, must have some effect of the gene to be an effective therapy. It’s probably the largest size of tissue that has been targeted by gene therapy. The pipeline is continuing to issue products and that is nothing but good news for patients.

What have been some of the most exciting advances in the field over the past 12 months? 

FLOTTE: The emergence of more proof-of-concept data around gene editing technology has been very exciting… next-generation CRISPR technologies, such as prime editing and base editing; RNA-guided transcription activators; Cas9-guided transcription activators; different modalities of cancer immunotherapy; and the persistence of researchers to make progress in spite of the ups and downs in the investment climate.

The successful treatment of Victoria Gray and dozens of other SCD patients in the Vertex-CRISPR Therapeutics Exa-cel trial is an undeniably great story. Do you see any reason why that application should not receive FDA approval this year? 

FLOTTE: I see no obstacles. Based on my view of the trial data, the treatment is promising both with regard to safety, efficacy and duration. It’s amazing that we can see these gene editing technologies moving forward for diseases that have a high global prevalence.

One issue is that the current ex vivo approach, which has clearly worked well for Victoria and the other patients in her cohort, may not translate well to Africa?

FLOTTE: Maybe not to Africa, but there’s a directed focus on bringing more therapies to middle income countries, which may not be sub-Saharan Africa at present.

Adeno-associated virus (AAV) has become arguably the most popular gene therapy delivery vector. How is AAV being adapted and evolving for clinical success? 

FLOTTE: We’re coming into a sharper focus around the dose-related safety toxicity issues of AAV. The data continues to accumulate regarding innate immune responses that may occur at very high doses of intravenous (IV) AAV vectors—generally, in excess of 1014 genomes per kilogram. There are a range of potential toxicities—hepatotoxicity, thrombocytopenia, and thrombotic micro angiopathy from complement activation. These toxicities are being studied very carefully in a variety of trials which involve diseases like muscular dystrophy, where IV is the route of administration and the doses required are very high.

As you alluded, there continues to be a proliferation of other versions of the AAV capsid, which have different targeting properties. Some of the AAV engineering feats include novel ways to use the limited packaging of AAV to deliver genome editing components. These components include the guide RNA, which can be expressed from an AAV expression cassette. You also need to have the Cas protein. There are more compact Cas proteins or they can be delivered in two AAV vectors with inteins. These different combinations are important when we’re trying to accomplish in vivo gene editing. In some cases, AAV is an important way to deliver a template for gene editing. The homology directed repair (HDR) templates seem to work better in the context of certain AAVs, such as AAV6. Harnessing AAV as a delivery vehicle must adapt to what it has to deliver.

There are still adverse events in patients being reported. Graphite Bio, for example, halted its sickle cell program earlier this year after complications in the first dosed patient. Why are we still encountering problems in clinical trials? 

FLOTTE: Animal models have been imperfect at predicting human immune responses to AAV vectors and other technologies, including CRISPR components. In addition, human clinical studies often have small numbers of recipients. [Individual variation] requires a lot of time and aggregation of the experience at multiple centers to identify some of these toxicities.

It’s become clear from the post-licensure studies that Zolgensma, the AAV9 SMA product, does have a significant hepatotoxicity in a subset of patients. In most patients, the hepatotoxicity is easily treated with steroids, indicating that it’s an immune response. There is also a smaller subset of patients that either have innate or adapted responses that are not easily treated. Even in a condition that was seemingly such a home run with a moderate number of patients in the efficacy trial, you identify potential toxicities when you do more patients with more individual variation. You then have to understand both the characteristics of the host and the vector to [devise an effective method to manage that toxicity].

It’s the failure of models, but also the [genetic] variability of human beings. That’s what makes clinical research hard. Unlike our mice, we’re not all inbred! We don’t eat the same food and drink the same water. There are so many variables in clinical research. I often say that’s why we need statistics.

This year’s ASGCT conference in Los Angeles is shaping up to be the biggest gene therapy conference in history. Are there any sessions or presentations you’re particularly looking forward to? 

FLOTTE: There will be a talk by David Williams [Boston Children’s Hospital], who will be recognized with the Founders Award, which was awarded to Francis Collins last year. It will be wonderful to see the sweep of ex vivo gene therapy and the work David has done with childhood and adult illnesses that can be corrected with ex vivo hematopoietic stem cell gene therapy.

My group will be presenting a clinical trial spotlight symposium on our latest Tay-Sachs gene therapy. In another session, we  will be presenting work related to deeper characterization of immune responses, which we looked at in great depth compared to some of the small trials that we’ve done. I hope to learn what others are seeing as mechanisms of immune responses, whether it be those immediate innate phase responses or the adaptive response with either antibodies or T cells.

More broadly, I’m interested to see where and when there might be further inroads in immune-oncology based on gene therapy. CD19-directed CAR T-cells could have major impacts and approved therapies in B-cell leukemias and lymphomas. Getting into solid tumors has been more problematic… I’m looking forward to learning more about what being done across some of those platforms.

You’re involved in a clinical trial on Tay-Sachs disease. Will there be new results in that area? 

FLOTTE: [Tay-Sachs] is one of the classic genetic diseases and a hard target. When you look across the field of gene therapy, you can see certain targets where it was very logical to approach them earlier because the targets were more accessible. Examples include Luxturna targeting the retina and various hemophilia products that are now approved in Europe and the United States.

Tay-Sachs is a difficult disease because it starts so early and it’s global across the scope of the nervous system. We have been pushing hard at deep brain injection into the thalamus on each side. Dose escalation has shown some interesting dose-response information. It will take many iterations to get to something that can really change the course of history of that particular disease. I continue to get emails from families who have other even rarer diseases. Pushing on these harder to reach targets is very important to give those families and patients hope for the future.

Are you concerned about the high prices that pharma companies are asking for newly approved gene therapy drugs, or is that fair reward for the time and expense of leading the research and trials? 

FLOTTE: The model in which there is substantial reward for those who invest in the development of novel therapies has worked from the utilitarian aspect. I’m not trying to judge the fairness of it per se. [The model] has incentivized investment in the industry. Everything that involves equity markets has had some downturns lately. That risk-reward ratio has to be factored into all of this. I have no doubt that over time, the unit prices of some of these expensive therapies are going to come down.

At this time, I have to believe that [the current pricing] is functioning to the benefit of those who need completely different therapies to get their disease treated. It’s working to get people who have resources to put those resources toward very difficult problems. It’s probably better for society to invest a lot of money in some breakthrough technologies that later on could have a more affordable price point. We spend a lot of money on a lot of things and people make money on a lot of crazy things. At least this is doing good for some people.

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