Gene therapy stalled in the early 2000s as adverse effects came to light in European trials (leukemias triggered by the gene delivery vector) and following the 1999 death of U.S. patient Jesse Gelsinger. But after 30 years of development, and with the advent of safer vectors, gene therapy is becoming a clinical reality. It falls into two main categories:

In vivo: Direct injection of the gene therapy vector, carrying the desired gene, into the bloodstream or target organ.

Direct injection of the gene therapy vector, carrying the desired gene, into the bloodstream or target organ. Ex vivo: Removal of a patient’s cells, treating the cells with gene therapy, and reinfusing them back into the patient, as in hematopoietic stem cell transplant and CAR T-cell therapy.

A recent panel at Boston Children’s Hospital, hosted by the hospital’s Technology and Innovation Development Office (TIDO), explored where gene therapy is and where it’s going. Here were the key takeaways:

1. Gene therapy is “hot.”

Gene therapy has sparked great interest because it offers the possibility of a permanent cure. It’s of high interest in the rare disease community in particular, for single-gene diseases such as sickle-cell disease, severe combined immune deficiency (SCID, a.k.a. “bubble boy” disease), adrenoleukodystrophy and other metabolic diseases, hemophilia and genetic forms of progressive blindness and deafness. Philip Reilly, MD, JD, of Third Rock Ventures, has been approached by several families asking if they can start their own gene therapy company.

2. The diseases are many, the regulatory paths complex.

There are as many as 7,000 rare diseases, and gene therapy for each would have to go through a different regulatory process. In the rare disease space, populations are often very small, making it hard to put a trial together. And because the diseases are rare, their natural history is often unknown, making it harder to establish a benefit for gene therapy.

Philip Gregory, DPhil, chief scientific officer of bluebird bio, also notes the difficulty of standardizing trial processes to regulators’ satisfaction when patients are few and far between. “For situations where there are maybe 10 or 15 patients a year, that’s a real challenge,” he said. “It’s our obligation to figure out how to have this conversation with the regulators.”

But there are sometimes work-arounds. Reilly noted that for adrenoleukodystrophy, bluebird bio funded a natural history study that was a retrospective review of 300 charts of mostly deceased patients. The study convinced the FDA that “we did not really have to do a placebo-controlled trial, because these are kids who are dying.” There was clearly an urgent unmet medical need in this disease.

Also helpful is that both the FDA and the European Medicines Agency now have accelerated approval mechanisms that allow a rolling assessment of patients, so scientists don’t necessarily have to enroll and complete a full trial if things are going well.

3. The bench-to-bedside translation process is slow.

There’s no single process: Each disease has its own biological pathway and its own research path to gene therapy. Navigating this takes time and resources.

“The NIH doesn’t have a funding mechanism that goes from proof-of-concept to GMP manufacturing,” noted David Williams, MD, chief scientific officer at Boston Children’s, president of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and founder of the Center’s gene therapy program. (He is also founder of Alerion Biosciences and scientific advisor for Orchard Therapeutics.) “You end up having to do up to four separate grants to obtain adequate funding to get to a clinical human trial. This is why institutional support is critical, as has been the case in our program with funding from the Department of Medicine in particular.”

And even when a vector has been shown safe, regulatory agencies currently require separate safety studies for each new gene therapy treatment with that vector. In these early days of gene therapy, and given past history, such caution is probably justifiable.

“It’s a medicine,” says Williams, who was involved in redesigning vectors after the early leukemia cases. “But unlike any medicine we’ve used before, in that you’re changing a person’s genome.”

But as experience with gene and cell therapy grows, it may be possible to scale back on safety testing, especially when the condition is life-threatening. “I think there will be an argument for a limited safety assessment of what you changed,” said Gregory.

Williams agreed: “The U.K. allows ‘N of 1’ human testing to precede formal clinical trials.”

4. Gene and cell therapy face technical challenges.

The challenges include:

Giving a therapeutic dose

Delivering the gene to the right tissues and cells

Ensuring proper expression of the introduced genes — enough but not too much

Ensuring long-term effects

Product manufacturing challenges

Determining when best to intervene (some advocate for prenatal screening and fetal therapy).

5. Pricing could be a barrier for gene therapy.

Even though gene therapy can potentially cure a disease in a single dose, its price could well run in the hundreds of thousands of dollars. Some people have proposed spreading the payments over time.

For disorders like sickle-cell disease or cystic fibrosis, where the lifetime costs of care are very high, gene therapy could be a bargain and may be embraced by payers, especially when children are involved. “I believe that gene therapy in children that makes a dramatic change in their future is not sensitive to price controls at this time,” said Reilly. “The issue I see is pressure on Medicaid budgets at the state level.”

“It has to be a transformational therapy,” said Gregory. “These are not cheap medicines to generate.”

The bottom line

All the panelists felt that the potential of gene therapy is tremendous, but that more science is critical.

“It’s a wonderful time to be in the field,” said Williams. “I think we all recognize the challenges, but we can look forward to an increase in the number of diseases that are addressed by gene therapy technology.”

More about gene therapy trials at Dana-Farber/Boston Children’s.