Gene therapies must develop faster
WASHINGTON, DC — Former Director of the National Institutes of Health (NIH) in the USA and currently President Biden’s acting scientific advisor, Francis Collins, MD, PhD, recently told a packed house at the American Society of Gene and Cell Therapy (ASGCT) annual conference “my heart is in what you are all doing here at this meeting.”
Collins had made the quick trip across town from the White House to accept the ASGCT’s inaugural Founder’s Award. He was praised by society president Beverly Davidson, PhD, not only for his service as NIH director (stepping down at the end of 2021) but also for his stewardship of the Human Genome Project (HGP), without which many gene therapy programs would be years behind their current schedule.
Collins began by paying tribute to the 2,400 scientists in six countries who made the initial draft of the human genome sequence possible in 2003. But that was only a draft. “It’s only in the last couple of months that the full sequence has been accomplished,” he said, highlighting the recent work of the Telomere-to-Telomere consortium. The advent of long-read sequencing meant that the complete sequence of centromeres, telomeres, and the short arms of acrocentric chromosomes, had finally been assembled.
“We’ve celebrated the human genome a few times. This time it’s for real, people!”
The success of the HGP has enabled close to 7,000 human genetic disorders to be identified. But most of those rare diseases still lack treatment and are still waiting for their turn,” Collins said. And while human gene therapy had made great strides over the past two decades, many disorders “won’t be managed by an ex vivo* therapy approach.” (* Ex vivo gene therapy involves the genetic modification of cells outside of the body to produce therapeutic factors and their subsequent transplantation back into the body.)
“Many current gene therapies are produced as one-offs”, Collins said. “We need a transformative approach” so it’s less painful to take a good idea to the clinic and on to approval by the FDA.
Gene editing in the body
“Why in vivo? Why gene editing?” Collins asked rhetorically as he returned to his central theme. “There are thousands of rare diseases. I want to find something that’s scalable.”
As a natural example, Collins chose sickle-cell disease, which he worked on as a postdoc in the 1980s at Yale University. “At last, ‘the first molecular disease’ has a molecular therapy,” Collins said. Indeed, it has several: Lentiglobin, from the work of Collins’ NIH colleague John Tisdale, MD, and Bluebird bio, has shown a “remarkable benefit of clinical response,” with no patients experiencing any vaso-occlusive events following treatment. Other ex vivo approaches, including an oligonucleotide strategy led by David Williams, MD, (Boston Children’s Hospital) and CRISPR (Vertex Pharmaceuticals and CRISPR Therapeutics) are also working well.
But these successes highlight the need to produce in vivo delivery methods wherever possible. “In most diseases, it’s not feasible to take out tissue,” Collins said. You can’t do ex vivo therapy on the brain, for example. Moreover, current ex vivo approaches are complex, risky, and expensive.
Genome editing is not limited to just gene replacement or recessive diseases. (HGPS is a case in point, as it is caused by gain-of-function mutations.) Another goal is to deliver the therapeutic via a single infusion, which should limit the need for long-term therapy and reduce overall costs.
Delivery a real challenge
“Delivery is the real challenge! We need a post code system for human tissues,” Collins said, a method to deliver the gene-editing apparatus to the right cells safely and effectively.
The work essentially “cures SCD in a mouse model,” Collins said. And he could not resist noting that he led the discovery of that upstream globin variant as a postdoc way back in 1985, in work published in Nature. Along with unpublished data from Intellia, Collins said this approach is “not so pie in the sky as I’d have thought a couple of years ago.”
Clearly, ex vivo therapy for 100,000 SCD patients is out of the question, even before acknowledging that most of the patients are spread across Africa and India. “We have to come up with a strategy” to help these patients, Collins said.
In a collaboration with the Bill and Melinda Gates Foundation, NIH is mounting an effort for a one-shot SCD cure that could be administered in a low-resource setting. Ambitiously, Collins said his team thought, “let’s cure HIV at the same time.”
Collins concluded by thanking his audience while urging them to do more. “Of nearly 7,000 genetic disorders, only 500–600 have an FDA-approved therapy,” he said. The goal is to develop therapies for the thousands of disorders for which patients and their families are still waiting in vain.
SOURCE: Genetic Engineering News, May 18, 2022
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