Fear Replaced by Understanding, Optimism, and Miracles: Part I

For decades, cell and gene therapies (CGT) seemed elusive, relegated to the world of science fiction. In the 1970s, in fact, TIME magazine featured a cover story titled, “The DNA Furor: Tinkering With Life,” which heightened public fears over the nascent field of genetic engineering, human gene transfer, and the creation of virulent microorganisms.

In 1975, these concerns culminated in the Asilomar Conference on Recombinant DNA, discussing the potential biohazards and regulation of biotechnology. The first-of-its-kind conference marked the beginning of an extraordinary era for science and for public discussion of science policy. It’s also where researchers proposed an oversight framework that later became NIH Guidelines for oversight of research involving genetic engineering, gene therapy, and gene editing.

With new regulatory foundations, CGT work persisted, but not without some highly publicized setbacks in the late 1990s and early 2000s, including the French SCID trial where pediatric subjects developed leukemia, and the death of Jesse Gelsinger. Since the turn of the century, however, much progress has been made in developing safety features for gene transfer technology. The FDA, for instance, has established guidance documents for CGT research. Advancements in biotechnology, an emphasis on translational medicine, and increased investment have also helped lay the groundwork for a CGT clinical trials boom. 

In March 2023, the Journal of Gene Medicine had entries for 3,900 CGT clinical trials in 46 countries. Most trials focused on cancer (68.3 percent) or inherited monogenic diseases (13.1 percent), with the US leading the world in the most trials undertaken: 2,054 (52.7 percent). As of September 2024, the FDA has approved 38 cell and gene therapies versus seven in 2023. But it’s not nearly enough, given the life-changing potential in these curative therapies for the 7,000 rare diseases without treatment.

“It would be a shame if all we manage to do is approve another two or three gene therapies a year – that’s a failure,” said Peter Marks, Director, FDA Center for Biologics Evaluation and Research (CBER) in a 2023 Biospace interview. “Success would be that we start to watch what should be, if not exponential, at least some logarithmic progression toward more and more gene therapies being approved.” 

Great promise, greater hope
 

In 2015, Investigational New Drug (IND) applications for gene therapies sharply increased with the first FDA approval for a gene therapy, a genetically engineered herpesvirus intended to treat melanoma. In 2017, came the first two approvals for chimeric antigen receptor (CAR) T cells, a type of gene-modified cellular therapy. CAR-T cells start as white blood cells typically obtained from the patient and genetically reprogrammed to target and kill the patient’s cancer. This approach has been successful in B cell leukemias and lymphomas where previously refractory or resistant cases are now seeing overall response rates as high as 90-pus percent. 

Researchers pushed this approach forward to B cell-mediated autoimmunity to treat conditions such as lupus, where the aim is to suppress the abnormal immune activity causing disease symptoms. Researchers at UC Davis Health were able to eliminate or reduce lupus symptoms with a single infusion of CAR-T cells with no relapses among the study’s patients after two years of monitoring.

“CAR-T cell therapy paved the way for success in oncology, and now technologies like gene replacement therapy, gene editing, and RNA editing hold tremendous promise as a treatment or cure in many rare diseases where there is significant unmet need,” said Meagan Vaughn, associate clinical director at Krystal Biotech. Krystal is a gene therapy biotechnology company focused on developing and delivering medicines to patients with genetic life-threatening or rare diseases. The company’s Vyjuvek is the first and only re-doseable gene therapy for the treatment of dystrophic epidermolysis bullosa. 

“Right now, our focus is on re-doseable gene therapy using a viral vector to deliver the therapeutic gene. We are working towards this as a treatment for Cystic Fibrosis, for patients who do not have any other treatment options,” added Vaughn. Gene therapies typically involve a viral vector, a genetically engineered virus used as a delivery vehicle for a potentially therapeutic gene.

When it comes to rare diseases, CGT offers hope to those who feel the most hopeless, such as the family of Evelyn Villarreal. She was born with spinal muscular atrophy (SMA) – a recessive disease that gradually paralyzes and kills children by the time they are about two years old. Tragically, the Villarreals already had one daughter die of the same disease at 15 months. So, the parents quickly enrolled Evelyn in a clinical trial for an investigational, one-time gene therapy when she was just eight weeks old. 

Not long after, doctors saw progress. Evelyn was the first baby in the clinical trial who was able to roll over – a big breakthrough. “Our neurologist just cried,” recalled Evelyn’s mother, Elena, whilst speaking with the CDC. “As Evelyn progressed, she was the first one to walk. It brought so much hope.” Now, Evelyn goes to school, enjoys science and art, writes stories, swims, and flies kites. Miraculously, Evelyn has beaten the odds and grown into a flourishing ten-year-old – a marvel never before possible in SMA1 patients – as documented in Science.

Overall, the disease areas seeing the greatest success and FDA approvals from novel CGT science are oncology (10 approvals), infectious disease vaccines (8 approvals), and rare diseases (11 approvals). As science evolves, the life sciences industry will likely start to categorize cell and gene therapies not according to disease area but, rather, according to technology. Recharacterizing CGT based on its science can open doors to eventually treating a wider range of diseases.

Look out for part 2 where Daniel Eisenmann delves into the clinical trial initiation process and how modern technologies, such as decentralized approaches and AI, can help accelerate research in cell and gene therapies.