Like the mythological phoenix bird, gene therapy has risen from the ashes and is spreading its wings.
September 17 marked 20 years since the death of 19-year-old Jesse Gelsinger in a gene therapy trial. That tragedy halted the fledgling field, with the outlook worsening when, soon after, boys with an inherited immune deficiency developed leukemia when a gene therapy went off course. The momentum that had been slowly building since the first clinical trial in 1990 fizzled.
A Slow Comeback
Researchers rebuilt the viruses that ferry in working copies of genes, and gradually clinical trials resumed. But it took until late 2017 for the first FDA approval of a gene therapy: Luxturna, for blindness due to mutation of a gene called RPE65.
My book The Forever Fix: Gene Therapy and the Boy Who Saved It, from 2012, chronicles the history of the field as a backdrop to the Luxturna story. The “boy,” Corey Haas, was 8 when he was treated in 2008. He’s made amazing progress.
Seven years later, Amy Reif reports that her daughter, who was treated in July 2018 when she was 7, can see in a dimly-lit room where previously she couldn’t see at all. “She can stay outside to play in the evening at dusk much longer than she could prior to Luxturna. She can see a rainbow, stars, lightning bugs. She overall just gets around more easily, shows more confidence, and is more sure of herself.”
The second and most recent gene therapy approval, Zolgensma, is for spinal muscular atrophy, treats a condition that is typically lethal in infancy. FDA approved it in May 2019, after Novartis picked it up from biotech company AveXis, which commercialized research from Nationwide Children’s Hospital. Academia to small biotech to big pharma is a common trajectory in drug development.
SMA’s gene therapy approval comes three years after approval of a different biotech approach, antisense oligonucleotides, that reawakens a normally-silenced copy of the mutant gene. (See “Two New Ways to Treat a Deadly Disease: Spinal Muscular Atrophy.”)
The sacrifices of Jesse Gelsinger and others who have participated in clinical trials have made recent advances possible. Classic gene therapy adds working genes aboard viral vectors; gene editing more precisely fixes a mutation.
The vectors have evolved, getting away from the adenovirus implicated in Jesse’s death and retooling the retroviruses that harpooned the oncogene, causing leukemia. Dozens of companies and most clinical trials today use the much safer adeno-associated viruses (AAVs), detailed in this DNA Science post.
I consulted clinicaltrials.gov to see which diseases gene therapy is addressing, but instead of using a fancy algorithm to analyze the data, I just made a list. Although the website is a great source of info, anyone can register anything. And, like email that hasn’t been curated in ages, clinicaltrials.gov includes many studies that ended years ago. You have to pay attention to discern what’s relevant.
Searching clinicaltrials.gov for “gene therapy” under “conditions or disease” led to 564 entries, but under “other terms” had 4,080 hits. That’s about twice what the list was last time I looked (I think about a year ago), but it includes many cancer trials. When I think of gene therapy, I envision the single-gene (Mendelian) diseases, which are rare.
Trends, Tips, and Treatments in Gene Therapy Clinical Trials
Danon disease weakens the heart and skeletal muscles. Treatment is a single intravenous infusion of a gene, LAMP2b, aboard an AAV vector, from Rocket Pharmaceuticals. Danon disease is on the X chromosome and so affects males.
3. Clinical trials not only help patients, they teach researchers. One listing for a gene therapy for choroideremia, a form of blindness, cites an article in which Janet Davis, of the Bascom Palmer Eye Institute at the University of Miami, describes how to gently place the loaded viruses under the retina without harming nearby structures, while keeping track of the AAV dose. It’s useful advice to treat several types of retinal diseases.
4. Preclinical research continues to shape the protocols that move into clinical trials. In 2018, James Wilson, the person held responsible for Jesse Gelsinger’s death, discovered that high doses of AAV could harm, and kill, monkeys (see “A Hiccup In Gene Therapy Progress?). He raised the concern that muscle diseases may require dangerously high doses to treat so much of the body. Wilson’s company, Passage Bio, is developing treatment for single-gene conditions of the central nervous system.
5. Cost continues to be a concern. A gene therapy approved in Europe came off the market due to a tiny patient population and a price tag in excess of $1 million (see “Pulling the Plug on the First Gene Therapy Drug”). For the eye gene therapy Luxturna, which costs $850,000, as of June 30 insurance had paid for all 137 eyes treated, with Spark Therapeutics covering co-pays and travel costs. But the SMA gene therapy Zolgensma, at $2.1 million, is evoking pushback. The flip side is comparing the costs of a “one-and-done” treatment to the alternatives: a lifetime of tests and therapies, a disability, a chronic illness, or even early death. Doing the math must consider costs replaced. Consider hemophilia B. Conventional treatment runs about $270,000 a year, and to more than $1 million with complications. A one-time, or even once-a-decade, gene therapy would save in the long run.
6. Which gene therapies will make it to market next? My posts have followed a few contenders.
I’m thrilled to see gene therapy moving forward. But a caveat: These are the families and stories I’ve been writing about for years – I’m sure I’ve left many out. Please contact me about other gene therapy success stories.
Source: PLOS EveryONE