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
- The list of clinical trials still includes the “usual suspects,” diseases that gene therapy has been tackling for years. The overrepresentation of immune deficiencies is because they’re amenable to an “ex vivo” approach: modifying a patient’s cells outside of the body and then infusing them. Here are a few:
- ADA (adenosine deaminase) deficiency, an immune deficiency that started the field in 1990.
- SCID X1 (severe combined immune deficiency X1)
- XCG (X-linked chronic granulomatous disease); 5 children received gene therapy in December 2018 in Germany
- AAT (alpha anti-trypsin) deficiency, a form of inherited emphysema
- hemophilia A, in the US and the UK and hemophilia B
- Some newer approaches and conditions (filed in 2019) to appear in the gene therapy roster are:
- A form of Batten disease, CLN1 (infantile neuronal ceroid lipofuscinosis). The thumbs-up to start a clinical trial came in May. Efforts of the family of Taylor King, who died a year ago at age 20, as well as those of AAV guru Steve Gray, at UT Southwestern, lie behind the clinical trial about to begin, which Abeona Therapeutics is sponsoring. In “Run to the Light,” Taylor’s sister Laura King Edwards tells their story.
- Fabry disease, in which a fatty sugar builds up in tiny blood vessels, causes heart and kidney failure and other symptoms. A single intravenous dose of AAV provides the gene that encodes the missing enzyme (alpha-galactosidase A). Sangamo Therapeutics is sponsoring the trial.
- People with Alzheimer’s disease who have two copies of a mutation in the ApoE4 gene. Participants have evidence of amyloid buildup and have mild cognitive impairment to full-blown dementia. The treatment is actually the gene encoding ApoE2, introduced directly into the brain, at Weill Medical College. The strategy: one type of apolipoprotein will be processed in a way that ups amounts of the deficient type.
- 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.
- The parents of Hannah Sames and Eliza O’Neill, treated in 2016 for giant axonal neuropathy and Sanfilippo syndrome type A, respectively, aren’t permitted to say much as they observe their children’s progress. It will take years to tell if and to what degree the gene therapy is slowing the courses of their neurological diseases. (Eliza’s mom, Cara Parsons O’Neill, MD, just won the WorldSymposium 2020 award, which represents families with lysosomal storage diseases.)
- After gene therapy, boys with myotubular myopathy (MTM), who would otherwise have been motionless and dependent on a ventilator, can move and breathe on their own. Time will tell if the effects persist. Audentes Therapeutics developed the gene therapy, which I chronicled here. Like the first approved gene therapy, Luxturna, the MTM gene therapy story began with a natural mutation in dogs.
- Kids given gene therapy for metachromatic leukodystrophy are doing well, in a heart-wrenching situation. The clinical trials, in Europe, treated younger siblings who weren’t yet affected, of children who had or would soon die from the disease. The older kids made it possible to diagnose the younger ones at an age when treatment would help. I told their story here.
- Gene therapy is helping the “butterfly children,” who have recessive epidermolysis bullosa (RDEB), so-called because of the fragility of a patient’s skin due to mutation in a collagen gene. The slightest touch evokes painful blisters and peeling skin and daily bandage changes are agonizing. With the gene therapy, developed at Abeona Therapeutics, wounds healed in patients over age 18 in a clinical trial.
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.