Robin Alderman faces a painful reality: gene therapy could cure her son Camden’s rare hereditary immune deficiency. But it’s not for him.
In 2022, London-based Orchard Therapeutics stopped investing in an experimental treatment for the condition, Wiskott-Aldrich syndrome. And there are no gene therapy studies he can participate in.
“We feel like we’ve been forgotten,” said Councilwoman, who has been advocating for her 21-year-old son since he was a baby.
Collectively, approximately 350 million people worldwide suffer from rare diseases, most of which are genetic. But each of the 7,000 individual conditions may affect a few in a million people or fewer. There is little commercial incentive to develop or commercialize these one-off therapies to repair defective genes or replace them with healthy ones. This leaves families like the councilors looking for help and some trying to raise money themselves for cures that may never come.
“These children have been unlucky twice: A, because they have a genetic disease, and B, because the disease is so rare that no one cares,” says Dr Giulio Cossu, professor of regenerative medicine at the University of Manchester in England. “Companies want to make a profit.”
Scientists say this dynamic threatens to thwart progress in emerging gene therapy, erasing the potential of a new type of drug just as a steady stream of research points toward promising treatments for various conditions. Researchers look for solutions and often turn to charities, patient groups and governments.
A major Italian charity announced in February that it was adopting the Wiskott-Aldrich treatment that Orchard was pursuing. And a division of the charity Fighting Blindness helped found a company, Opus Genetics, to support the gene therapy work of researcher Dr. Jean Bennett of the University of Pennsylvania and a colleague.
In many ways, that effort was inspired by patients’ families.
“Some of them have bake sales. One family mortgaged their home to give some money for research into their rare disease,” said Bennett. “I just feel responsible to help them.”
The pain of families
The councilors have experienced years of pain and frustration.
Camden Alderman was diagnosed as an infant with Wiskott-Aldrich, caused by a mutated gene on the X chromosome. It mainly affects boys – up to 10 in a million – and can cause frequent infections, eczema and excessive bleeding.
When he was a toddler, doctors removed his spleen due to uncontrolled bleeding. As a young boy, he often ended up in the hospital and was told he couldn’t play baseball.
One treatment is a bone marrow transplant. But he is black and of Korean descent, making it difficult to find a donor; people are most likely to match with someone of a similar ancestral or ethnic background. Robin Alderman remembers one doctor saying, “Basically the only chance of a cure for your son is gene therapy.”
He also told her researchers that they were not accepting U.S. residents for a clinical trial at the time, which “broke my heart,” she said.
Today, Camden Alderman is a rising senior at North Carolina Agricultural and Technical State University. He takes penicillin daily and gives himself weekly immunoglobulin infusions under his skin, which help fight infections. Yet he has ended up in the hospital a few times in recent years and has developed a kidney problem.
While he doesn’t see gene therapy as a panacea, he said, “It would only help me live an easier life.”
That turned out to be true for patients who underwent the experimental therapy, like Dr.’s 14-year-old son. Priya Stephen, who participated in a clinical trial in Italy that was accepting Americans at the time.
Although Stephen is grateful, she says, she still feels guilty that her family has been given an opportunity that others don’t: “It’s just not ethically acceptable to get a treatment that we know works, that we know that it is safe, and all of those people suddenly don’t have access to it.”
For a while, it seemed that gene therapy for Wiskott-Aldrich was on track for wider availability. Genethon, a French nonprofit research organization, sponsored promising clinical trials but had no funding to continue development, said CEO Frédéric Revah.
Drugmaker GlaxoSmithKline has transferred another therapy to Orchard, which announced in 2019 that it had received a designation from the U.S. Food and Drug Administration intended to accelerate development and review. But Orchard stopped investing in this and two other treatments for rare diseases a few years ago, with CEO Dr. Bobby Gaspar said the company sympathized with the affected families and would look for other ways to advance the therapies.
“There are a large number of diseases that could benefit from gene therapy, but for which there is no profitability model because investment in research is high, production costs are high and the number of patients is very low,” Revah said.
Most genetic conditions are rare, affecting fewer than 200,000 people in the US at any time. For many of them, the investigation has not yet progressed past the early stages.
Lacey Henderson’s daughter, 5-year-old Estella, has childhood alternating hemiplegia, a neurological condition that affects 300 people in the US. Estella has a cognitive delay, has limited use of her hands and is temporarily completely or partially paralyzed. said Henderson. Medicines can curb the symptoms, but there is no cure.
Her Iowa family is raising money through GoFundMe and a website to develop a gene therapy. They raised about $200,000.
“We have three different projects with different researchers,” said Henderson. “But the problem is that everything is underfunded.”
‘Unaligned’ stimuli
Financial barriers are hampering the process from drug discovery to development, scientists say.
The amount of work that goes from a laboratory to human testing and through the drug approval process is “incredibly expensive,” says Dr. Donald Kohn, professor of microbiology, immunology and molecular genetics at the University of California, Los Angeles.
According to him, investments in gene therapy have largely dried up in recent years.
“If you have to spend $20 or $30 million to get approval and you have five or 10 patients a year, it’s hard to get a return on your investment,” Kohn says. “So we have successful, safe therapies, but it’s more the financial and economic elements that keep them from becoming approved drugs.”
Ultimately, most biotech companies will go public and have to focus on shareholder returns, says Francois Vigneault, CEO of Seattle biotech Shape Therapeutics.
“The board is the thing that gets in the way; they are trying to maximize profits,” said Vigneault, whose company is privately held. “That’s just greed. That’s just an incentive that is not well aligned with the corporate structure and what we should be doing that is good for the world.”
Even if treatments hit the market, they may not stay there. The same year that Orchard stopped investing in the Wiskott-Aldrich treatment, it also stopped distributing a drug called Strimvelis, which was approved in Europe to treat the rare disease ADA-SCID, or “bubble boy” syndrome’.
‘Huge challenge’
Claire Booth, professor of gene therapy and pediatric immunology at University College London, is among those pushing for change. She co-founded Access to Gene Therapies for Rare Disease, which brings together people from across Europe representing academic groups, patient advocates, regulators, funders and drug manufacturers. They hope to establish an independent nonprofit organization that can support market authorization and access to therapies that are not commercially sustainable.
A related initiative in the US, the Bespoke Gene Therapy Consortium, was organized by the Foundation for the National Institutes of Health and includes the FDA, several NIH institutes, and several pharmaceutical companies and nonprofits. The group’s goals include supporting a handful of clinical trials and exploring ways to streamline regulatory processes.
Some researchers are trying to tackle the problem scientifically. Dr. Anna Greka said the Broad Institute of MIT and Harvard have launched an effort to look for similarities behind different conditions – or nodes, which can be likened to branches coming together in a tree trunk. Repairing the junctions with gene therapies or other treatments, rather than certain DNA ‘mistakes’ responsible for one condition, could tackle multiple diseases at once.
“What this does is increase the number of patients who can benefit from the therapy,” said Greka, a member of Broad. “It also makes it infinitely easier or more attractive for anyone, like a biopharmaceutical company, to pursue the project and try to take it to the clinic because they’ll have a bigger market.”
In the meantime, affected families are working together with each other and scientists to help move the needle. Genethon was founded by an association of patients and their relatives to develop treatments for various rare diseases. And a foundation leader involved with Opus Genetics has a child with a rare genetic retinal disease.
There is also new hope for families dealing with Wiskott-Aldrich and bubble boy disease. Last year, the Telethon Foundation in Italy took over responsibility for the production and distribution of Strimvelis. This year, the charity announced it had been selected for a European Medicines Agency pilot program that could help its Wiskott-Aldrich gene therapy through the regulatory process there.
Still, scientists say these efforts do not negate the larger financial dilemma surrounding therapies for rare diseases, and that it may still be a while before such genetic treatments are available to patients around the world.
“This is a huge challenge, and I’m not entirely sure we can overcome it,” Booth said. “But we have to try, because we’ve spent decades and millions creating these transformative treatments. And if we don’t try, it will feel like the end of an era.”
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