Robin Alderman faces a painful truth: Gene therapy can cure her son Camden’s rare, inherited immune deficiency. But this is not available to him.
London-based Orchard Therapeutics stopped investing in an experimental treatment for Wiskott-Aldrich syndrome in 2022. And there are no gene therapy studies for him to participate in.
“We feel like we’ve been forgotten,” said Alderman, who has been an advocate 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 disorders affects perhaps a few people per million or fewer. There is little commercial incentive to develop or bring to market these one-off treatments to fix faulty genes or replace them with healthy ones. This leaves families like Aldermen scrambling for help and some trying to raise money themselves for treatments that will never come.
Professor of regenerative medicine at the University of Manchester in England, Dr. “These children have a double misfortune: A, because they have a genetic disease, and B, because the disease is so rare that no one cares,” Giulio Cossu said. “Companies want to make a profit.”
Scientists say this dynamic threatens to hinder progress in the nascent field of gene therapy, erasing the potential of a new type of drug, just as a steady stream of research points to promising treatments for a variety of disorders. Researchers often look for solutions by turning to charities, patient groups and governments.
A major Italian charity announced in February that it was taking over the Wiskott-Aldrich treatment pursued by Orchard. And an arm of the philanthropic Foundation Fighting Blindness, University of Pennsylvania researcher Dr. He helped found a company called Opus Genetics to advance the gene therapy work of Jean Bennett and a colleague.
This effort was inspired in many ways by the patients’ families.
“Some of them sell baked goods. “One family mortgaged their house to give them some money for a study into their rare disease,” Bennett said. “I feel responsible for helping them.”
The pain of families
Council members have faced years of pain and disappointment.
Camden Alderman was diagnosed with a baby with Wiskott-Aldrich disease, caused by a mutated gene on the X chromosome. It primarily affects boys (up to 10 per 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 was hospitalized multiple times and was told he couldn’t play baseball.
One of the treatments is bone marrow transplant. But he is black and of Korean descent, which makes finding donors difficult; people are most likely to match with someone of similar ancestry or ethnicity. Robin Alderman recalls one doctor saying: “Your son’s only chance for a cure will actually be gene therapy.”
He also said his researchers did not accept U.S. residents into a clinical trial, which “kind of broke my heart.”
Today, Camden Alderman is a rising senior at North Carolina Agricultural and Technical State University. He takes penicillin every day and receives weekly injections of immunoglobulin under his skin, which helps fight infection. Still, he was admitted to the hospital several times in recent years and developed problems with his kidneys.
While he doesn’t see gene therapy as a cure-all, he said “it would just help me have an easier life.”
This led to Dr. D., who was participating in a clinical trial in Italy, which was accepting Americans at the time. It was also true for patients undergoing experimental therapy, like Priya Stephen’s 14-year-old son.
While Stephen was grateful, he said he couldn’t help feeling guilty that his family had an opportunity others didn’t: “It’s ethically unacceptable to have a treatment that we know works, we know is safe, and people are all working together.” Suddenly I can’t access it.”
For a time, it appeared that Wiskott-Aldrich gene therapy was on the path to wider availability. Genethon, a French nonprofit research organization, sponsors promising clinical trials but lacks funding to continue development, CEO Frédéric Revah said.
Drugmaker GlaxoSmithKline has turned over another treatment to Orchard, announcing in 2019 that it had received a designation from the U.S. Food and Drug Administration to speed up development and review. But Orchard stopped investing in this and two other rare disease treatments a few years ago; CEO Dr. Bobby Gaspar said the company sympathizes with the affected families and will look for other ways to advance treatments.
“There are many diseases that could benefit from gene therapy, but there is no profitability model because the research investment is high, the production cost is high, and the number of patients is very low,” Revah said.
Most genetic conditions are rare; each affects fewer than 200,000 people in the United States at any given time. For most of the research, it did not advance past the early stages.
Lacey Henderson’s 5-year-old daughter, Estella, has childhood alternating hemiplegia, a neurological condition that affects 300 people in the United States. Estella is cognitively delayed, has limited use of her hands, and part or all of her body is temporarily paralyzed. said Henderson. Medications may reduce symptoms but there is no cure.
The Iowa family is fundraising through GoFundMe and a website to develop a gene therapy. They brought in about $200,000.
“We have three different projects with various researchers,” Henderson said. “But the problem is that everything is underfunded.”
‘Misaligned’ incentives
Financial disincentives negatively impact the process from drug discovery to development, scientists say.
Professor of microbiology, immunology and molecular genetics at the University of California, Los Angeles. Donald Kohn said the amount of work to be done, from the laboratory to human testing to the drug approval process, is “incredibly expensive.”
Gene therapy investment has largely dried up in the past few years, he said.
“If you have to spend $20 million or $30 million to get approval and you have five or 10 patients a year, it’s hard to get a return on investment,” Kohn said. “So we have successful, safe treatments, but it’s more the financial and economic factors that limit them from becoming approved drugs.”
After all, most biotech companies go public and must focus on shareholder profit, said Francois Vigneault, CEO of Seattle biotech Shape Therapeutics.
“Wood is what gets in our way; they’re trying to maximize revenue,” said Vigneault, whose company is privately held. “This is just greed. “This is nothing more than an incentive to create a mismatch between the corporate structure and what we should be doing that is good for the world.”
Even when treatments are introduced, they may not stay there. That same year, Orchard stopped investing in the Wiskott-Aldrich treatment and also stopped distributing Strimvelis, a drug approved in Europe to treat the rare disease ADA-SCID, or “balloon boy syndrome.”
‘A big challenge’
Claire Booth, professor of gene therapy and pediatric immunology at University College London, is among those working for change. She co-founded Access to Gene Therapies for Rare Diseases, which brings together people from across Europe representing academic groups, patient advocates, regulators, funders and drug manufacturers. They hope to create an independent, non-profit organization that can support market empowerment and access to therapies that are not commercially sustainable.
A related study in the US, the Bespoke Gene Therapy Consortium, was organized by the National Institutes of Health Foundation and involves the FDA, several NIH institutes, and several pharmaceutical companies and non-profit organizations. The group’s goals include supporting a handful of clinical trials and exploring ways to streamline regulatory processes.
Some researchers are trying to solve the problem scientifically. Dr. Anna Greka said the Broad Institute of MIT and Harvard has launched an effort to look at the commonalities behind various conditions, or knots that can be likened to branches meeting on a tree trunk. Rather than specific “mistypes” in DNA being responsible for a single disorder, correcting the tangles with gene therapies or other treatments could address multiple diseases at once.
“What this does is it increases the number of patients who can benefit from therapy,” Broad member Greka said. “It also makes it much easier or more attractive for anyone, like a biopharmaceutical company, to take the project forward and bring it into the clinic because they will have a larger market.”
In the meantime, affected families are collaborating with each other and scientists to help move the needle. Genethon was created by an association of patients and their relatives to improve the treatment of many rare diseases. And the leader of the foundation involved in Opus Genetics has a child with a rare genetic retinal disease.
There’s also new hope for Wiskott-Aldrich and families dealing with bubble 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 pilot program by the European Medicines Agency that could help guide Wiskott-Aldrich gene therapy through the regulatory process there.
Still, scientists say these efforts do not eliminate the larger financial dilemma surrounding treatments for rare diseases, and it may be some time before such genetic treatments are available to patients worldwide.
“This is a huge challenge, and I’m not entirely sure we can overcome it,” Booth said. “But we should give this a chance because we have spent decades and millions of years trying to achieve these transformative treatments. And if we don’t try, then it feels like the end of an era.”
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