Robin Alderman faces a sad truth: Gene therapy can cure her son Camden’s inherited immunodeficiency. But it is not available to him.
In 2022, London-based Orchard Therapeutics stopped investing in a diagnostic treatment for the condition, Wiskott-Aldrich syndrome. And no studies of gene therapy can join.
“We feel like we’re the ones being forgotten,” said Alderman, who has been advocating for her 21-year-old son since he was a child.
Altogether, about 350 million people worldwide suffer from rare diseases, many of which are genetic. But each of the 7,000 individual diseases affects perhaps a few in a million people or less. There is little commercial incentive to develop or bring to market these one-time cures to correct defective genes or replace them with healthy ones. This leaves families like Aldermans scrambling to find help and others trying to raise money themselves for treatment that may never come.
“These children have been twice unlucky: A, because they got a genetic disease, and B, because the disease is so rare that no one cares,” said Giulio Cossu, MD, professor of regenerative medicine at the University of Manchester in England. “Companies want to make a profit.”
Scientists say this power threatens to hinder progress in the nascent field of gene therapy, wiping out the potential for a new class of medicine as well as the steady flow of research leads toward promising treatments for a number of disorders. Researchers are looking for solutions, often turning to charities, patient groups, and governments.
A large Italian charity announced in February that it was taking over the Wiskott-Aldrich medical park that it had been monitoring. And the charity Foundation Fighting Blindness helped launch a company, Opus Genetics, to advance gene therapy work with University of Pennsylvania researcher Jean Bennett, MD, PhD, and a colleague.
In many ways, the effort was fueled by the patients’ families.
“Some of them have bake sales. One family mortgaged their house to raise money for research into their rare disease,” Bennett said. “I feel a responsibility to help them.”
Family Pain
Aldermans have faced years of pain and frustration.
Camden Alderman was diagnosed as a child with Wiskott-Aldrich, caused by a mutated gene on the X chromosome. It primarily affects boys — up to 10 in a million — and can cause frequent infections, eczema, and heavy bleeding.
When he was a small child, doctors removed his spleen because of heavy bleeding. As a young boy, he was hospitalized many times and was told he could not play baseball.
One treatment is a bone marrow transplant. But he is Black and of Korean descent, making it difficult to find donors — people are more likely to match someone of the same ancestry or ethnicity. Robin Alderman remembers one doctor saying: “Basically, your son’s only chance of a cure would be gene therapy.”
He also told his researchers at the time they weren’t accepting US residents into the clinical trial, which “broke my heart,” he said.
Today, Camden Alderman is a rising senior at North Carolina State Agricultural and Technical University. He takes penicillin daily and gives weekly immunoglobulin infusions under his skin, which help fight infection. Still, he has been to the hospital a few times in recent years and has developed kidney problems.
Although he doesn’t see gene therapy as a cure-all, he said, “it would help me live a simpler life.”
That proved to be true for patients undergoing investigational treatments, such as the 14-year-old son of Priya Stephen, MD, who participated in a clinical trial in Italy that accepted Americans at the time.
Although Stephen is grateful, he said, he can’t help but feel guilty that his family had an opportunity that others don’t: “It’s unacceptable to have a treatment that we know works, that we know is safe, that all of the people don’t have. All of a sudden it’s out of reach.”
For a while, it seemed that gene therapy for Wiskott-Aldrich was on the way to becoming more widely available. Genethon, a French non-profit research organization, funded promising clinical trials but lacked funding to continue development, CEO Frédéric Revah, PhD, said.
Drugmaker GlaxoSmithKline transferred another treatment to Orchard, which announced in 2019 that it had received designation from the FDA intended to expedite development and review. But Orchard halted investment in this and two other rare disease treatments a few years ago, with CEO Bobby Gaspar, MD, PhD, saying the company empathizes with the affected families and will look for other ways to advance the treatment.
“There are a large number of diseases that can benefit from gene therapy but there is no example of profit because the research investment is high, the production costs are high, and the number of patients is very small,” Revah said. .
Most genetic conditions are rare — each affecting at least 200,000 people in the United States at any given time. Research has not made it past the preliminary stages for most of them.
Lacey Henderson’s 5-year-old daughter, Estella, has childhood hemiplegia, a neurological condition that affects 300 people in the U.S. Estella is mentally retarded, has limited use of her hands and is temporarily paralyzed in part or all of her body, Henderson said. . Medicines can reduce the symptoms, but there is no cure.
His Iowa family is raising money through GoFundMe and a gene therapy website. They have brought in nearly $200,000.
“We have three different projects with different researchers,” Henderson said. “But the problem is that everything is underfunded.”
‘Misdirected’ incentives
Financial constraints plague the process, from drug discovery to development, scientists say.
The amount of work to get from the laboratory to human testing and through the drug approval process is “very expensive,” said Donald Kohn, MD, professor of biology, immunology, and molecular genetics at the University of California Los Angeles.
In the past few years, he said, gene therapy investment has dried up significantly.
“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 and safe treatments, but it’s financial and economic factors that prevent them from becoming approved drugs.”
Ultimately, many biotech companies are public and must focus on shareholder returns, said Francois Vigneault, PhD, CEO of Seattle Biotech Shape Therapeutics.
“The board is the thing that’s holding it back; they’re trying to maximize profits,” said Vigneault, whose company is privately held. “That’s just greed. That’s a misplaced incentive between the corporate structure and what we should be doing that’s good for the world.”
Even if the treatment reaches the market, it may not be available there. The same year Orchard stopped investing in Wiskott-Aldrich treatment, it also stopped distributing a drug called Strimvelis, approved in Europe to treat the rare disease adenosine deaminase deficiency, or “bubble boy syndrome.”
‘The Big Challenge’
Claire Booth, MBBS, PhD, professor of genetic therapy and pediatric immunology at University College London, is among those working for change. He founded Access to Gene Therapies for Rare Diseases, which brings together people across Europe representing academic groups, patient advocates, regulators, donors, and drug manufacturers. They hope to create an independent non-profit organization that can support market approval and access to treatments that are not commercially sustainable.
A related effort in the United States, The Bespoke Gene Therapy Consortium, was organized by the Foundation for the NIH and includes the FDA, various NIH institutes, and several pharmaceutical companies and non-profit organizations. The group’s goals include supporting limited clinical trials and exploring ways to streamline regulatory processes.
Other researchers are trying to address the problem scientifically. Anna Greka, MD, PhD, said the Broad Institute of MIT and Harvard has launched an effort to look at the common factors behind various conditions – or nodes, which can be compared to the branches that meet on the trunk of a tree. Fixing nodes with gene therapy or other treatments, rather than “mis-spellings” in the DNA responsible for a single disease, can address multiple diseases simultaneously.
“What this does is increase the number of patients who can benefit from the treatment,” said Greka, a Broad member. “It also makes it much easier or more attractive for anyone, like a herbal medicine company, to take the project forward and try to bring it to the clinic, because they will have a bigger market.”
Meanwhile, affected families are collaborating with scientists to help move the needle. Genethon was created by an association of patients and their relatives to develop treatments for several rare diseases. And the leader of the institution responsible for Opus Genetics has a child with a rare retinal disease.
There is also new hope for families dealing with Wiskott-Aldrich and bubble boy syndrome. Last year, the Telethon Foundation in Italy took over 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 guide its Wiskott-Aldrich gene therapy through the regulatory process there.
Still, scientists say these efforts do not ignore the enormous financial crisis surrounding the treatment of rare diseases, and it may be some time before such genetic therapies are available to patients worldwide.
“This is a big challenge, and I’m not at all sure we’re going to be able to overcome it,” Booth said. “But we have to let it because we’ve spent decades and millions developing these transformative treatments. And if we don’t try, then it feels like the end of an era.”
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