Gene Therapy Breakthroughs: Hope and Hurdles for Rare Disease Patients

Gene therapies are already saving lives, but many patients continue to wait for treatment. The root of the problem lies in a system that struggles to address rare diseases effectively.

Last spring, a biotechnology company announced it had, for the first time, utilized a novel gene-editing technology to correct a faulty gene causing a severe immune disorder in a human. In June, an infant born with a life-threatening metabolic disorder was discharged from the hospital after a six-month effort by scientists who developed a customized treatment. Increasingly, “Bubble Babies,” born without functioning immune systems, are approaching their teenage years following a one-time experimental gene therapy administered in early childhood.

Therapies that tackle genetic diseases at their source are no longer a distant prospect; they are here, and more are on the horizon. However, despite a growing number of gene therapy tools changing the lives of individual patients, many remain in a medical limbo because they don’t fit the existing model for translating breakthroughs into accessible treatments.

Gene Therapy Restores Immune Systems in Children

Donald Kohn, a pediatrician specializing in bone marrow transplantation at the University of California in Los Angeles, has successfully restored the immune systems of children with gene therapy in the clinic for over a decade, though it remains unlicensed as a medication. “There are several dozen rare diseases in a similar situation, where there’s a therapy that looks promising in academic clinical studies, but it’s very difficult to get to the point of getting a drug approved,” Kohn stated.

The potential public health impact, while seemingly small individually, is enormous. Worldwide, an estimated 300 million people are affected by rare diseases, approximately 70 percent of which have a genetic basis.

Life-Saving Remedies That “Come and Go”

Typically, drug development is a relay race. Academic labs, often supported by federal funding, conduct early foundational research. Companies then take the next step, translating these findings into medications. While scientists now have an expanding arsenal of gene therapy technologies to combat potentially thousands of diseases, finding someone to take the baton can be difficult when a single therapy might only help a handful of patients – or even just one.

This uncertainty has prompted scientists to experiment with new business models and more efficient methods for testing new therapies to fill a market gap. They are founding biotech companies not focused on maximizing profit, launching non-profit organizations, and developing new types of clinical trials. Even the Trump administration intervened, with the Food and Drug Administration outlining a pathway in November to bring certain treatments for rare diseases with a clear biological cause to market.

“Unfortunately, the FDA has heard from patients, parents, researchers, clinicians, and developers that the current regulations are burdensome and unnecessarily complex, do not provide clear patient protection, and stifle innovation. We share that view,” FDA officials wrote in the New England Journal of Medicine. “Nearly 30 years after the sequencing of the human genome, personalized therapies are within reach.”

The story of Eliana Nachem exemplifies both the promise and the challenges. In 2014, Eliana’s parents learned their daughter had Adenosine Deaminase Deficiency-Severe Combined Immunodeficiency (ADA-SCID). Living near woods in Fredericksburg, Virginia, the Nachems were forced to limit exposure to even minor germs.

At 10 months old, Eliana received an experimental gene therapy, which proved successful. As her immune system rebuilt, her parents were allowed to kiss her and take her outside. By 18 months, the Nachems were pushing her in a shopping cart. A recent study in the New England Journal of Medicine, co-authored by Kohn, followed 62 children with ADA-SCID treated with a one-time gene therapy, including Eliana. Nearly all experienced full immune system recovery, sustained for an average of almost eight years. Eliana is now in the sixth grade. “She’s amazing. She’s artistic, she’s a force of nature. Nothing holds her back,” said Caroline Nachem.

However, the therapy stalled. Orchard Therapeutics initiated a plan to develop the therapy in 2016 but halted investment a few years later. Orchard returned the therapy to its academic inventors in 2022. Researchers in Kohn’s lab formed Rarity Public Benefit Corporation to advance the development into a medication. The bottleneck now isn’t proving efficacy, but another crucial part of the drug approval process – developing commercial manufacturing.

“I’ve seen the highs and lows of this therapy,” said Paul Ayoub, CEO of Rarity. “The therapies work, but they get stuck in this academic phase… We wanted to take it into our own hands – to carry the proven science all the way to the end.” Meanwhile, families wait. Maria Thianthong, of Los Angeles, is one of them. Her three-year-old daughter, Eliyah, has been on the waiting list for the therapy since birth.

Scientists are hopeful that simplified federal regulations will expedite the process. David Liu, a biochemist at the Broad Institute, recently demonstrated that a single therapy could treat multiple diseases with a single edit. He and colleagues are also working to establish a non-profit center for gene surgery to advance cures “that industry is unlikely to pursue quickly because the disease is so rare.”

Prime Medicine, co-founded by Liu, recently announced promising initial results in treating two patients with a rare inherited immune deficiency. However, the company announced it would pause the program to focus on other diseases, and is exploring pathways for approval with existing data rather than treating additional patients.

The case of “Baby KJ” Muldoon, an infant who received a customized gene-editing therapy for a rare metabolic disorder at Children’s Hospital of Philadelphia last year, paves the way for the future. KJ celebrated his first birthday at home this year, is learning to walk, and is reaching developmental milestones. But he is just one patient. Other children suffer from similar disorders, urea cycle disorders, caused by different mutations in several different genes. KJ’s treatment team is launching an “umbrella” study to treat five more children, using the same basic approach but tailored to different genes, and mutations.

The hope is that the collected insights will help support approval of the treatment. Musunuru’s team recently published a step-by-step guide for their interactions with regulators in the American Journal of Human Genetics. He and other researchers, encouraged by the FDA’s recent announcement of a new pathway, await further instructions on how it will function. “We believe there are many patients like KJ who need therapies now,” Musunuru said. “The clock is ticking, and we know People can make it happen.”