In Colorado and Wyoming, nearly every baby born since 2020 is tested for signs of a mutation in the SMN1 gene, an indicator of spinal muscular atrophy (SMA). And in 4 years, genetic counselor Melissa Gibbons has seen 24 positive results. She has prepped 24 different pediatricians and family doctors to deliver the news: A seemingly perfect newborn likely has a lethal genetic disease.
Most of these clinicians had never cared for a child with SMA before, nor did they know that lifesaving gene therapy for the condition now exists. Still, the physicians were foundational to getting babies emergency treatment and monitoring the child’s safety after the fact.
“They are boots on the ground for this kind of [work],” Gibbons, who is the newborn screen coordinator for SMA in both states, told Medscape Medical News. “I’m not even sure they realize it.” As of today, the US Food and Drug Administration has approved 16 g ene therapies for the treatment of rare and debilitating diseases once considered lethal, such as SMA and cerebral adrenoleukodystrophy.
The newest addition to the list of approvals is Elevidys, Sarepta’s gene therapy for Duchenne muscular dystrophy (DMD). These conditions can now be mitigated, abated for years at a time, and even cured using treatments that tweak a patient’s DNA or RNA.
This is a world we are creating right now, quite literally.
Hundreds of treatments are under development using the same mechanism. Viruses, liposomes, and other vectors of all kinds are being used to usher new genes into cells, correcting faulty copies or equipping a cell to fight disease. Cells gain the ability to make lifesaving proteins — proteins that heal wounds, restore muscle function, and fight cancer.
Within the decade, a significant fraction of the pediatric population will have gone through gene therapy, experts told Medscape Medical News. And primary care stands to be a lynchpin in the scale-up of this kind of precision genetic medicine. Pediatricians and general practitioners will be central to finding and monitoring the patients that need these treatments. But the time and support doctors will need to fill that role remain scarce.
Stanley Nelson, MD
“This is a world we are creating right now, quite literally,” said Stanley Nelson, MD, director of the Center for Duchenne Muscular Dystrophy at the University of California, Los Angeles. These cases — some before gene therapy and some after — will show up in primary care offices before the textbook is written.
Unknown Side Effects, New Diseases
Even now, gene therapy is sequestered away in large academic medical research centers. The diagnosis, decision-making, and aftercare are handled by subspecialists working on clinical trials. While the research is ongoing, trial sponsors are keeping a close eye on enrolled patients. But that’s only until these drugs get market approval, Phil Beales, MD, chief medical officer at Congenica, a digital health company specializing in genome analysis support, said. Afterward, “the trialists will no longer have a role in looking after those patients.”
At that point, the role of primary care clinicians will be critically important. Although they probably will not manage gene-therapy patients on their own — co-managing them instead with subspecialists — they will be involved in the ordering and monitoring of safety labs and other tests.
General practitioners “need to know side effects because they are going to deal with side effects when someone calls them in the middle of the night,” said Beales, who also is chief executive officer of Axovia Therapeutics, a biotech company developing gene therapies.
Some of the side effects that come with gene therapy are established. Adeno-associated virus (AAV) or AAV-mediated gene therapies carry an increased risk for damage to the heart and liver, Nelson said. Other side effects are less well known and could be specific to the treatment and the tissue it targets. Primary care will be critical in detecting these unexpected side effects and expediting visits with subspecialists, he said.
In rural Wyoming, pediatricians and family doctors are especially important, Gibbons said. In the 30-90 days after gene therapy, patients need a lot of follow-up for safety reasons.
But aftercare for gene therapy will be more than just monitoring and managing side effects. The diseases themselves will change. Patients will be living with conditions that once were lethal.
Christy Duncan, MD
In some cases, gene therapy may largely eliminate the disease. The data suggest that thalassemia, for example, can be largely cured for decades with one infusion of a patient’s genetically modified hematopoietic stem cells made using bluebird bio’s Zynteglo, according to Christy Duncan, MD, medical director of clinical research at the gene therapy program at Boston Children’s Hospital.
But other gene therapies, like the one for DMD, will offer a “spectrum of benefits,” Nelson said. They will be lifesaving, but the signs of the disease will linger. Clinicians will be learning alongside specialists what the new disease state for DMD and other rare diseases looks like after gene therapy.
“As we get hundreds of such therapies, [post–gene therapy] will amount to a substantial part of the pediatric population,” Nelson said.
Many of these rare diseases that plague young patients are unmistakable. Children with moderate or severe dystrophic epidermolysis bullosa, for instance, carry a mutation that prevents them from making type VII collagen. The babies suffer wounds and excessive bleeding and tend to receive a quick diagnosis within the first 6 months of life, according to Andy Orth, chief commercial officer at Krystal Bio, manufacturer of a new wound-healing gene therapy, Vyjuvek, for the disorder.
Other rare neurologic or muscular diseases can go undiagnosed for years. Until recently, drug companies and researchers have had little motivation to speed up the timeline because early diagnosis of a disease like DMD would not change the outcome, Nelson said.
But with gene therapy, prognoses are changing. And finding diseases early could soon mean preserving muscular function or preventing neurologic damage, Duncan said.
Newborn sequencing “is not standard of care yet, but it’s certainly coming,” Josh Peterson, MD, MPH, director of the Center for Precision Medicine at Vanderbilt University Medical Center, in Nashville, Tennessee, told Medscape Medical News.
A recent survey of 238 specialists in rare diseases found that roughly 90% believe whole-genome sequencing should be available to all newborns. And 80% of those experts endorse 42 genes as disease predictors. Screening for rare diseases at birth could reveal a host of conditions in the first week of life and expedite treatment. But this strategy will often rely on primary care and pediatricians interpreting the results.
Most pediatricians think sequencing is a great idea, but they do not feel comfortable doing it themselves, Peterson said. The good news, he said, is that manufacturers have made screening tests straightforward. Some drug companies even offer free screenings for gene therapy candidates.
Peterson predicts pediatricians will need to be equipped to deliver negative results on their own, which will be the case for around 97%-99% of patients. They also will need to be clear on whether a negative result is definitive or if more testing is warranted.
Positive results are more nuanced. Genetic counseling is the ideal resource when delivering this kind of news to patients, but counselors are a scarce resource nationally — and particularly in rural areas, Nelson said. Physicians likely will have to rely on their own counseling training to some degree.
“I feel very strongly that genetic counselors are in short supply,” Gibbons in Colorado said. Patients need a friendly resource who can talk them through the disease and how it works. And that discussion is not a one-off, she said.
The number of board-certified genetic counselors in the United States has doubled to more than 6000 in the past 10 years — a pace that is expected to continue, according to the National Society of Genetic Counselors. “However, the geographical distribution of genetic counselors is most concentrated in urban centers.”
Equally important to the counseling experience, according to Duncan at Boston Children’s, is a primary care physician’s network of connections. The best newborn screening rollouts across the country have succeeded because clinicians knew where to send people next and how to get families the help they needed, she said.
But she also cautioned that this learning curve will soon be overwhelming. As gene therapy expands, it may be difficult for primary care doctors to keep up with the science, treatment studies, and commercially available therapies. “It’s asking too much,” Duncan said.
The structure of primary care already stretches practitioners thin and will “affect how well precision medicine can be adopted and disseminated,” Peterson said. “I think that is a key issue.”
Artificial intelligence may offer a partial solution. Some genetic counseling models already exist, but their utility for clinicians so far is limited, Beales said. But he said he expects these tools to improve rapidly to help clinicians and patients. On the patient’s end, they may be able to answer questions and supplement basic genetic counseling. On the physician’s end, algorithms could help triage patients and help move them along to the next steps in the care pathway for these rare diseases.
The Whole Patient
Primary care physicians will not be expected to be experts in gene therapy or solely in charge of patient safety. They will have support from industry and subspecialists leading the development of these treatments, experts agreed.
But generalists should expect to be drawn into multidisciplinary care teams, be the sounding boards for patients making decisions about gene therapy, help arrange insurance coverage, and be the recipients of late-night phone calls about side effects.
All that, while never losing sight of the child’s holistic health. In children so sick, specialists, subspecialists, and even parents tend to focus only on the rare disease. The team can “get distracted from good normal routine care,” Nelson said. But these children aren’t exempt from check-ups, vaccine regimens, or the other diseases of childhood.
“In a world where we mitigate that core disease,” he said, “we need a partner in the general pediatrics community” investing in their long-term health.
Donavyn Coffey is a Kentucky-based journalist reporting on healthcare, the environment, and anything that affects the way we eat. She has a master’s degree from NYU’s Arthur L. Carter Journalism Institute and a master’s in molecular nutrition from Aarhus University in Denmark. You can see more of her work in Wired, Scientific American, Popular Science, and elsewhere.