NEW ORLEANS – Genetic counselors should help patients set realistic expectations when sorting through the risks and benefits of gene therapy, according to panelists at the National Society of Genetic Counselors annual meeting Saturday.
The US Food and Drug Administration has approved several gene therapies in recent years that promise to treat the underlying cause of intractable diseases, including CSL Behring's Hemgenix (etranacogene dezaparvovec) and Pfizer's Beqvez (fidanacogene elaparvovec-dzkt) for hemophilia B; Spark Therapeutics' Luxturna (voretigene neparvovec) for Leber congenital amaurosis; Sarepta Therapeutics' Elevidys (delandistrogene moxeparvovec-rokl) for Duchenne muscular dystrophy; and Vertex and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) and Bluebird Bio's Lyfgenia (lovotibeglogene autotemcel) for sickle cell disease. Despite the promise that these one-time gene therapies may slow progression, significantly improve symptoms, or even cure their disease, they are costly medicines that carry the risk of adverse events, they might not live up to patients' expectations, and not all patients may be eligible to receive them.
As such, patients must grapple with whether this is a treatment approach they wish to pursue, and genetic counselors should provide transparent information to support patients and their families in navigating the benefits and risks of treatment, the panelists said. These decisions may be shaped by differences in disease severity, current treatment options, and the efficacy of the particular gene therapies, as well as uncertain short- and long-term risks.
Kristy Lee, a genetic counselor in the department of genetics at the University of North Carolina-Chapel Hill who sees patients with hemophilia and retinopathies, said during the panel discussion that while some patients she's seeing are certainly excited about the possibility of accessing gene therapies, others are less enthusiastic, and "it turns out, that [these] decisions … are not going to be terribly straightforward" for many of them.
Genetic counselors have surveyed both these groups of patients recently to better understand their attitudes on gene therapies. In a survey between May 2023 and May 2024 of 54 hemophilia A and hemophilia B patients at UNC, most said they were somewhat to extremely knowledgeable about gene therapy, but 70 percent said they would consider such treatment in the future, but not now.
In contrast, in a survey published this year of patients with inherited retinal diseases, more than 90 percent of respondents said they would accept gene therapy if offered, noted Emily Place, a genetic counselor at Massachusetts Eye and Ear Hospital.
One factor that patients weigh in their decisions around gene therapies is the availability and effectiveness of current non-gene therapy options. For instance, in hemophilia, there are both short-acting and long-acting recombinant factor replacement therapies and bypassing agents available to patients. In the survey Lee and her colleagues conducted of patients with severe hemophilia A or B, 76 percent were satisfied or very satisfied with their current treatment. This, she noted, could in part account for why hemophilia patients are willing to wait for gene therapy, as could the knowledge that there are additional treatments under investigation.
In other disease settings, though, patients may not have other treatment options. Leber congenital amaurosis, or early-onset retinal dystrophy due to variants in the RPE65 gene, is progressive and patients lose their eyesight, becoming legally blind by about 16 years of age. Duchenne muscular dystrophy, due to mutations in the DMD gene, is also progressive, leading to a loss of ambulation, cardiac dysfunction, and early death. In these settings, the lack of alternative therapeutic options may make patients more eager to try gene therapies sooner.
Place noted, though, that patients may have misperceptions about how gene therapy will affect their condition. Two-thirds of respondents to the survey of inherited retinal disease patients she cited said correctly that gene therapy can slow the progression of disease, while 53 percent erroneously said it could restore vision to normal. "In reality, Luxturna and other gene therapies that are becoming available for IRD are not restorative therapies, not ones that will restore vision back to quote-unquote normal," Place cautioned.
She added that uncovering these knowledge gaps presents an opportunity for genetic counselors and others to speak with patients about gene therapies and what the treatments can and cannot do.
Other gene therapies may also not be curative, despite drugmakers' ambitions. Brianna Gross, a genetic counselor at Children's Hospital of Philadelphia, cautioned that gene therapies for Duchenne muscular dystrophy aim to transform patients' disease into a milder condition akin to Becker muscular dystrophy. Becker is caused by a reduced expression of the dystrophin protein, not its loss like in Duchenne, and has a later age of onset and slower rate of progression.
Similarly, in hemophilia B, gene therapies reduce the number of bleeding episodes that patients have — from 4.1 bleeds per year to 1.9 or from 4.5 bleeds per year to 2.5 bleeds per year, in their respective trials — but do not eliminate them, UNC's Lee added. With treatment, she noted, severe hemophilia may become mild hemophilia and require fewer treatments for bleeding episodes.
Still, with some gene therapies, there may be the possibility of a cure. CRISPR-based gene therapy for sickle cell may be considered curative, said Akshay Sharma, a pediatric hematologist, oncologist, and transplant physician at St. Jude Children's Research Hospital, referring to Casgevy. He added that bone marrow transplants may also be curative.
"Understanding an individual's motive and perception of therapy is really necessary," said Place, adding that "we really need to first and foremost talk to patients and understand their perspective when it comes to treatment. That's the first step in the decision-making process."
At the same time, patients must weigh the side effects of gene therapies, as the treatment experience can be grueling. Patients receiving gene therapies for spinal muscular atrophy often must take steroids for months and undergo weekly blood draws, Gross noted. She noted that patients are often treated like they are in a COVID-19 bubble to prevent them from getting sick just before or after treatment, as the risk of side effects from treatment rise with an immunological response.
Similarly, Lee noted that about 80 percent of hemophilia patients receive steroid therapy for months. Some patients have reactions to steroids while others do not, and how a patient will react can't be predicted.
With gene therapies for Duchenne, Gross added that there are other, grave side effects, such as myocarditis and death, which have been reported in some of the microdystrophin trials.
"I challenge you to put yourself in a family's position, in which they have a child with Duchenne muscular dystrophy and with knowing what this life is going to look like and when they likely will pass away," Gross said. "And [consider] if you would be willing to risk potentially death in your child if that meant you might be able to prolong their ability to ambulate and prolong their life."
As there is little long-term data, there remain questions about how long the effects of gene therapies may last. And choosing to undergo a gene therapy now may preclude patients receiving a newer one in the future, as gene therapies often rely on similar viral vectors to deliver their payload. People with antibodies to those viral vectors, such as patients who have been previously dosed, are ineligible for treatment. A decision to pursue gene therapy might mean cutting off potential future therapies, Lee noted.
However, for some conditions, like hemophilia B, there are two gene therapies that rely on different viral vectors, so re-dosing may be possible, though whether insurance companies would cover a second treatment, given their multimillion-dollar price tags, is unclear.
According to the panel, genetic counselors need to help patients sort through all these different concerns and uncertainties. "Setting up expectations and being transparent about what we know and don't know is going to be key for us [as genetic counselors]," Lee said.
Gross noted that CHOP provides patients resources they can review at home and learn more about their disease and what the treatment options, including gene therapy, are. Lee added that arranging opportunities for patients and families to speak with people who have already gone through the treatment process has also been helpful.
It is important to be honest and understand the "patient's perspective … and what would be most meaningful for them," Place added. "There's a lot that we don't know."