FDA Approval of Omaveloxolone for Friedreich’s Ataxia Marked Progress Amid Ongoing Gene Therapy Research and Community Hopes

Gene Therapy Poses Risks and Uncertainty

Gene therapy using an adeno-associated virus (AAV) to deliver frataxin-expressing constructs has shown promise in mouse models. In one study, researchers treated FXN-MCK mice, which have an FXN gene ablation preventing frataxin expression in cardiac and skeletal muscle, with an intravenous injection of an AAV8 vector containing human or mouse FXN genes, under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, the AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits, and increased survival without apparent toxicity in the heart or liver for up to 12 weeks post-dose. Frataxin protein expression in heart tissue was detected and dose-dependent, showing a wide distribution throughout the heart, similar to wild-type but with a more speckled pattern.

Despite these promising results, gene therapy presents challenges and risks. For one, viral vectors can lead to immunotoxicity. The early adaptive immune response can be managed by adjusting vector dose, employing immunomodulation strategies, and considering administration routes to minimize off-target effects.

There are also risks associated with excess frataxin levels. Unlike many other conditions where the therapeutic protein amount is not tightly regulated, FA has a narrow therapeutic window, Barry Byrne, MD, PhD, associate chair of pediatrics and director of the Powell Gene Therapy Center at the University of Florida, Gainesville, explained. This means the therapy needs to elicit precisely the correct amount of frataxin to alleviate symptoms without causing toxicity. To mitigate disease progression and symptoms, the goal is to elevate frataxin levels to match at least 50% of the wild-type level, equivalent to one of their parents.

Byrne said this “Goldilocks effect” has been one of the most crucial recent findings. “A better understanding of the level of frataxin restoration by gene therapy has helped various groups reposition their approach to avoid overexpression,” he said.

 

Patients and Caregivers May Have Differing Perspectives

Despite the challenges around gene therapy, some patients and caregivers expressed a sense of urgency for clinical trials of the approach.

In one small qualitative study, researchers from the Murdoch Children’s Research Institute, Parkville, Australia, interviewed 13 people with FA aged between 15 and 43 years and 6 parents of children with FA aged 4 to 12 years about their views on gene therapy. Most participants relayed concerns about the risks and benefits of the approach, emphasizing the need for clear and accurate information to inform their decisions.

In a larger recent survey, designed at the University of Florida and published in Molecular Therapy Methods & Clinical Development, researchers gathered opinions about gene therapy from 141 caregivers and patients with early-onset disease presentation. Participants received educational materials about gene therapy then answered an online questionnaire.

Around half of the respondents believed gene therapy would cease progression or minimize symptoms, whereas nearly one-fourth expected to be cured. “This high level of optimism and willingness to participate despite potential risks highlights the community’s urgent need for effective treatments and may reflect the serious impact of the disease on their quality of life,” said Manuela Corti, PhD, associate professor in the Department of Pediatrics at the University of Florida College of Medicine.

The survey also revealed that participants prioritize treating balance and walking issues, as they interfere most with their quality of life. More caregivers than patients prioritized treating cardiomyopathy, which may reflect the caregivers’ concerns about the long-term health of their loved ones.

Dr. Corti said the study provides valuable insights into the priorities, beliefs, and expectations of the FA community regarding gene therapy and could guide future gene therapy opinion studies and trial design.

“It is important to note that while there is a clear sense of urgency for a gene therapy treatment, there are still many unknowns about its benefits and risks,” she said. “Therefore, it is crucial to continue research and education to ensure that patients and their families make informed decisions about participating in clinical trials.”

Although the survey did not detail which risks concern participants the most, it did indicate a significant difference in how patients and caregivers understand the risks, suggesting a disparity in their perception and possibly their readiness to confront these risks.

“Caregivers tend to show a higher level of concern about the risks associated with gene therapy than patients. This might be because caregivers often assume the responsibility of managing potential adverse outcomes and are more cautious about long-term implications and the safety profile of experimental treatments,” Dr. Corti said. “In contrast, patients, driven perhaps by a direct experience of the disease’s impact, might prioritize potential benefits over risks, reflecting a more urgent desire for effective treatments.”

The results illustrate the importance of incorporating patient and caregiver perspectives in the design and implementation of gene therapy trials.

“It’s crucial for future research to focus on the efficacy and safety of gene therapy and continue engaging with the FA community to ensure that their concerns and preferences are thoroughly understood and considered,” Dr. Corti said.