The recent approval of Regeneron’s Otarmeni underscores the maturation of gene therapies across a range of diseases. Here, BioSpace reviews genetic medicines in development for the central nervous system, retinal, cardiac and neuromuscular diseases.
Last month, the FDA approved Regeneron Pharmaceuticals’ Otarmeni for a specific type of hearing loss, validating the concept of genetic medicines. As these medicines continue to advance, countless more conditions stand to benefit from the approach. Researchers are taking note.
“The hegemony of all cell and gene therapy has been [oncology] for a long time,” Roger Hajjar, head of Mass General Brigham’s Gene & Cell Therapy Institute and chief medical officer at gene therapy company Medera, told BioSpace. “Now, we’re seeing a switch toward neuro diseases, ophthalmology, cardiac diseases.”
The ear is also a common focus, he noted. Otarmeni, the first gene therapy for hearing loss, is intended for individuals with congenital deafness caused by a deficiency of the otoferlin protein, which is critical for the hearing process. Eli Lilly, too, is working on an otoferlin-targeted gene therapy for the same condition.
The first wave of gene therapies homed in primarily on cancer because of the otherwise very limited treatment options, according to Hajjar. Over time, however, as scientists and doctors have gained experience with novel approaches, “these experimental vectors have become the mainstay of gene therapy and now are being used for other diseases where they can deliver missing genes or they can correct genes.”
Amid that ongoing evolution, as researchers continue to branch out beyond oncology for the next wave of targeted gene therapies, a handful of therapeutic areas stand out as prime targets.
Lilly, UniQure, Lexeo, more target the CNS
Several therapies are currently in development to treat diseases of the central nervous system (CNS).
Lexeo Therapeutics, for example, is studying an adeno-associated virus (AAV)-based gene therapy designed to deliver an APOE2 gene variant to treat early to moderate Alzheimer’s disease. Research shows that those with two copies of APOE2 are significantly less likely to develop Alzheimer’s, suggesting that the gene variant may offer some neuroprotective qualities, per the company’s website.
Meanwhile, Eli Lilly and Bayer’s AskBio are among those advancing experimental gene therapies for Parkinson’s disease. AskBio’s candidate, AB-1005, aims to restore continuous production of the GDNF protein, enabling nerve cells to trigger healthy body movement, according to the biotech’s website. Lilly’s asset, currently in a Phase 1/2a trial, is intended for patients with at least one mutation in the GBA1 gene. Harboring mutations in this gene is known to increase risk of Parkinson’s.
Taysha Gene Therapies, meanwhile, is targeting the rare neurodevelopmental disorder Rett syndrome with an AAV-based therapy of its own. Rett syndrome is caused by mutations in the MECP2 gene, which aids in regulating brain function; TSHA-102 delivers a form of the gene directly to the cerebrospinal fluid.
Passage Bio, meanwhile, is developing PBFT02, which delivers a modified DNA encoding copies of the granulin gene directly to the cerebrospinal fluid for a range of neurodegenerative disorders. The company’s lead program is in frontotemporal dementia, but the asset is also being studied in amyotrophic lateral sclerosis (ALS) and Huntington’s disease.
Huntington’s is a common target. Last September, uniQure shared Phase 1/2 data revealing that its gene therapy AMT-130, which aims to silence the mutant huntingtin gene, had slowed disease progression by 75% after three years. Excitement over the results was stymied, however, by the announcement that the FDA will require a sham surgery-controlled Phase 3 trial before it will consider AMT-130 for approval, though uniQure has vowed to continue conversations with the regulator about alternate routes forward.
As time goes on, precision approaches like these will be a core aim of gene therapy developers, according to Hajjar.
“The next frontier is going to be about improving our delivery systems with novel vector systems,” he said, adding that the genetic material being delivered and editing tools being used will also continue to improve. “All these things are evolving toward genetic therapies becoming much more targeted. And as they become more targeted, they will be safer to use.”
REGENXBIO, AbbVie, 4D target VEGF in eye disease
Among the handful of companies developing gene therapies to treat various eye diseases are REGENXBIO and AbbVie, which have teamed up to study a potential treatment for wet age-related macular degeneration (AMD) and diabetic retinopathy—two vascular endothelial growth factor (VEGF)-driven conditions in which patients “face high treatment burden that leads to undertreatment and ultimately vision loss over time,” a REGENXBIO spokesperson told BioSpace via email.
VEGF stimulates the growth of new blood vessels and increases the permeability of existing ones, causing fluid and blood to leak into the macula, an area at the center of the retina responsible for sharp, central vision.
AbbVie and REGENXBIO’s gene therapy, dubbed sura-vec, is delivered either subretinally or suprachoroidally—injected between the sclera and choroid—to inhibit VEGF and fluid accumulation in the retina, potentially preventing disease progression and preserving vision. Pivotal data in wet AMD are expected to arrive in the fourth quarter of this year, with dosing set to begin in a Phase 2b/3 diabetic retinopathy trial this quarter, the spokesperson said.
Also studying a gene therapy approach to wet AMD is 4D Molecular Therapeutics. Its 4D-150, which is designed to durably suppress four different VEGF family members, is currently being studied in two Phase 3 trials, along with an early-phase study in diabetic macular edema. 4D-150 is delivered intravitreally.
Tenaya, Medera target cardiovascular disease
Targeted treatments are on the rise in cardiovascular indications. Hajjar noted a “longstanding trend” of using gene therapies to treat more common diseases like congestive heart failure via well-characterized pathways, but he added that companies are increasingly seeking to replace the faulty genes at the root of genetic cardiomyopathies. Straddling that line between rare and prevalent heart conditions are Tenaya Therapeutics and Hajjar’s company, Medera.
Tenaya’s clinical-stage pipeline includes a pair of gene therapies being studied in hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy. The biotech is also conducting early-stage development of gene therapies in certain types of heart failure.
Furthest along is the HCM candidate TN-201, which aims to correct for mutations in the MYBPC3 gene, a key player in modulating the heart’s contractions. Early data have shown that after at least one year of follow-up, “multiple parameters of disease had moved toward normal,” CEO Faraz Ali told BioSpace in an email.
“With TN-201, we have a unique opportunity to address the underlying genetic cause of disease and to halt and even reverse disease progression for all forms of the disease,” he said.
Meanwhile, Medera’s trio of cardiac gene therapies span two common forms of heart failure as well as the much rarer Duchenne cardiomyopathy. Lead program SRD-002 is being developed for heart failure with preserved ejection fraction (HFpEF). Early data on the candidate have been positive, with Medera CEO Ronald Li pointing to “consistent and durable improvements in cardiac hemodynamics and functional measures.” He also noted in an email to BioSpace that no gene therapy–related serious adverse events or side effects have been observed so far, attributing this at least in part to Medera’s intracoronary delivery, where a catheter provides entry directly into the coronary arteries. This approach, Li said, allows for “up to ~300-fold lower vector doses compared to conventional systemic intravenous approaches,” which can reduce costs in addition to improving safety.
The company’s approach is “fundamentally different” from the current standard of care, Li explained, as it seeks to address the root causes of impaired heart function rather than saddling patients with a lifetime of disease management.
In HFpEF specifically, which affects approximately half of all heart failure patients and where disease-modifying options remain limited, Medera’s approach could represent “a meaningful step toward redefining the treatment paradigm,” he said. “More broadly, it demonstrates how aligning biology, delivery and human-relevant modeling can enable gene therapy to move beyond rare diseases into large, complex indications.”
Sarepta, REGENXBIO tackle muscle deficiency in DMD
Gene therapies have made significant inroads in neuromuscular diseases. To date, two gene replacement therapies have been approved by the FDA for spinal muscular atrophy: Novartis’ Zolgensma, cleared in 2019 for children under the age of 2, and the Swiss pharma’s Itvisma, greenlit last fall for patients with SMA aged 2 and older.
Also active in the neuromuscular space is Sarepta Therapeutics, though it hasn’t been all smooth sailing for the biotech. After earning FDA approval in 2023 for its first gene therapy, Elevidys—which delivers a gene that instructs the body to make a shortened version of the dystrophin protein to treat Duchenne muscular dystrophy (DMD)—Sarepta was plagued last year by multiple patient deaths linked to its platform. This led to a brief pause in Elevidys sales, ultimately followed by the installation of a narrower label and black box warning.
Meanwhile, REGENXBIO reported positive topline Phase 3 results last week from its own DMD candidate, RGX-202, showing that 93% of patients achieved microdystrophin expression above 10%. There was also a “statistically significant correlation” between this expression and functional improvement, the company said in its press release, “supporting [the] validity of the surrogate endpoint.”
RGX-202 comprises a differentiated microdystrophin construct that encodes key regions of naturally occurring dystrophin, including the C-Terminal (CT domain). Previously, interim one-year data showed positive effects on functional measures, as well as cardiac stability, with a safety profile that indicated no evidence of liver injury and no serious adverse events. All together, the spokesperson said, those findings highlight “the potential of RGX-202 to be a differentiated gene therapy option for Duchenne.”
