MeiraGTx Holdings plc (Nasdaq: MGTX) presented four groundbreaking posters at the American Society of Gene and Cell Therapy (ASGCT) 2025 Annual Meeting in New Orleans, showcasing significant advances in their gene therapy platforms targeting severe pediatric obesity, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD).
The presentations highlighted the company's progress in developing highly potent gene therapies that could potentially transform treatment paradigms for these challenging conditions, while also advancing fundamental gene therapy technologies through promoter optimization.
Novel Approach to Treating Severe Pediatric Obesity
MeiraGTx's most striking results came from their work on severe pediatric obesity, where they've developed a highly potent AAV-BDNF vector targeting the ventromedial hypothalamus (VmH). This approach addresses the underlying pathophysiology of severe early-onset obesity syndromes characterized by hyperphagia and food-related distress.
The optimized BDNF clinical construct expresses brain-derived neurotrophic factor (BDNF) at levels up to 143-fold greater than basal levels in vivo. In diet-induced obesity (DIO) mouse models, this therapy demonstrated remarkable efficacy, with treated animals experiencing up to 40% weight loss that plateaued at levels comparable to wild-type lean controls.
"This magnitude of weight reduction significantly outperforms current treatments," noted a company spokesperson. "For comparison, DIO animals treated with daily semaglutide injections plateaued at approximately 12% weight loss."
The weight loss effects have been maintained for at least three months in the ongoing studies, suggesting potential durability of the treatment. Additionally, AAV-BDNF-expressing mice showed significantly improved glucose tolerance compared to control animals.
Safety assessments revealed no concerning signals. Despite BDNF's role in multiple hypothalamic functions, treated animals displayed normal pro-social behaviors and feeding capabilities, with only an expected increase in locomotion.
Advancing Promoter Technology for Gene Therapy
MeiraGTx also presented groundbreaking work on promoter optimization, a critical component for improving gene therapy safety and efficacy. The company has engineered novel CAG promoter variants that are both shorter and more potent than traditional promoters used in gene therapy.
Of the 82 new CAG promoter variants developed, 51 are smaller than the original CAG, with 22 fewer than 1000 base pairs in length. In human cell models, 67 variants demonstrated stronger activity than the original CAG sequence, with the most potent showing a 13-fold improvement.
In primary human hepatocytes and myotubes, four CAG variants drove 15-fold higher transgene expression while being approximately 40% shorter in length. When packaged into AAV9 and administered to mice, one variant (C178) outperformed the original CAG in muscle, liver, heart, and brain tissue while being 700 base pairs shorter.
"These advancements address a critical need in the field," explained a MeiraGTx researcher. "By increasing vector potency, we can potentially lower therapeutic doses, which may reduce immune responses and improve the safety profile of gene therapies."
The company is also investigating transcription factor binding sites (TFBS) to further enhance synthetic promoter activity. Their research has identified specific TFBS that can boost expression from core promoters by up to six-fold, providing additional tools for optimizing gene therapy vectors.
Novel Gene Therapy for ALS and FTD
MeiraGTx's fourth presentation focused on an optimized AAV-hUPF1 gene therapy for ALS and FTD. The company has reduced the size of the original hUPF1 construct by 1.5kb while improving therapeutic efficacy in both in vitro and in vivo models.
Up-frameshift 1 (hUPF1), a central regulator in nonsense-mediated RNA decay, has shown promise in mitigating toxicity in multiple ALS models, including those with TDP-43 and C9orf72 mutations. In a Fused in Sarcoma (FUS) mouse model of ALS, the optimized AAV-hUPF1 significantly improved motor neuron survival to levels comparable to wild-type controls at approximately 36% transduction.
"What's particularly exciting about this approach is that it could potentially benefit the majority of ALS patients regardless of their genetic background," said a company representative. "Over 95% of ALS cases are associated with dysregulation of TDP-43, which our therapy targets indirectly through the NMD pathway."
The company is currently developing a robust potency assay based on RNA homeostasis to support the manufacturing of clinical therapeutics as they advance this program toward human trials.
Implications for Future Therapies
These developments position MeiraGTx at the forefront of gene therapy innovation. The company's vertically integrated approach, which includes end-to-end manufacturing capabilities across five global facilities, provides a strong foundation for advancing these therapies toward clinical application.
"Our comprehensive manufacturing capabilities, including two GMP-licensed viral vector production facilities, give us a significant advantage in translating these promising preclinical results into therapies that can benefit patients," explained a senior executive at MeiraGTx.
The company's work on severe pediatric obesity represents a potentially transformative approach for children with genetic forms of obesity who respond poorly to existing treatments. Similarly, their ALS/FTD program addresses a devastating neurodegenerative condition with limited treatment options.
Beyond these specific indications, MeiraGTx's advances in promoter technology could have broad implications across the gene therapy field, potentially enabling more effective treatments for a wide range of genetic and acquired diseases.
As these programs advance toward clinical development, they underscore MeiraGTx's commitment to developing innovative genetic medicines that address significant unmet medical needs through targeted, potent, and potentially durable therapeutic approaches.
