Rett syndrome, a neurodevelopmental disorder primarily affecting girls, is characterized by a regression in speech and motor skills. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are the primary cause. While current treatments like trofinetide can alleviate some symptoms, they do not address the underlying genetic deficiency. Now, gene therapies from Neurogene and Taysha Gene Therapies are in Phase 1/2 clinical trials, seeking to correct the root cause of Rett syndrome by restoring MECP2 function.
MECP2: Restoring Brain Function
The discovery of the MECP2 gene's role in Rett syndrome by Huda Zoghbi's team at Baylor College of Medicine opened avenues for potential therapies. Subsequent research, including the development of animal models lacking MECP2 by Adrian Bird's group at the University of Edinburgh, demonstrated the reversibility of Rett syndrome symptoms upon reintroduction of a healthy MECP2 copy. This groundbreaking work paved the way for gene therapy approaches.
Stuart Cobb, also at the University of Edinburgh, collaborated with Bird to show that restoring MECP2 expression in mice exhibiting Rett-like symptoms could reverse these neurological deficits. "At the time, Rett syndrome and neurodevelopmental disorders in general were considered basically untreatable because the view was that the nervous system had developed abnormally, and there wasn't much you could do about that. So, we developed an experiment to test that," said Cobb. The results defied expectations, demonstrating that the brain's condition was not irreversible in this case.
Fine-Tuning Gene Expression
One of the critical challenges in developing MECP2 gene therapies is the need for precise gene expression. Both insufficient and excessive MECP2 levels can lead to severe neurodevelopmental disorders, namely Rett syndrome and MECP2 duplication syndrome, respectively. As Rachel McMinn, founder and CEO of Neurogene, explained, "It kills mice even faster than when they don't even have any MECP2 at all," highlighting the need for a "genetic thermostat."
To achieve this precise control, Neurogene developed the EXACT technology, a microRNA-based regulatory system. This system co-expresses a healthy copy of MECP2 with a microRNA that inhibits the MECP2 transgene, preventing overexpression. Taysha Gene Therapies employs a similar strategy, utilizing a microRNA Responsive Auto-Regulatory Element (miRARE) in their TSHA-102 therapy. Sukumar Nagendran, President and Head of Research and Development at Taysha Gene Therapies, noted, "Our technology is actually very sensitive to both the endogenous MECP2 and its own MECP2 which is exogenous," ensuring that MECP2 levels remain within a safe and therapeutic range.
Delivery Methods and Clinical Trials
Neurogene's NGN-401 is administered via an intracerebroventricular (ICV) injection, delivering the therapy directly into the cerebrospinal fluid (CSF) within the brain's ventricles. Taysha Gene Therapies, on the other hand, uses a lumbar puncture to deliver TSHA-102 into the CSF at the base of the spine. Both methods are standard neurosurgical procedures, though lumbar punctures are more commonly performed.
Taysha Gene Therapies is currently conducting two clinical trials: one for pediatric Rett syndrome patients and another for adolescents and adults. Interim data from the low-dose cohort of both trials have shown promising clinical improvements with no serious adverse events reported. Neurogene is also conducting a trial for NGN-401 in young girls with Rett syndrome, with initial data expected in the fourth quarter of 2024.
Hope for a Disease-Modifying Treatment
The development of gene therapies targeting the underlying genetic cause of Rett syndrome represents a significant advancement in the field. With preliminary data suggesting promising safety profiles and potential efficacy, these therapies offer hope for a disease-modifying treatment that could significantly improve the lives of individuals with Rett syndrome. As Nagendran stated, "Frankly, I'm blown away as a physician seeing what I'm seeing in a very complex disease, but I think we need time. We need to collect all the data, analyze it."
