A Review of Gene Therapy Clinical Trials

RSRT is constantly working hard to accelerate cures for Rett syndrome. In 2023, the initial patients were dosed in the first-ever clinical trials of gene therapy for Rett syndrome. Two biotech companies, Taysha Gene Therapies and Neurogene, advanced these trials with deep involvement from previously funded RSRT scientists. In 2024, we saw the first report on data from these trials. There are safety concerns to be addressed, but also lots to be hopeful about, with trial participants showing improvement in motor skills, communication, seizure activity, and more.

Here’s a summary of the trials, their treatment approaches, and the latest results:

The Treatment: Taysha's gene therapy for Rett syndrome, called TSHA-102, adds a shortened “mini-gene” version of the MECP2 gene to cells. It includes the miRARE technology, which is designed to tune the amount of MECP2 protein that is made from the gene therapy since too much MECP2 can have negative effects. The gene therapy is packaged in a viral vector and delivered via a one-time injection into the spinal fluid. RSRT trustee Adrian Bird, PhD, generated the TSHA-102 minigene.

The Trials: The REVEAL phase I/II trial will establish the safety and efficacy of two doses in adolescent/adult and pediatric patients. Initially, adult and pediatric patients were given a low dose. Once preliminary safety was established, the remaining patients were given high-dose treatment.

The Location: Trials of adolescent/adult participants aged 12 and older are taking place in the US and Canada. Pediatric trials are underway in the US and the UK. 

Interim Results: In Spring 2023, Taysha broke ground, dosing the first Rett patient in history with gene therapy. This was an adolescent/adult patient who was given a low dose. A second adolescent/adult patient was given a low-dose treatment in Fall 2023. The patients experienced no severe adverse events, and, as of the last data reported by Taysha, the patients showed increasing improvements in fine and gross motor skills, communication, autonomic function, and seizure activity. This marks 52 weeks of data (adolescent/adult patient 1) and 25 weeks (adolescent/adult patient 2), respectively. 

Two pediatric patients have been given the low-dose gene therapy. Again, the treatment was well-tolerated, and the patients showed improvement in the same domains as adult patients as early as four weeks after treatment, with increasing improvements at 12 (pediatric patient 1) and eight (pediatric patient 2) weeks after treatment. 

Taysha considers the low-dose treatment arm of the study completed, having successfully derisked testing a higher dose. Two adolescent/adult and one pediatric patient have been given high-dose treatments with no severe adverse events. A third adolescent/adult participant was dosed but no data on this participant has been revealed. Stay tuned! They are continuing to enroll adult/adolescent and pediatric participants and expect to share more data by the end of Q2 2025.

The Treatment: Neurogene’s gene therapy for Rett syndrome, called NGN-401, delivers a full length MECP2 gene and EXACT, a technology that controls the amount of MECP2 protein made by the gene. The therapy is packaged in a viral vector and delivered using a one-time injection into the cerebral ventricles, which are fluid-filled structures deep within the brain. The goal is to maximize spread of the gene therapy throughout the brain. Stuart Cobb, PhD a researcher who has worked closely with RSRT for over a dozen years, is Neurogene’s chief scientific officer.

The Trial: This phase I/II trial will assess the safety and efficacy of NGN-401 in pediatric patients aged 4 to 10 years old. Like the Taysha trial, Neurogene was first tested at a low-dose treatment for safety, and once safety was established at that dose, they began testing a high-dose treatment. 

The Location: This trial is being conducted at Rett centers across the US, as well as in Australia and the UK. 

Interim Results: Neurogene gave its first two participants a low-dose treatment in November 2023 with no severe adverse events. So far, five participants have received a low-dose treatment. Interim data was shared with the first four participants, all showing symptom improvement on clinical and caregiver assessment scales. Neurogene stated that improvements included complex skills rarely seen in Rett patients and rarely relearned after regression. Symptom amelioration and skill gain have continued to improve over time.  

In the Fall of 2024, Neurogene gave high-dose treatment to three participants. The first two experienced no severe adverse effects. The third participant had a severe immune reaction to the virus used to deliver the gene therapy. Immune reactions are a known risk of viral delivery that has occasionally occurred with other gene therapies. The risk of immune reactions increases with the treatment dose, since higher dose treatment requires higher levels of virus. Tragically, the patient passed away. You can read more of our thoughts here. 

Neurogene has decided to halt the high-dose arm of the trial and will continue with the lower dose only. We remain hopeful about the therapeutic potential of the low-dose treatment and are committed to helping develop new, safer methods for delivering gene therapies.

Looking Ahead to 2025

Expect more safety and efficacy results from both trials. We expect to learn more details about what symptoms improved, by how much, and whether the improvements have continued or plateaued.