Lab findings support Rett gene therapy advancing in late-stage clinical trials
Study shows NGN-401 treatment rapidly boosts vital MeCP2 levels within 1 week
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NGN-401, an experimental gene therapy for Rett syndrome, acts quickly in the nervous system to increase levels of the critical protein MeCP2, which is missing or defective in patients, according to new preclinical data. The therapy, developed by Neurogene, is currently in late-stage clinical trials.
“We found that NGN-401’s single-stranded design produced rapid and durable expression of the fully functional, full-length MECP2 gene, which we believe is consistent with the early and sustained clinical improvements observed in our Phase 1/2 trial,” Rachel McMinn, PhD, founder and CEO of Neurogene, said in a company press release.
Rett syndrome is a genetic disorder caused mainly by mutations in the MECP2 gene, which provides instructions to make the MeCP2 protein. Without enough working MeCP2 protein, the brain and nerves cannot function properly, leading to the hallmark symptoms of the disease.
NGN-401 is designed to deliver a healthy version of the MECP2 gene directly to nerve cells, restoring MeCP2 protein production to address the root cause of Rett. Notably, because abnormally high levels of that protein can also be toxic to cells, the gene therapy includes molecular machinery to prevent too much MeCP2. Specifically, the therapy uses molecules called microRNAs (miRNAs) to regulate and control how much protein is made from the delivered gene.
How the therapy delivers its payload
To deliver the healthy gene and accompanying miRNAs, NGN-401 uses a viral vector, a modified virus engineered to carry therapeutic genes rather than cause infection. NGN-401 specifically uses an adeno-associated virus (AAV) vector, a common delivery vehicle for gene therapies.
Genetic material can be packaged inside an AAV vector in different ways. NGN-401 uses a single-stranded AAV (ssAAV) vector, which carries genetic material as a single strand rather than a double strand, with the genetic material basically balled up like a roll of yarn. This format is necessary because it is the only way to fit both the MECP2 gene and miRNAs inside the same vector capsid.
A second gene therapy in development for Rett, Taysha Gene Therapies‘ TSHA-102, also uses an AAV vector to deliver MECP2 and regulatory elements to cells. Instead of a single-stranded design, TSHA-102 uses a self-complementary AAV (scAAV) vector, in which the genetic material is folded up within the vector rather than balled up.
Because of these structural differences, scientists long assumed that ssAAV vectors, like the one in NGN-401, take longer to start working than scAAV vectors like the one used in TSHA-102. However, the new preclinical data challenge that assumption: researchers found that the ssAAV vector restored MeCP2 protein production across the nervous system within a week (the earliest time point assessed), and that protein levels remained stable over months of follow-up.
Neurogene said these laboratory results align with its Phase 1/2 clinical trial, where all 10 participants with Rett syndrome experienced developmental gains after receiving NGN-401. In most cases, these improvements were noticeable within a few months of treatment.
Challenging assumptions about safety controls
The new data also examined another key assumption about how NGN-401 may work biochemically. Researchers previously believed that the miRNA elements would dynamically sense how much MeCP2 protein already existed in a treated cell and adjust production accordingly. However, laboratory experiments revealed that the therapy’s activity was essentially the same in cells with or without their own MeCP2 protein.
“Two widely held assumptions in Rett syndrome gene therapy are that single-stranded AAV leads to slower expression than self-complementary AAV and that miRNA-based transgene auto-regulatory technology can selectively regulate expression based on a cell’s MeCP2 levels. Our preclinical studies were designed to directly and rigorously test those assumptions,” McMinn said.
McMinn added that the cell data “demonstrated that miRNA-based auto-regulatory technology is not responsive to endogenous [naturally occurring] MeCP2 levels on a cell-by-cell basis but rather dampens [therapeutic gene] expression regardless of MeCP2 levels.” In other words, the miRNAs act more like a steady dimmer switch that prevents runaway protein production, rather than an automatic sensor that tunes itself to individual cells.
Neurogene is currently running a Phase 3 study called Embolden (NCT05898620), testing NGN-401 in 25 female Rett patients 3 years and older. The study finished dosing earlier this year, and, assuming the findings are positive, Neurogene hopes to use the results as a basis for seeking regulatory approval for NGN-401.
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