Rett gene therapy NGN-401 safe, effective in preclinical models
Phase 1/2 trial now testing treatment's low dose in young girls with Rett
NGN-401, a gene therapy candidate for Rett syndrome that’s now being tested in a Phase 1/2 clinical trial, was demonstrated to ease symptoms and improve survival in a mouse model of the disease, per new study data.
The Neurogene therapy, which uses the company’s proprietary EXACT technology, also showed a positive safety profile in both female and male mice with Rett-like disease, and in healthy nonhuman primates.
“NGN-401 gene therapy for Rett syndrome is our first product candidate incorporating EXACT, which was intentionally developed to deliver therapeutic and tolerable MeCP2 levels,” Rachel McMinn, PhD, founder and CEO of Neurogene, said in a company press release. MeCP2 is the protein lacking in most cases of Rett syndrome.
“The preclinical data [now] published … and the translation of the platform into the clinic support the proposition that EXACT has the potential to overcome the limitations of conventional gene therapy to address Rett syndrome and other devastating disorders,” McMinn added.
The study, “Self-regulating gene therapy ameliorates phenotypes and overcomes gene dosage sensitivity in a mouse model of Rett syndrome,” was published in the journal Science Translational Medicine.
Researcher calls development of NGN-401 ‘a major advancement’
Affecting females almost exclusively, Rett syndrome is most commonly caused by mutations in the MECP2 gene. Such mutations disrupt the function of a protein of the same name, which is involved in the regulation of other genes. The loss of MECP2 in Rett affects the growth and connectivity of nerve cells, giving rise to cognitive, emotional, sensory, and motor symptoms.
The basic concept behind gene therapy for Rett syndrome is to deliver a healthy version of MECP2 to the body’s cells, thereby restoring the gene’s activity. However, gene therapy for Rett is complex because it’s not enough to simply increase MECP2 gene activity: If gene activity gets too high, it can cause problems.
Instead, it’s necessary to finely tune MECP2 activity to a sweet spot of sorts — one that can simultaneously address the disease’s cause but also avoid safety issues.
Achieving this fine balance of MeCP2 levels through gene therapy is even more challenging due to Rett-associated mosaicism in female patients. This results in normal MeCP2 levels in some cells, but MeCP2 deficiency in others.
NGN-401 aims to solve this conundrum using the company’s EXACT technology. It uses a harmless and modified adeno-associated virus serotype 9 to deliver both a healthy version of the MECP2 gene and regulatory machinery that can reduce the gene’s activity if it gets too high, which all works on a cell-by-cell basis.
As such, the one-time therapy, delivered directly into the brain’s fluid-filled cavities, is expected to ensure that gene activity remains in that sweet spot.
Gene therapy with [gene activity] regulation holds the potential to treat a variety of dosage-sensitive disorders that currently have no disease-modifying options available.
“The development of a potential treatment option for Rett syndrome was the impetus for creating EXACT, and its translation to NGN-401 is a major advancement,” said Stuart Cobb, PhD, chief scientific officer of Neurogene and the study’s senior author. “Gene therapy with [gene activity] regulation holds the potential to treat a variety of dosage-sensitive disorders that currently have no disease-modifying options available.”
NGN-401 has been granted regenerative medicine advanced therapy designation in the U.S. for treating Rett syndrome. This status aims to speed the development of promising treatments that have the potential to fill unmet medical needs.
Ongoing trial testing safety of Rett gene therapy in girls ages 4-10
In this study, NGN-401 was tested in multiple preclinical models, including mouse models of Rett syndrome and healthy nonhuman primates.
Initial testing in a commonly used male mouse model of Rett, which completely lacks the MECP2 gene, showed that NGN-401 treatment reduced Rett-like symptoms and extended survival.
In a female mouse model of Rett, which closely resembles the mosaicism in female Rett patients, NGN-401 treatment was well tolerated. By contrast, a conventional gene therapy that delivered the MECP2 gene without the EXACT regulatory machinery led to severe toxicity for these animals.
In healthy nonhuman primates, which have normal MeCP2 levels in all cells, NGN-401 was similarly well tolerated whereas conventional gene therapy resulted in more variable and much higher MeCP2 levels in key tissues relative to NGN-401.
The now-published preclinical results had supported the launch of a first-in-human NGN-401 trial.
That ongoing Phase 1/2 study (NCT05898620) was designed to test two doses of NGN-401 in up to 16 girls, ages 4 to 10, with Rett syndrome. As of late 2024, the study was still enrolling at sites in the U.S., the U.K., and Australia.
All participants are being treated with NGN-401, with the main goal of assessing its safety for up to five years.
Preliminary data from the first three girls given the therapy’s low dose supported NGN-401’s favorable safety profile. That low dose was associated with the attainment of new developmental milestones and meaningful skill gains in the first four treated girls.
However, a girl given NGN-401’s high dose experienced a severe immune reaction, which led to the discontinuation of further high-dose treatments. Testing of the low dose is still ongoing.
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