Non-toxic NGN-401 Gene Therapy Lets Rett Mice Live Longer

NGN-401, a new gene therapy in the pipeline from Neurogene, extended the lifespan and reduced the disease burden in mice with a form of Rett syndrome, the company announced.

Researchers also observed that the therapy was safe when delivered to mice or early in the life of nonhuman primates, showing the potential for clinical application.

Rett syndrome is most often caused by a mutation in MECP2, a gene that codes a protein needed for the normal development of the nervous system. The disease occurs almost only in girls, as boys will not likely survive early infancy if there is a MECP2 mutation.

To make up for the faulty version of the gene, the researchers delivered a healthy copy of human MECP2 into cells. And to fine-tune its levels, they used EXACT, a technology that allows the researchers to control how much of the delivered gene is on. This lets researchers avoid the toxicity associated with too much MECP2 activity seen with conventional gene therapy.

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“I am pleased that NGN-401, our lead program utilizing EXACT technology, has demonstrated a significant survival benefit and reduced disease burden in a robust preclinical Rett model,” Stuart Cobb, PhD, chief scientific officer at Neurogene, said.

Cobb presented the data in a presentation titled “A self-regulating gene therapy for Rett syndrome” at this year’s American Society of Gene and Cell Therapy (ASGCT) annual meeting in Washington, D.C.

“These data, along with a substantial body of additional preclinical data are foundational to advancing NGN-401 to the clinic,” Cobb said. Cobb is a Simons Fellow and Reader in Neuroscience at the Patrick Wild Centre and Centre for Discovery Brain Science at the University of Edinburgh.

For the preclinical testing, Cobb’s team turned to a mouse model wherein MECP2 had been stripped off. These mice mimic the hallmark symptoms of the human disease. Their median lifespan is 11.7 weeks, and they display motor problems and breathing difficulties.

The researchers delivered MECP2 aboard the adeno-associated virus serotype 9 (AAV9) directly into the cerebrospinal fluid in order for it to bypass the blood barrier in the brain and find its way throughout the central nervous system. The cerebrospinal fluid is the fluid that flows in and around the brain and the spinal cord.

A dose of 1×10¹¹ vector genomes (vg) was enough to extend the lifespan of male mice to a median 22.9 weeks. A higher dose of 3×10¹¹ extended the lifespan further to approximately 37 weeks. Both doses led to an improvement in clinical scores.

In contrast, male mice treated with comparable doses of conventional gene therapy, lacking the EXACT technology, showed signs of toxicity associated with too much MECP2 activity and most died early at around three weeks.

“These data support the use of the EXACT technology in the further development of an effective gene therapy for Rett syndrome that avoids the safety concerns with conventional unregulated gene replacement,” the scientists wrote.

To further study toxicity, the team turned to another mouse model in which MECP2 is switched off in only some of the body cells. Female mice treated with NGN-401 showed no signs of toxicity, while those treated with comparable doses of conventional gene therapy died early. Similar findings were obtained in nonhuman primates.

Cobb’s team has been collaborating with the Rett Syndrome Research Trust (RSRT) to advance NGN-401.

“Once additional preclinical studies and regulatory requirements are completed, Neurogene will request regulatory approval to progress into clinical trials for females affected by Rett syndrome. Following regulatory clearance, Neurogene will be in a position to advance NGN-401 into a human clinical trial,” the company wrote in a letter to the Rett community.

Last year, Neurogene was cleared by the U.S. Food and Drug Administration (FDA) to start a clinical trial of NGN-101, an investigational gene therapy to treat a form of Batten disease.

“The FDA is carefully scrutinizing gene replacement programs, and the fact that Neurogene achieved clearance to move forward with a clinical trial to treat Batten disease, a disorder that, like Rett syndrome, has no genetic-based therapies, is a very positive milestone,” Randy Carpenter, chief medical officer at RSRT, said in a RSRT press release. “I have total confidence in the Neurogene team and look forward to supporting them in their efforts to advance NGN-401.”