Rett Syndrome Research Trust Helping to Advance HRP-12975

Potential small molecule therapy aims at reactivating silent MECP2 gene

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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The Rett Syndrome Research Trust (RSRT) is supporting ongoing studies of HRP-12975, an investigational therapy for Rett syndrome, using mouse models of the disease.

HRP-12975, being developed by Herophilus, is reported to be the first small molecule therapy with the potential to reverse MECP2 gene deficiency, the leading cause of Rett syndrome.

“Reactivation of the silent MECP2 gene is an important therapeutic strategy for us and we are encouraged by Herophilus’ progress,” Monica Coenraads, CEO of the RSRT, said in a press release.

The amount of the funding given was not specified.

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Goal is to restore MeCP2 protein production, of importance to brain

Most cases of Rett syndrome are due to mutations in the MECP2 gene, which provides instructions to produce the MeCP2 protein. This protein is involved in processes that regulate the brain’s development and function. Since the gene is located on the X chromosome, the disease occurs almost exclusively in girls.

Affected males usually don’t survive infancy and those that do have more severe symptoms, because males lack a second X chromosome with a healthy MECP2 gene copy to compensate for mutations.

Females have two X chromosomes, with only one active in each cell. In the cells where the mutated gene copy is active, the healthy copy is inactive and the cells lack functional MeCP2 protein. HRP-12075 is intended to reactivate the MECP2 gene copy on the silenced X chromosome in brain cells of Rett patients.

This way of gene reactivation avoids the risk of excessive MECP2 expression, which is toxic and is found in other proposed gene therapies, Herophilus stated.

HRP-12075, the company’s the lead treatment candidate, was discovered from a library of 12,000 target compounds for MeCP2 reactivation in neurons and supporting cells, using 3D organoid models of Rett. Specifically, Herophilus uses stem cells derived from patients to generate brain region-specific organoid models, which capture the nerve cell communication network, their activity, as well as tissue structure.

The company also uses machine learning and an integrated automation, software and analytics platform to better understand human brain disease and identify disease modifying therapies.

A collaboration between Herophilus and RSRT started in 2018, and included the development of inducible pluripotent stem cell lines and organoids derived from Rett patients. Of note, induced pluripotent stem cells are created by collecting patients’ cells and reprogramming them back into stem cells, which can differentiate into virtually any cell type in the body.

RSRT now is partly supporting studies by Herophilus into the safety and efficacy of HRP-12975 using genetic mouse models of Rett syndrome. This work, called in vivo studies, allows a potential therapy to be tested in a living organism.

“The Rett Syndrome Research Trust has been instrumental in catalyzing therapeutics development for a devastating, currently incurable, neurodevelopmental disease, and we are grateful for the support and recognition of the potential of our program,” said Saul Kato, PhD, the company’s CEO and co-founder.

Since 2008, the RSRT has awarded $64 million in funding to advance research in Rett syndrome.