Ovid, UConn Collaborating to Develop shRNA Gene Therapy for Angelman

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by David Melamed |

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Researchers at Ovid Therapeutics and the University of Connecticut (UConn) have announced a collaborative effort to expedite the development of a short hairpin RNA (shRNA) therapy for patients with Angelman syndrome.

This novel therapeutic approach has potential as a standalone therapy, or in combination with OV101 (gaboxadol), an investigational treatment for Angelman that is currently in a Phase 3 clinical trial (NCT04106557) called  NEPTUNE. Volunteers are still being recruited.

Angelman syndrome is a genetic condition usually caused by a loss-of-function mutation in the UBE3A gene, which provides instructions for making a protein that is involved in nerve cell communication.

shRNA refers to an artificially designed strand of RNA — the intermediate molecular template between information contained within DNA and protein production — that features a tight hairpin turn in its structure.

The sequence of shRNA is designed to block gene expression, the process by which information in a gene is synthesized to create a working product, like a protein. The goal of the research collaboration is to identify target sequences for the shRNA therapy to bind to and limit the expression of UBE3A-antisense, the molecule that causes Angelman by lying opposite of the UBE3A gene and stopping it from working properly.

By restricting UBE3A-antisense expression, researchers hope to restore normal UBE3A gene function in Angelman patients.

“Our lab shares in Ovid’s demonstrated commitment to advance innovative therapeutic options for Angelman syndrome,” Stormy Chamberlain, PhD, said in a press release. Chamberlain is a UConn faculty member involved in the research collaboration.

The use of shRNA has advantages over other gene therapy approaches, as the structure of shRNA is durable, and the method of delivery uses plasmids — small rings of DNA with instructions to code for shRNA — which are stable in the cellular environment.

These advantages potentially could translate into a decrease in the frequency of treatment administration.

“An shRNA therapeutic can target the genetic cause of Angelman syndrome at its source and may offer potential advantages to other next-generation approaches, including antisense oligonucleotide therapy, via a lower rate of degradation and turnover and plasmid delivery allowing for a less-frequent dosing profile,” said Chamberlain.

In the partnership, Ovid gains access to genetic research being conducted at UConn by Stormy Chamberlain, PhD, and Noelle Germain, PhD, including identified sequences that show promise for shRNA development.

“This collaboration with Drs. Chamberlain and Germain, both accomplished scientific leaders in the field of Angelman syndrome, will enable us to accelerate and share in their mission to identify and develop next-generation genetic therapies,” said Amit Rahkit, MD, president and chief medical officer of Ovid.

The researchers at UConn will gain access to Ovid’s resources for preclinical and clinical medication development.

“Ovid is uniquely positioned to accelerate an shRNA therapeutic through late preclinical and clinical development, and our lab looks forward to working with the team at Ovid towards our common objective of impacting the lives of individuals living with Angelman syndrome and their families,” Chamberlain said.

Ovid is developing OV101, a small molecule designed to activate specific neuronal receptors called GABA receptors. GABA is a neurotransmitter, a chemical used by nerve cells to communicate.

OV101, being investigated in the Phase 3 NEPTUNE trial, has been granted orphan drug designation and rare pediatric disease designation by the U.S. Food and Drug Administration.

“Ovid is deeply committed to the Angelman syndrome community. We have made great progress and are excited to see the topline data from our Phase 3 NEPTUNE trial with OV101 expected in [the fourth quarter of] 2020,” Rahkit said.

“We believe OV101 has the potential to serve as a core therapy for this disorder and are now focused on building a comprehensive and strategic Angelman syndrome longer term pipeline. If successful, OV101 may be used in combination with genetic approaches in the future to address the needs of Angelman syndrome,” he said.