Experimental Rett Therapy Now an Orphan Drug in Europe

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by Steve Bryson, PhD |

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The European Commission has granted orphan drug designation to TSHA-102, an investigational gene therapy for the treatment of Rett syndrome.

The designation encourages the development of medicines to diagnose, prevent, or treat life-threatening or debilitating diseases that affect fewer than five in 10,000 people living in the European Union. Its benefits extend protocol assistance in clinical trials, reduced regulatory fees and, if approved, market exclusivity.

“The receipt of orphan drug designation from the European Commission represents an important regulatory milestone that has the potential to expedite the global clinical development of TSHA-102, a one-time gene therapy with disease modifying potential,” RA Session II, founder and CEO of Taysha Gene Therapies, the therapy’s developer, said in a press release.

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The therapy, delivered by injection into the fluid surrounding the spinal canal (intrathecally), uses a harmless adeno-associated virus (AAV) to deliver a copy of the MECP2 gene, which is faulty in most cases of Rett. This gene provides instructions to make the MECP2 protein, which regulates the activity of other genes and plays an essential role in brain development and function.

TSHA-102 is a one-time gene replacement therapy because it contains a shorter, but functional, version of the MECP2 gene with components that activate the gene only in nerve cells. The treatment also includes the novel self-regulating element — miRARE — designed to prevent toxicity due to the overproduction of MECP2 protein.

In preclinical studies, TSHA-102 safely and effectively expressed (activated) the MeCP2 gene in the brain of a Rett mouse model in areas specifically affected by the disease, thereby normalizing the levels of MeCP2 protein. The miRARE element appeared to work as designed by preventing toxic levels of MeCP2. As a result, the Rett mice had significantly enhanced survival.

“Promising preclinical data demonstrate that TSHA-102’s novel self-regulatory feedback mechanism, miRARE, has the ability to regulate MECP2 expression in a genotype-dependent manner on a cell-by-cell basis,” Session said.

“We are highly encouraged that this novel treatment approach can help effectively address a disease that has historically been difficult to treat, and we look forward to submitting [regulatory applications] in the second half of this year and initiating a Phase 1/2 clinical trial by year-end,” he said.

TSHA-102 received orphan drug designation in the U.S. in 2020. It also was granted rare pediatric disease designation, which prioritizes experimental treatments that have the potential to yield meaningful benefits to children who live with serious or life-threatening rare diseases.

Yale University in Connecticut, the Cleveland Clinic, in Ohio, UT Southwestern, in Texas, and biopharma company Catalent are collaborating with Taysha to support their gene therapy programs, which include treatments for other neurodevelopmental disorders, as well as neurodegenerative diseases and genetic epilepsies.