Kabuki Syndrome Foundation Testing Vafidemstat in Kabuki Syndrome Mouse Model

Thanks to donations made by Kabuki syndrome families, the Kabuki Syndrome Foundation is funding $300,000 to test Oryzon’s vafidemstat in a Kabuki syndrome mouse model. Researchers believe vafidemstat could improve the cognitive and behavioral symptoms seen in Kabuki syndrome. This mouse study aims to validate the therapeutic potential of vafidemstat and its associated pathway (LSD1), shedding light on a future decision to invest $5 million in the first industry-led clinical trial for people with Kabuki syndrome. 

What is Vafidemstat?

Vafidemsat is an LSD1 inhibitor developed by Oryzon. This orally administered small molecule drug has been administered to more than 400 people across multiple ongoing and completed clinical trials. It has shown some promise in modifying cognitive function and behavior in autism, adult Attention Deficit Hyperactivity Disorder, Alzheimer’s disease, and Borderline Personality Disorder. Its efficacy in people with Kabuki syndrome has not yet been determined, but there is data that indicates an LSD1 inhibitor could be a promising treatment candidate for Kabuki syndrome.

Kabuki syndrome is caused by mutations in the genes KMT2D and KDM6A, which are crucial for epigenetic regulation and gene expression. Given that vafidemstat targets a parallel pathway involved in gene expression, researchers hypothesize that it could help restore some of the disrupted epigenetic mechanisms seen in Kabuki syndrome. If successful, the drug could potentially improve cognitive deficits and other symptoms associated with the condition.

In 2022, Oryzon announced a collaboration with Dr. Jacqueline Harris and later KSF to design a Phase 1/2 clinical trial that would evaluate vafidemstat in people with Kabuki syndrome, called HOPE that could begin in 2024. Due to a shift in the economic climate, Oryzon reorganized their drug development pipeline to focus the development of vafidemstat in other indications that had an ongoing clinical trial and due to lack of funding, they deprioritized the Kabuki syndrome HOPE trial. Oryzon shared with KSF that a $5-6 million investment would be needed to start the HOPE clinical trial at this time. This is not uncommon in rare disease drug development and illustrates the crucial role that community-led foundations like KSF play to ensure potential treatments reach patients. 

Why Test Vafidemstat in Kabuki Syndrome Mice Now?

Following conversations with industry advisors and a thorough evaluation of data shared by Oryzon, KSF recognized the need for additional preclinical data, such as testing in a mouse model, before moving forward with fundraising and investing in this clinical trial. Currently, only one published study has explored the LSD1 pathway in Kabuki syndrome, using a compound owned by Takeda Pharmaceutical Company; this compound is distinct from vafidemstat. Testing vafidemstat in a mouse model will help determine if it can produce meaningful benefits for people with Kabuki syndrome. Additionally, this preclinical work can help determine whether targeting the LSD1 pathway is a viable therapeutic strategy for Kabuki syndrome and could unlock opportunities to explore other therapies that target this pathway.

How is Vafidemstat Tested in Kabuki Syndrome Mice?

To generate data crucial for furthering our understanding of vafidemstat and the LSD1 pathway, KSF engaged InnoSer, a preclinical contract research organization (CRO), to conduct several studies in a mouse model of Kabuki syndrome. InnoSer has specialized experience in rare disease studies and is committed to improving the health of patients. The current Kabuki syndrome studies at InnoSer include:

• Pharmacokinetics to understand how the drug is absorbed and metabolized by the body,
• Molecular studies to understand the drug’s impact at the cellular level, and
• Behavioral testing and neurogenesis (formation of new brain cells) assessments to evaluate the drug’s impact on learning, memory, and functional outcomes.

Results are anticipated later in 2025 and will be shared with our family and research communities.

The Kabuki syndrome mouse model will continue to be available at InnoSer for future therapeutic testing. This enables future studies on potential treatments to be initiated more quickly and accelerate therapeutic development for the Kabuki syndrome community.

What This Means for Kabuki Syndrome Families

While dosing the mice with vafidemstat has just started, this research represents the power of our community to not only advance but to also accelerate Kabuki syndrome drug development. If vafidemstat proves beneficial in mouse models, it could pave the way for a clinical trial, offering hope for a targeted therapy that addresses cognitive and behavioral challenges in individuals with Kabuki syndrome.

The Kabuki Syndrome Foundation remains committed to sharing updates on this and other promising research. We have invested in several potential treatments for Kabuki syndrome within a diversified pipeline to maximize our chances of finding effective treatments. Sign up below to stay connected as we continue advocating for Kabuki syndrome treatments.Families, we invite you to join Kabuki Count, the global census and contact registry.

Resources for Researchers

If you are a researcher interested in Kabuki syndrome, please visit our Resource page or contact our Director of Research, Dr. Clara Tang.