Drug repurposing offers hope for SYNGAP1 patients

The SynGAP Research Fund 501(c)(3) has awarded a pair of grants to Dr. Clement Chow, a geneticist and Associate Professor in the Department of Human Genetics at the University of Utah. These grants are crucial steps in advancing therapeutic development for SYNGAP1-Related Disorders (SRD). 

Dr. Chow has a strong track record with drug discovery with publications and patients being treated in NGLY1 deficiency, Charcot-Marie-Tooth Disease (CMT4J), Retinitis Pigmentosa, and Congenital Disorders of Glycosylation (NGLY1, PIGA-CDG, DPAGT1-CDG) diseases. 

The first grant, awarded in 2023, used a commercially available raskol RNAi knockdown Drosophila (fruit fly) model that replicates the SYNGAP1 mutation observed in patients, providing a critical tool for drug screening. Through this model, Dr. Chow's team screened approximately 1,600 primarily FDA-approved drugs, leading to the identification of N-acetyl-L-leucine (NALL) as a promising candidate for treating SRD. NALL, a modified amino acid, has demonstrated potential in stabilizing brain function and enhancing cellular processes like autophagy. It has been explored in clinical trials for conditions such as cerebellar ataxia and Niemann-Pick disease type C, where it has shown some efficacy in improving motor function and overall quality of life in patients. 

Building on these promising results, the follow-up grant, funded in 2024, supports advanced studies to validate NALL's therapeutic potential and understand how it may alleviate the symptoms of SYNGAP1-Related Disorders. These preclinical studies are not only critical for fast-tracking potential treatments into clinical settings but also for deepening our understanding of the underlying biology of SYNGAP1 mutations.

NALL was approved by the FDA for NPC on September 24, 2024 under the brand name AQNEURSA™ (levacetylleucine). 

Why SRF is supporting this project

The Syngap Research Fund (SRF) is committed to advancing the development of treatments that can improve the quality of life for individuals affected by SRD. Drug repurposing is a key strategy in this mission, as it allows researchers to identify potential treatments from molecules that are already known to be safe in humans. By screening existing FDA-approved drugs, researchers can bypass early stages of drug development, such as safety testing, since these drugs have already been approved for other uses. This approach can significantly shorten the timeline from discovery to clinical application, which is critical for families and patients dealing with the urgent and debilitating symptoms of SYNGAP1-Related Disorders.

SynGAP Research Fund's Scientific Director, Lindsay Wieczorek, PhD, says, "For families grappling with the challenges of SYNGAP1-Related Disorders, the standard timeline of drug and treatment development is simply too long. Each day without an effective therapy feels like an eternity when you're watching your child and family struggle. That's why drug repurposing is so critical-;It allows us to streamline the process and focus on what truly matters: finding and delivering solutions that can make a real difference now. At SRF, we're committed to pursuing every possible avenue to bring these treatments to our community as quickly as possible."

Mike Graglia, Founder of SRF, says "Dr. Chow is exceptionally collaborative. We are lucky to be working with him. This was the fastest follow-on grant we have ever approved, both because of the impact of this work and because Dr. Chow and his lab are such good partners. I encourage all patient advocacy groups to reach out to him."

Potential impact of the research

Dr. Chow's research has the potential to significantly accelerate the development of effective therapies for SYNGAP1-Related Disorders through the innovative use of drug repurposing. By leveraging existing FDA-approved drugs, this approach can bypass the lengthy and expensive early stages of drug development, focusing instead on identifying compounds that may offer immediate therapeutic benefits for SYNGAP1 patients.

The identification of NALL as a top candidate for treatment demonstrates the promise of this strategy. If further studies validate NALL's effectiveness, it could be transitioned into clinical trials more quickly than a new drug might be. While this research primarily focuses on SRD, the success of this approach could also provide valuable insights for applying drug repurposing to other rare neurodevelopmental conditions, potentially broadening the impact of these findings.

We want to help people living with SYNGAP1 however we can. By combining the unique advantages of the fruit fly with drug repurposing we can quickly uncover a potential therapy that may change lives. Drug repurposing holds the potential to help SYNGAP1-related disorders and many other rare diseases."

Dr. Clement Chow, Geneticist and Associate Professor, Department of Human Genetics, University of Utah