Lay Summary of the 2024 Research Roundtable

by Pangkong Fox, PhD, CACNA1A Foundation Science Engagement Director

The CACNA1A Foundation held its third annual Research Roundtable on July 18, 2024. The National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), the largest funding body for scientific research in the United States, generously hosted us in their offices at the Neuroscience Center, in Rockport, Maryland. Fifty researchers and clinicians from the CACNA1A Research Network, including grant program managers from NINDS, members of the CACNA1A Foundation Board and Leadership Team, industry representatives, and researchers and clinicians from around the world, gathered to discuss accelerating the pathway to clinical trials for CACNA1A-related disorders. 

The roundtable began with a focus on the priority symptoms and treatment gaps identified by the CACNA1A community. Data from the CACNA1A Quality of Life Survey and the CACNA1A Disease Concept Model were presented to the Research Network. According to the community, the top three symptoms impacting daily life are ataxia, communication issues, and seizures. These symptoms contribute to a significant burden, including frequent appointments and hospitalizations, multiple intensive therapies for physical and emotional needs, financial strain, and anxiety and stress, all leading to a decreased quality of life.

This third roundtable featured four sessions, each focused on the goals and outputs of three CACNA1A working groups which were launched last fall after the October 2023 Roundtable. 

Session 1 - Quantifying CACNA1A-related disorders: Identifying Biomarkers, Outcome Measures, and Endpoints for Clinical Trials

This session focused on approaches to assess changes in ataxia and communication, the top two most impactful CACNA1A symptoms reported by the community. Outcome measures and endpoints are crucial as they define how a potential treatment will be evaluated. The more precise these parameters, the higher the chance the treatment will be approved. Discussions included potential new treatments for episodic ataxia and the relevant outcome measures that could be used.There was also discussion surrounding the Observer-Reported Communication Ability (ORCA), developed as a communication outcome measure for other rare, neurodevelopmental diseases, and its potential application to our community. Additionally, a summary of the CACNA1A Natural History Study data was presented, highlighting potential outcome measures and endpoints for clinical trials.

Session 2 - What’s New in Translational Research: Multiple Shots on Goal

This session showcased three different approaches for treating CACNA1A-related disorders. One approach focused on targeting Cav2.1, our calcium channel, by prolonging the presence of healthy channels. However, because cells are very sensitive to calcium levels, both too little and too much can be harmful. Therefore, researchers are exploring alternative molecules or cellular components, such as SK channels, which respond to calcium levels and are crucial for neuronal communication. Manipulating SK channels could potentially improve ataxia. Additionally, Bexacaserin, a molecule affecting neurotransmitters in the central nervous system that does not act on Cav2.1, was also discussed as an anti-seizure treatment.

Session 3 -  Refining CACNA1A Variant Classification

This session addressed the challenge of classifying CACNA1A variants as Loss-of-Function (LoF) or Gain-of-Function (GoF). This classification is not straightforward, as the impact of each variant on channel function can vary based on the experiments and preclinical models used, such as cells, human neurons, or animal models. The session also considered the relevance of variant functionality for treatment. For treatments targeting the Cav2.1 channel, distinguishing between LoF and GoF variants is crucial. However, some treatments may focus on alleviating the consequences of a variant rather than directly addressing the channel function. In these cases, the functional impact of variants may not be as important. The session also explored how to best represent the spectrum of symptoms associated with different variants and how this information can be aggregated and curated in the CACNA1A Data Portal for use in treatment development.

Session 4 - The Preclinical to Clinical Pathway

This session featured work aimed at bridging the gap between basic research (fundamental disease knowledge) and translational research (applying knowledge to treat patients). Roscovitine, a drug that is in phase 2 clinical trials for another disease, was tested on CACNA1A mouse models and showed potential for treating CACNA1A-related epilepsies. CNV’944, a drug that impacts Cav2.2—a different but similar calcium channel—was tested in mammalian cells, human iPSC neurons, and brain slices from CACNA1A mice. While the results did not immediately indicate a clear impact of CNV’944 on CACNA1A-related disorders, next steps were outlined to continue exploring this drug and to establish a pipeline for testing potential drugs in the future. Additionally, this session touched on potential collaborations with the NIH, notably the National Center for Advancing Translational Sciences (NCATS), to screen for new drugs to test on CACNA1A preclinical models.

Key Takeaways  

To achieve successful clinical trials for CACNA1A-related disorders, the CACNA1A Foundation, community, and Research Network must learn from other groups that have reached these milestones. 

• Different approaches will be needed to address the diverse symptom presentation in our community. While we cannot focus on all strategies simultaneously, we are identifying the critical research gaps that need to be filled to move forward with multiple approaches.

• Gathering data from our community over a long period of time is key to understanding disease progression and determining which treatments are needed as symptoms evolve. We must come to a consensus on the type of data required to develop treatments that will advance to clinical trials, and collect it systematically, minimizing strain on our CACNA1A community. 

• Collecting this information is crucial, as is making it accessible to all stakeholders– researchers, clinicians, industry, and families. The goal is to aggregate all the data into the CACNA1A Portal, making it readily available for those who need it. 

• Stratifying variants according to their functional consequences remains a challenge. However, pathways to clinical trials without in-depth knowledge of variant function have been identified and can be pursued.

• Developing consensus treatment guidelines for CACNA1A-related disorders is a priority. A proactive care plan for the community, including recommendations for managing movement disorders, hemiplegic migraine, epilepsy, and developmental symptoms, is being developed as a resource for families and providers.

• A collaborative pathway is the only way forward. To achieve our mission of finding better treatments and a cure for CACNA1A-related disorders, we must continue a strong partnership between the families, the Foundation, and the research network. Families will provide the information and tools to understand our disease. Researchers will utilize these assets to develop and test treatments. And, the Foundation will bridge these two communities, supporting and holding them together to move forward.