Lay Summary of the 2023 Research Roundtable
The CACNA1A Foundation hosted its second Research Roundtable: Collaborating to Accelerate the Path to CACNA1A Clinical Trials on October 9-10th at the New York Academy of Medicine in New York City. There were over 55 attendees, including 48 researchers, clinicians, trainees, and representatives from industry and the NIH. In addition, the Foundation Board, its Leadership Team, and a CACNA1A family who came to share their story were there. The overarching purpose was to exchange ideas and build collaborations among the CACNA1A Research Network to develop CACNA1A-specific treatments and push them into clinical trials for FDA approval. The meeting was divided into four sessions, each focused on one of the following goals:
Develop strategies for identifying biomarkers and endpoints for CACNA1A-related disorder. Session #1 focused on discussing approaches to help quantify the spectrum of CACNA1A-related disorders, especially those that are episodic in nature, in order to design effective clinical trials. Biomarkers are measurable traits or outcomes used to assess the impact of a treatment. There are currently no validated biomarkers for our disease.
Develop a more comprehensive framework for classifying CACNA1A variants. It is clear that variants do not always fall into discrete functional categories of Loss-of-Function (LoF) or Gain-of-Function (GoF). Session #2 focused on utilizing existing functional and clinical data to collectively identify criteria to help us better classify variants and guide treatment development.
Explore new approaches to understand and target the pathophysiology (disease mechanisms) of CACNA1A-related disorders. Session #3 highlighted research in diverse model systems (cells/animals/flies, etc.), identified which systems can be used to determine critical windows of treatment, and identified variants or other molecules that could be ideal therapeutic targets. All of these allow for better design and testing of treatments for our disease.
Identify the components needed to build a robust proof-of-concept package to attract industry partnerships. In collaboration with the CACNA1A Research Network and rare disease partners, the Foundation continues to build a robust preclinical research portfolio to support therapeutic development. Session #4 highlighted a new parallel focus: how to form partnerships with industry to help advance potential treatments from preclinical work to clinical trials.
At the conclusion of the meeting, the Research Network agreed to continue the work laid out and tackle the gaps and challenges ahead by joining committees that will meet monthly. Please read on for a summary of the talks and, at the end of this post, a discussion of the working groups and next steps.
Session #1: Quantifying CACNA1A Phenotypes: Developing Outcome Measures and Endpoints for CACNA1A-Related Disorders. Chair: Elsa Rossignol, MD, MSc, FRCP, University of Montreal
These talks laid the groundwork for how the CACNA1A Foundation and Research Network can identify robust biomarkers for the CACNA1A community to prepare for clinical trials. Because there’s a lot to learn from those who have already done this successfully, we kicked off the session with Jennifer Panagoulias, Head of Regulatory Affairs for the Foundation for Angelman Syndrome Therapeutics (FAST) and Chief Regulatory and Compliance Offer for Mahzi Therapeutics, who explained how the Angelman Syndrome community successfully identified a Delta power EEG biomarker through their Angelman Biomarkers and Outcome Measures Alliance (ABOM), which has been validated as a reliable marker that can be used to assess if a treatment is effective for the Angelman community. Kevin Bender, PhD (University of California San Francisco Weill Institute for Neurosciences) also spoke about biomarkers. He presented work from his lab identifying an eye reflex biomarker for SCN2A-related disorders. This Vestibular Oculomotor Reflex (VOR), which measures the stability of the eyes when the head moves, was found to be more sensitive in children with SCN2A-related disorders than those without. If the VOR is restored or improves with a potential treatment, it could be an ideal biomarker or outcome measure for clinical trials in the SCN2A community.
Joanna Jen, MD, PhD (Icahn School of Medicine at Mount Sinai) and Jacqueline French, MD (NYU Grossman School of Medicine) spoke about how clinical trials have been designed for Episodic Ataxia Type 2 (EA2) and rare pediatric epilepsies, respectively. Dr. Jen outlined small, published clinical studies that trialed Acetazolamide (Diamox) and 4-aminopyridine (4-AP), two current treatments for Episodic Ataxia Type 2 (EA2). She emphasized the importance of identifying reliable biomarkers/outcome measures for EA2, focusing on identifying what is important to measure: severity, duration, frequency, cognition, cerebellar atrophy, etc. Dr. French outlined important considerations when designing clinical trials for rare pediatric epilepsies, emphasizing that current treatments consist of general anti-epileptic drugs that address seizures across many genes. However, they do not address the underlying cause of each disorder, which remains a challenge when developing the gene-specific treatments we are striving for. The challenge also lies in how to accurately assess the impact of a drug on a disease with a diverse spectrum of seizures and non-seizure phenotypes (such as CACNA1A-related disorders). Well-defined biomarkers and outcome measures are one way to help remedy this.
Session #2: Improving CACNA1A Variant Classification. Chair: Alfred George, MD, Northwestern University
Simply stated, understanding the mechanism of a variant should help with diagnosis and treatment. This session explored the work being done to improve the classification of variants. First, Laina Lusk, MMSc, LCGC (Children’s Hospital of Philadelphia), presented an overview of the clinical spectrum of 455 CACNA1A patients identified from the scientific literature or patient cohorts from neighboring sites. Just over 300 unique variants were reported, with 24 of them recurrent in the population studied. An analysis was done across all patients to compare symptoms between all variants and within recurrent variants. Based on preliminary data, she and her team are able to predict the likelihood of specific symptoms based on variants.
Focusing on the molecular aspect of variants, Jen Pan, PhD (Broad Institute of MIT and Harvard), presented her work functionally characterizing 50 CACNA1A variants. She first tested the impact of individual CACNA1A variants on channel function in a cellular system, which gave an initial readout of either LoF (too little calcium entering the cell) or GoF (too much calcium entering the cell). The next level of characterization was done using predictive computer modeling to explore the impacts on the neural networks within the cerebellum, where CACNA1A impacts balance, coordination, and motor function. Some variants showed different effects between the two model systems, suggesting that the LoF or GoF effects can change depending on cell type, which must be taken into account for treatment development.
Marina Hommersom, MSc (Radboud University Medical Center), also explored the impact of CACNA1A variants but in a different model system, cortical neurons derived from patient iPSCs (reprogrammed stem cells). These types of neurons impact seizures, cognition, and behavior. Marina found that cortical neurons from a LoF patient showed a disruption in their firing patterns, which is how the neurons transmit information. Additionally, treatment with 4-AP was able to partially restore the firing pattern back to normal. Computer modeling was also used to predict the impact of the LoF variant on neural networks. These predictions were similar to what was found in the derived cortical neurons. While further work is needed to explore other types of variants, the framework she is building has the potential to help classify CACNA1A variants in specific cell types.
After the presentations highlighting the clinical and molecular spectrum of CACNA1A variants concluded, Dennis Lal, PhD (University of Texas Health Science Center at Houston), wrapped up the session with a demonstration of the updated CACNA1A Portal, where data from 450 variants have been aggregated and curated for use by families, researchers, and clinicians. Over the last two years, Dennis and his team have worked closely with the CACNA1A Foundation and Research Network to build this open science portal. Features include educational resources, a searchable variant database, and tools for deeper scientific analysis of variants. The portal is set to launch by the end of this year.
Session #3: Strategies for Targeting the Pathophysiology of CACNA1A-related Disorders. Chair: Jeffrey Noebels, MD, PhD, Baylor College of Medicine
After breakfast and an update on the developing Clinical Care Guidelines, we started day two by discussing how different model organisms (fruit flies and roundworms) can be utilized to help with variant classification and treatment development. Michael Wangler, MD (Baylor College of Medicine) spoke about previous work in his lab using Drosophila melanogaster (fruit flies) to characterize two CACNA1A variants, R1664Q and R1673P. Overall, R1664Q showed LoF effects in the fly system and was much less severe than R1673P, which showed more GoF effects. However, both variants had similar clinical presentation in patients. Interestingly, additional work in cells showed that R1673P had both LoF and GoF effects on calcium channel activity, suggesting that some variants are more complex than others.
Peri Kurshan, PhD (Albert Einstein College of Medicine), shared her work using Caenorhabditis elegans (worms) to model pathogenic CACNA1A variants and further demonstrated the complexity of variants that impact channel function and brain development. All variants studied reduced the amount of the calcium channel at the synapses where neurotransmission occurs. However, some variants showed an increase in neurotransmission even with reduced levels of channel present. The worm system is also set up to easily screen potential drug treatments.
Fikri Birey, PhD (Emory University College of Medicine), presented work in a new model system that has not been previously used to study CACNA1A-related disorders. Brain organoids are 3-D models of neural networks that can be generated from patient-derived iPSCs. This model allows for an even more detailed analysis of how variants impact the dynamics of brain formation. How do neurons move, grow, and connect when CACNA1A is disrupted? And how does this translate to the symptoms and disorders seen among CACNA1A variants? Fikri’s work has led to the discovery of new mechanisms of disease linked to other calcium channel genes and has the potential to be applied to CACNA1A-related disorders.
Lastly, Sam Young, PhD (University of Iowa), presented his work on developing new viral vectors to efficiently and safely deliver CACNA1A into the cerebellum, a precursor to gene replacement therapy. Previously used vectors are too small to package up the large CACNA1A gene for gene therapy. However, using a combination of cellular systems and mouse models, Sam showed that this new vector can deliver the gene to the cerebellum and express it in Purkinje cells, setting up the potential for a treatment that can address the root cause of CACNA1A-related disorders and not just the symptoms.
Session #4: Developing a Proof-of-Concept Package for CACNA1A-Related Disorders: The Industry Perspective. Chair: Yael Weiss, PhD, Mahzi Therapeutics
The last session focused on how to move potential treatments through the regulatory pathway (going from preclinical studies to clinical trials). Yael Weiss, PhD, CEO and Founder of Mahzi Therapeutics, outlined her company’s approach to support rare disease treatments. Mahzi is unique in that it partners with rare disease organizations still in the preclinical (basic) research stage but ready to start building proof-of-concept “packages” to apply for clinical trials. These critical proof-of-concept studies show that the disease/gene is amenable to the candidate treatment. She also re-emphasized the requirement for robust, disease-specific biomarkers to enter the regulatory pathway.
Scott Kanner, PhD, Co-Founder and Associate Director of Platform Sciences at Stablix, Inc., spoke about the therapeutic approach to disease his company focuses on. Scott, a former graduate student of the Foundation’s Scientific Advisory Board Member, Dr. Henry Colecraft, helped develop a technology that can target a protein to either be degraded (destroyed) by the cell or kept around longer. This approach has been used to successfully treat other ion channel disorders and has the potential to be applied to CACNA1A-related disorders.
Lastly, Sam Hopkins, PhD, Senior Vice President of Therapeutics at AskBio, presented guidance on identifying the pivotal studies that can help push drug approval from the FDA. He encouraged us to use the strong preclinical toolbox we have built with our patient and scientific communities to generate the right data. We should expand current translational research work within our research network by providing the right tools and promoting collaboration. Sam also pointed the Foundation to FDA programs that could provide support for the regulatory pathway.
Next Steps: CACNA1A Working Groups
The roundtable wrapped up with a presentation by Pangkong Fox, PhD, our Science Engagement Director, on the working groups that would be generated to actively tackle the key questions remaining in each of the main session topics. Each group will work with the Foundation over the following months and report to the entire Research Network at next year’s Research Roundtable in July 2024. The following groups are being formed:
Natural History Study. Purpose: Work with Wendy Chung, MD, PhD (Harvard University/Boston Children’s Hospital) to refine the CACNA1A Natural History Study to identify biomarkers/outcome measures and build an effective placebo arm for clinical trials. The main strategies include performing a more comprehensive analysis of the current data set, re-assessing the NHS publication, and re-assessing the NHS questionnaire for new questions or assessments.
Variant Classification. Purpose: Design a strategy to comprehensively classify CACNA1A variants. The primary strategy is to identify “gold standards” for clinical and functional characterization to build robust genotype-phenotype studies and help understand disease mechanisms. Also, consider the formation of a Variant Expert Curation Panel to help classify the pathogenicity of variants.
Biomarkers and Outcome Measures. Purpose: Identify outcome measures for CACNA1A-related disorders to support clinical trials. The primary strategy includes reviewing current outcome measures used in other rare neurodevelopmental diseases and validating them for our disease, analyzing CACNA1A patient data to identify new biomarkers, and identifying wearables or technology that could be utilized to find and/or validate biomarkers.
Preclinical-to-Clinical (PTC). Purpose: Identify and carry out pivotal studies to support proof-of-concept packages, apply for clinical trials, and eventually approve treatments for CACNA1A-related disorders. The main strategy includes building a regulatory framework, identifying synergies between the CACNA1A Research Network, promoting collaborations, and building a working relationship with the FDA in anticipation of clinical trials.
At the conclusion of the two-day meeting, the energy in the room was apparent among the research network. The members were enthusiastic to continue the discussions and join the working groups to collaborate and move us closer to specific treatments. We invite all of our families, friends, and donors to continue their partnerships with the Foundation so we can help not just improve the quality of life for our CACNA1A community but also change their lives.