Lay Summary of the September 2022 Research Roundtable
The CACNA1A Foundation hosted its first Research Roundtable: Collaborating to Accelerate the Path to CACNA1A Clinical Trials on September 22nd and 23rd at the New York Academy of Medicine in New York City. It was a historic event with 37 of the world's experts on CACNA1A, ion channels, genetics, ataxia, epilepsy, hemiplegic migraine, and eye movement disorders convening for the first time with the following goals in mind:
Identify gaps in understanding how CACNA1A variants lead to disease.
Identify the correct methods of obtaining this crucial data.
Apply the data to translational research for developing therapeutic treatments that will have the greatest impact on those living with CACNA1A-related disorders.
The two-day conference was divided into three sessions, each with four presentations, followed by a facilitated discussion. The meeting closed with a wrap-up session focused on next steps for the CACNA1A Foundation and the CACNA1A Research Network to move treatments into the clinical trial pipeline. Read on for a summary of the presentations. Please note that these presentations and discussions were geared towards a scientific audience. However, we have tried to simplify the science as much as possible for our readers.
Session #1: Understanding Genotype-Phenotype Correlations and Characterizing the Natural Evolution of CACNA1A-related Disorders
Wendy Chung, MD, PhD (Columbia University Irving Medical Center), in her talk, The Genotype-Phenotype Spectrum of CACNA1A Variants, shared data and early trends observed from the CACNA1A Natural History Study (NHS). She stated that there were some patterns in variant clustering based on a variant's location in the protein, and as result, more patients are needed to enroll in the NHS to validate the trends and tease out any other patterns, especially for genotype-phenotype (variant and associated patient symptoms) correlations. We know from our discussions with various biotech companies that a clear understanding of genotype-phenotype correlations is one of the key factors they use in determining which diseases to focus on from a therapeutic development standpoint. If we are able to get 500 individuals enrolled in the NHS, some of these patterns will become clearer and companies will be more interested in our disease.
Ingo Helbig, MD (Children's Hospital of Philadelphia), in his talk entitled Pediatric Presentation of CACNA1A-related Disorders, emphasized the differences in how CACNA1A-related disorders present in children versus adults. Furthermore, clinicians must know and understand this distinction to provide the proper care and treatment. He stressed the need for a more streamlined protocol for treatment, especially for hemiplegic migraines, the most poorly understood of CACNA1A-related disorders.
Anne Ducros, MD, PhD (University of Montpellier), in her talk, Understanding Genotype Phenotype Correlations and Long-term Outcomes in CACNA1A-related Familial Hemiplegic Migraine, provided insight into the presentation of Familial Hemiplegic Migraine Type 1 (FHM1) and how symptoms of FHM1 can change over the lifetime. While familial hemiplegic migraine is not as severe as the sporadic form, Dr. Ducros also echoed the need for clearer plans of treatment to avoid misdiagnosis or misinterpretation of symptoms.
Dennis Lal, PhD (Cleveland Clinic Lerner Research Institute), in his presentation, Organizing and Mining the CACNA1A Variant Database, provided updates on the CACNA1A portal that he had unveiled at the CACNA1A Creating Connections Family Conference in July. The portal now contains data from 280 patients pulled from the Natural History Study, Children's Hospital of Philadelphia, Boston Children's Hospital, Clinvar, and the UK Biobank. New additions included updated HPO terms (describing symptoms) and more data analysis available for variants. Dr. Lal also asked all the researchers and clinicians in attendance to send him any variant information they had. The more data that goes into the portal, the more accurate and valid the analysis will be for research purposes. To that point, more data is also needed before we will officially launch the portal, so if you haven’t done so, please sign up for the Natural History Study.
Session #2: From the Bench to the Brain: Translational Research and Trial Readiness
Xiaofei Du, MD (University of Chicago), in her presentation, Decoding the Phenotypic Heterogeneity of Calcium Channel Diseases, spoke about alpha1ACT (ɑ1ACT), the second protein encoded by the CACNA1A gene, and its potential use as a therapeutic for CACNA1A-related disorders. Dr. Du showed that when extra ɑ1ACT is expressed in a CACNA1A variant background, it has the ability to restore some of the defects seen including survival rate, ataxia, and neuron growth. Since ɑ1ACT is a transcription factor that can turn genes on, Dr. Du is also focused on looking at changes in the expression patterns of other related genes in the CACNA1A variant backgrounds. This could provide more molecular clues as to how CACNA1A-related disorders arise and how genes regulated by ɑ1ACT could be potential therapeutic targets.
Joanna Jen, MD, PhD (Icahn School of Medicine at Mount Sinai) spoke about how loss-of-function variants that are grouped together can still show differences in symptoms and severity, in a presentation entitled, Phenotypic Variability of Presumed Loss of Function. CACNA1A Mutations Missense variants that seem to lead to loss of ion channel activity are often lumped in with the more severe truncation or splice-site variants. However, there are likely different molecular pathways that lead to disease between these variants. We must be mindful of this since treatments can depend on which molecular pathway is affected.
Jeffrey Noebels, MD, PhD (Baylor College of Medicine), in his talk, Loss of Function Phenotypes in Mouse Models, discussed the complexities of studying CACNA1A variants (or any variants) within the brain. While we tend to focus on specific cells (i.e., in the cerebellum), cells in other parts of the brain are also affected when there is a global loss of CACNA1A function. Identifying which of these neuronal circuits are the most crucial and the window of time in development in which the loss has the most significant impact are vital to finding the right therapies. If treatments aren't administered during the correct period of development, they may not be effective.
Elsa Rossignol, MD, MSc, FRCP (Chu Ste-Justine, University of Montreal) provided unpublished data on gain-of-function variants linked to epilepsy in a presentation entitled, Functional Validation of Patient-Derived Mutations and Generation of Novel Animal Models. Her work also echoed the diversity of symptoms observed in different cell types and at different periods during development.
Session #3: Toward New CACNA1A Therapies
Zameel Cader, DPhil, MRCP (Oxford Headache Centre) presented on How iPSC Disease Models Can Accelerate Translational Research, describing how patient-derived induced pluripotent stem cells (iPSCs) can be used to study the disease mechanisms of CACNA1A-related disorders. There is a large gap in understanding how variants lead to disease. These cells provide more genetic information, such as variations in other genes that might influence how CACNA1A symptoms present in a patient. They can also be used to study whether the phenotypes seen in cells correlate to the clinical phenotypes observed in patients. Dr. Cader also discussed one of the biggest obstacles for CACNA1A treatments, which is getting them across the blood-brain barrier (BBB). However, new research initiatives focus on learning more about the BBB so that treatments can be developed for effective and safe delivery to the central nervous system.
Jen Pan, PhD (Broad Institute of MIT and Harvard), in her presentation, Sleep EEG as Biomarkers for Psychiatric and Neurodevelopmental Disorders, described the potential use of sleep biomarkers for CACNA1A-related disorders. She gave examples of how quantitative EEGs (qEEGs) have been used to identify consistent and unique patterns of brain activity, such as sleep spindles and oscillations during sleep cycles, in patients with schizophrenia. This type of analysis has also been used for other neurodevelopmental diseases such as Angelman's Syndrome and 22p11.2 Deletion Syndrome. Dr. Pan has been working on establishing metrics to define groups within patient populations with unique EEG signatures. This is especially important for the CACNA1A community, as our patients present with such diverse symptoms, even among patients with epilepsy. She hopes to identify signatures in CACNA1A patients and look for correlations between those signatures and specific symptoms in order to establish our first CACNA1A biomarker. Such a biomarker would allow researchers to see how well the body responds to a potential treatment for CACNA1A-related disorders. In addition, having a clear biomarker is another key factor that biotech companies use in determining which diseases to focus on from a therapeutic development standpoint.
Henry Colecraft, PhD (Columbia University Irving Medical Center) presented unpublished work using iPSC lines and mouse models of CACNA1A variants. In his talk entitled, A Multi-Step Approach Towards Developing CACNA1A Therapeutics, he also discussed some potential new treatments that looked promising based on preliminary findings in his lab.
Charlie Cohen, PhD (BioIntervene) provided a detailed analysis of how we can approach CACNA1A-related disorders by looking at treatments already available for other calcium ion channels in his presentation, Developmental Strategies for Therapeutics Targeting CACNA1A Disorders. Dr. Cohen recommended a few candidates that could be tested on available CACNA1A animal models and iPSC lines for both gain-of-function and loss-of-function variants. Some candidates target molecules that influence ion channel activity rather than the ion channel itself, giving us more options. He also pushed for partnerships with biotech companies with the technology to perform in silico (computer simulation) screens to find new drug candidates, which would be the most efficient way to do this. Dr. Cohen also echoed the need to find biomarkers outside the central nervous system.
The final Roundtable discussion centered on a few key items:
A consensus of treatment for all CACNA1A-related disorders. There was broad agreement that there needs to be a consensus set of treatment and management guidelines available for our patient community. Dr. Kristin Barañano, MD, PhD (Johns Hopkins Medicine) agreed to lead this international initiative and many of the attendees offered to contribute in their fields of expertise. Patient representatives from the Foundation will participate in developing and reviewing the guidelines. The goal will be to publish the guidelines, so they are widely accessible.
This endeavor will gather evidence to support the recommended treatments and medications. A centralized reporting system will be established so all members of the working group can access the data to form a consensus. Ultimately, we hope that clinicians will be able to use these guidelines to deliver the most effective treatment plan for CACNA1A patients, especially in acute emergency settings.
Expand CACNA1A preclinical assets. The CACNA1A Foundation will continue to build up our preclinical assets in order to accelerate translational research. While the Foundation has established a biobanking program, it is clear that isogenic control lines and mouse models that complement iPSC lines are necessary for a deeper understanding of how CACNA1A variants lead to disease. Current assays or experimental protocols will also be shared among researchers to increase transparency and collaboration. Having a catalog of all these tools in a central location accessible to the entire CACNA1A Research Network would be valuable, so the Foundation agreed to create such a catalog and add it to the variant database. The Foundation will continue to support the generation of such disease models, as well as projects that focus on how each variant impacts protein structure, function, and expression. Once this gap is filled, it will be easier to identify biomarkers, drug targets, and effective windows of treatment to ultimately match up the correct treatments to variants and their corresponding symptoms.
Build on current pharmacology. Scientific Advisory Board member Charlie Cohen, PhD strongly recommended that the CACNA1A Foundation look to available treatments for other calcium ion channels as a starting point rather than start a drug screen from scratch. The specific pore-forming domain of Cav2.1, the calcium ion channel encoded by the CACNA1A gene, is very similar in structure to Cav2.2 (CACNA1B) and Cav2.3 (CACNA1E). These two calcium ion channels currently have pharmacological agents available as treatments for their corresponding channelopathies. Drugs that bind to the pore-forming domains of Cav2.2 and Cav2.3 are promising candidates that could have the same effect on Cav2.1. Many at the Roundtable agreed that this would be the most efficient way to get treatments for CACNA1A-related disorders in the clinical trial pipeline in the next few years. The Foundation will continue to work with Dr. Cohen and support collaboration for in silico screening. The work on potential treatments presented by some of the academic researchers would continue to be supported in parallel with pharmacological endeavors.
Raise awareness at national conferences. There was discussion regarding how the CACNA1A Foundation finds patients and brings awareness to CACNA1A-related disorders. Lisa Manaster (President) and Sunitha Malepati (Vice-president) summarized the conferences that the Foundation attends each year. Organizing symposiums with the help of the Scientific Advisory Board would also raise awareness of CACNA1A-related disorders and bring more people into the Research Network.
In summary, it was an intense, science-filled two days, and a path to clinical trials has been laid out. The CACNA1A Foundation Board and team members left feeling grateful for all the scientists who came together to support and help our community. Most importantly, there was hope that specific and effective treatments are within reach. We will be able to get there together with all of your support and engagement!
In attendance:
Kristin Barañano, MD, PhD, Johns Hopkins Medicine
Kevin Bender, PhD, University of California San Francisco Weill Institute for Neurosciences
Allison Buchner, CACNA1A Foundation Treasurer
Zameel Cader, DPhil, MRCP, Oxford Headache Centre
Wendy Chung, MD, PhD, Columbia University Irving Medical Center
Charles Cohen, PhD, BioIntervene
Henry Colecraft, PhD, Columbia University
Irene de Boer, MD, MSc, PhD Candidate, Leiden University Medical Center
Xiaofei Du, MD, University of Chicago
Anne Ducros, MD, PhD, University of Montpellier
Pangkong Fox, PhD, CACNA1A Foundation Science Engagement Director
Alfred George, MD, Northwestern Medicine
Christopher Gomez, MD, PhD, University of Chicago
Ayan Goshal, PhD, Biogen
Scott Grossman, MD, NYU Grossman School of Medicine
Ingo Helbig, MD, Children’s Hospital of Philadelphia
Marina Hommersom, MSc, PhD candidate, Radboud University Medical Center
Elisabetta Indelicato, MD, PhD, Medical University of Innsbruck
Joanna Jen, MD, PhD, Icahn School of Medicine at Mount Sinai
Kamran Khodakah, PhD, Albert Einstein College of Medicine
Julia Koh, Boston Children’s Hospital
Sookyong Koh, MD, PhD, University of Nebraska Medical Center
Audra Kramer, PhD, University of Maryland School of Medicine
Peri Kurshan, PhD, Albert Einstein College of Medicine
Dennis Lal, PhD, Cleveland Clinic Lerner Research Institute
Doris Lin, MD, PhD, Johns Hopkins Medicine
Diane Lipscombe, PhD, Brown University
Sunitha Malepati, CACNA1A Foundation Vice President
Lisa Manaster, CACNA1A Foundation President
Hala Mirza, CACNA1A Foundation Board Member
Jacqueline Niu, PhD, Columbia University Irving Medical Center
Jeffrey Noebels, MD, PhD, Baylor College of Medicine
Jen Pan, PhD, Broad Institute of MIT and Harvard
Elsa Rossignol, MD, MSc, FRCP, CHU Ste-Justine, University of Montreal
Lacey Smith, MS, CGC, Boston Children’s Hospital
Gisela Terwindt, MD, PhD, Leiden University Medical Center
Kim Thalwitzer, MD, Children’s Hospital of Heidelberg
Chi-Kun Tong, PhD, Columbia University Irving Medical Center
George Umanah, PhD, National Institute of Neurological Disorders and Stroke
Vicky Whittemore, PhD, National Institute of Neurological Disorders and Stroke'
Gerald Zamponi, PhD, Cummings School of Medicine, University of Calgary; Hotchkiss Brain Institute