Research

Dr. David Liu, The Broad Institute of MIT and Harvard; Dr. Cat Lutz, the Rare Disease Translational Center, The Jackson Laboratory; Dr. Kathleen Sweadner, Harvard/MGH, Dr. Al George, Northwestern University

The Liu team is developing prime editing and base editing strategies for multiple AHC-causing mutations and investigating their efficacy and safety in cultured human and mouse cells. The Liu team, in a collaboration with The Jackson Laboratory Rare Disease Translational Center, is also evaluating an in vivo prime editing treatment to correct symptoms and enhance survival in two AHC mouse models. The results to date suggest the first-ever in vivo rescue of a neurological disease with prime editing. Dr. Liu is a pioneer and leader in genome editing.

Dr. Tim Yu, Harvard/ Boston Children’s Hospital; Dr. Al George, Northwestern University; Dr. Cat Lutz, the Rare Disease Translational Center, The Jackson Laboratory

Dr. Tim Yu is the leading scientist in the field of ASO-based therapeutics development and clinical application. Dr. Al George is an expert in AHC pathophysiology, with significant expertise in electrophysiological studies of patient-derived iPSCs. This effort is a collaboration of the Yu team at Harvard/BCH and the George team at Northwestern University to evaluate ASO as a therapeutic strategy for AHC and develop mutation-specific ASOs for AHC patients. The George team is evaluating molecular efficacy of candidate ASOs in patient-derived iPSC neurons in vitro. The Lutz team at The Jackson Laboratory is conducting in vivo toxicity studies.

 Dr. Cat Lutz, the Rare Disease Translational Center, The Jackson Laboratory

Dr. Lutz and her team at The Jackson Laboratory Rare Disease Translational Center have extensive expertise with mouse models of AHC. The Lutz team is evaluating ASOs (designed to target mouse AHC mutations) to evaluate ASO as a strategy for AHC. The proof-of-concept study in mice eliminates patient-specific variables and addresses a broader question of efficacy of ASO as a therapeutic strategy for AHC.

Dr. Cat Lutz, The Rare Disease Translational Center, The Jackson Laboratory; Dr. Al George, Northwestern University

Dr. Lutz and her team at JAX have evaluated the effects of gene therapy on a mouse model of AHC. Dr. George has demonstrated that the gene therapy vector rescues a pump current defect in patient-derived iPSC neurons.

Collaboration

A multidisciplinary team of AHC researchers and clinicians is contributing to the design of an upcoming study. Known compounds with multiple relevant mechanisms of action will be filtered, prioritized, and evaluated for their effect in appropriate model systems.

Dr. Sho Yano, University of Chicago; Dr. Miguel Holmgren, National Institute of Neurological Disorders and Stroke (NINDS), NIH; Dr. Pablo Artigas, Texas Tech University Health Sciences Center

Dr. Yano studies how disease-causing genetic variants affect the function of Na⁺/K⁺-ATPase. In a multi-institute collaboration, he and his collaborators are developing high-throughput in vitro assays with the goal of comparing larger numbers of gene changes and screening them against potential treatments.

Confidential

Dr. Steve Clapcote, Leeds University (UK)

Dr. Clapcote’s study was designed to investigate the effects of selected compounds on his AHC mouse model.

Dr. Emmanuel Flammand- Roze, Sorbonne University

Dr. Roze has previously published several clinical case studies on the effect of high flow oxygen in reducing duration of plegia and dystonia episodes in AHC patients^1,2.  Dr. Roze is conducting a clinical trial with a larger cohort of patients in France to evaluate this treatment protocol, which may add an additional interventional method to acute management of episodic symptoms of AHC and may help to improve AHC patient quality of life.

1. Welniarz Q, Gras D, Roubertie A, Papadopoulou MT, Panagiotakaki E, Roze E. Oxygen Therapy: An Acute Treatment for Paroxysmal Dystonia in Alternating Hemiplegia of Childhood?. Mov Disord. 2023;38(5):906-907. doi:10.1002/mds.29357

2. Papadopoulou MT, Welniarz Q, Roubertie A, et al. Effect of Oxygen Administration on Paroxysmal Motor Events in Alternating Hemiplegia of Childhood. Mov Disord. 2023;38(9):1759-1761. doi:10.1002/mds.29561

Arn van den Maagdenberg, Leiden University (Netherlands)

Dr. van den Maagdenberg brings decades of spreading depolarization expertise studying hemiplegic migraines to the study of AHC. Evidence of abnormal brain activity in AHC mouse models provides both a target for intervention and a potential biomarker for therapeutic efficacy.

Dr. Kathleen Sweadner, Harvard/MGH

Dr. Sweadner’s work on pathogenic cellular morphology in AHC contributes to therapeutics development in three primary ways: (1) elucidating the cellular, molecular, and biochemical mechanisms of dysfunction (2) pinpointing potential targets for therapy, and (3) providing a cellular model system to evaluate these.

Dr. Al George, Northwestern University

Dr. George’s work to investigate the electrophysiological defects of patient-derived iPSC neurons from patients of multiple genotypes provides insight into neuronal dysfunction and provides a model system to evaluate therapeutics for AHC.

Dr. Matt Campbell, Trinity College Dublin

Dr. Campbell’s recent discovery of a new AHC causal gene, CLDN5, has initiated a new line of investigation: blood brain barrier (BBB) pathology in AHC patients and mouse models of AHC.

Dr. Cat Lutz, Vice President, The Rare Disease Translational Center, The Jackson Laboratory

The Lutz team at The Jackson Laboratory has developed and characterized two distinct murine models of Alternating Hemiplegia of Childhood (AHC), each carrying one of the two most prevalent ATP1A3 variants observed in AHC patients (p.D801N and p.E815K). These mice have been used in behavioral evaluations of several candidate therapies for AHC. A mouse model incorporating a human DNA sequence in a segment of the ATP1A3 gene around the AHC-causing mutation L839P was recently developed and is being evaluated for key AHC-associated mouse phenotypes. Three more “humanized” mouse models of AHC are in the pipeline. These new mouse models would enable testing of candidate clinical genetic therapies (ASO and gene editing) in mice.

Dr. Anne Hart, Brown University

Dr. Hart has developed C. elegans models for four different AHC mutations, plus a number of experimental controls. Initial characterization experiments revealed neuromuscular dysfunction in the AHC models. Characterization of these whole-organism models of AHC is ongoing with an additional objective of identifying a phenotype amenable to a high through-put drug screen.

Dr. Fanny Elahi, Mount Sinai; Dr. Cat Lutz, The Rare Disease Translational Center, The Jackson Laboratory; Dr. Hendrik Rosewich, The University of Tübingen

AHC mouse models faithfully recapitulate clinically- relevant features of the disease. Proteomic analyses of plasma and brain lysates from these models are being conducted to (1) elucidate global molecular alterations associated with specific AHC mutations, (2) identify potential blood-based biomarkers for AHC, both at baseline and in correlation with episodic symptoms, and (3) inform a subsequent patient-based biomarker study. These findings may contribute to the development of surrogate endpoints for future clinical trials.

Dr. Anoopum Gupta, Harvard/MGH

The Gupta team is conducting a pilot study to assess the feasibility of their sub-movement analysis protocol, which integrates wearable device data with machine learning algorithms, to identify movement differences in AHC patients and distinguish paroxysmal episodes from baseline activity. This technology has been used previously to provide digital behavioral biomarkers for other neurological disorders like ALS, ataxia-telangiectasia and spinocerebellar ataxia^1-5. If successful in capturing AHC-associated movement disturbances, this technology could be used to measure efficacy of candidate therapeutics in AHC patients.

1. Gupta AS, Patel S, Premasiri A, Vieira F. At-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis. Nat Commun. 2023;14(1):5080. Published 2023 Aug 21. doi:10.1038/s41467-023-40917-3
2. Gupta AS, Luddy AC, Khan NC, Reiling S, Thornton JK. Real-life Wrist Movement Patterns Capture Motor Impairment in Individuals with Ataxia-Telangiectasia. Cerebellum. 2023;22(2):261-271. doi:10.1007/s12311-022-01385-5
3. Manohar R, Yang FX, Stephen CD, Schmahmann JD, Eklund NM, Gupta AS. At-home wearables and machine learning capture motor impairment and progression in adult ataxias. Preprint. medRxiv. 2024;2024.10.27.24316161. Published 2024 Oct 29. doi:10.1101/2024.10.27.24316161
4. Khan NC, Pandey V, Gajos KZ, Gupta AS. Free-Living Motor Activity Monitoring in Ataxia-Telangiectasia. Cerebellum. 2022;21(3):368-379. doi:10.1007/s12311-021-01306-y
5. Zhou H, Nguyen H, Enriquez A, et al. Assessment of gait and balance impairment in people with spinocerebellar ataxia using wearable sensors. Neurol Sci. 2022;43(4):2589-2599. doi:10.1007/s10072-021-05657-6

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Dr. Kathleen Sweadner, Harvard/MGH, Hek-293 cells;
Dr. Al George, Northwestern University; Patient-derived iPSC neurons;
Dr. Hendrik Rosewich, The University of Tübingen, Bioengineered Neuronal Organoids

Hek-293 cells; patient derived iPSC neurons; Bioengineered Neuronal Organoids

Hope for Annabel / RARE Hope

The RARE Hope registry comprises data from over 200 patients worldwide, representing approximately 20% of the estimated global AHC population. In collaboration with AHC patient representatives, RARE Hope designed and launched a survey to assess symptom prevalence, the frequency and duration of paroxysmal episodes, overall disease burden, and patient priorities for symptom elimination. Results of the survey are used to evaluate clinical relevance of experimental research in animal models of AHC (mice and nematodes) and to inform direction for future investigations. Additionally, RARE Hope has developed targeted patient questionnaires to address specific mechanistic research questions posed by scientists, facilitating more precise translational research efforts.

Stephen Henderson, Ph.D. (Parent of an AHC Patient)

Stephen Henderson developed an episode tracking mobile app for the unique requirements of AHC patients. The app allows patients to track paroxysmal events in relevant detail and share episode data and other clinical information with clinicians. The tracking app provides a validated, complementary technology for a range of applications, from disease monitoring initiatives to evaluations of therapeutics in patients.