Background: COL4A1/2-related disorders are genetically driven multisystem diseases characterized by small vessel cerebrovascular pathology, including fetal and perinatal strokes, intracranial hemorrhage, and progressive white matter damage. Despite increasing recognition of their neurological and systemic manifestations, targeted treatments remain lacking. This presentation outlines the clinical landscape, natural history studies, and ongoing translational efforts aimed at developing gene-targeted therapies for COL4A1/2 and related vascular disorders.
Methods: Key components of the therapeutic development pipeline were discussed, including the establishment of disease-relevant phenotypes through international natural history collaborations, in vitro and in vivo modeling of cerebrovascular dysfunction, and imaging-based biomarkers to track progression. Through academic and industry collaborations, advanced adeno-associated virus–pericyte re-targeted and lipid nanoparticles delivery strategies are being developed to enhanced specificity for vascular smooth muscle cells and pericytes—critical targets in restoring brain vascular and blood–brain barrier integrity.
Results: Several examples of preclinical gene targeted therapies for ultrarare vasculopathies were presented including an advanced program for targeted genome editing for ACTA2 R179H with results that inform a path toward submission of an Investigational New Drug (IND) application for first-in-human trials. General remarks about challenges specific to collagen biology and development, phenotyping COL4A1/A2, determination of biomarkers and clinical endpoints for clinical trials design were also discussed.
Conclusions: This work underscores the importance of collaborative infrastructure, biomarker-driven trial design, and tailored delivery vectors in advancing precision medicine for rare monogenic vasculopathies. The approaches and lessons from ACTA2 serve as a model for future therapeutic strategies targeting COL4A1/2 related disorders.
Funding
Dr. Musolino’s laboratory is supported by NIH grant R01NS117575, R01NS125353, RF1NS128217 and scientific research agreement with Agea Biotherapeutics.
Institutional Review Board Statement
Data on COL4A1 pateint-derived cells phenotyping presented are under an IRB approved natural history and biomarkers studies.
Informed Consent Statement
Informed Consent Statement was not sought.
Data Availability Statement
Data can be made available upon reasonable request.
Conflicts of Interest
Dr. Musolino is principal investigator for the Mucolipidosis type IV Natural History Study, Genetic Vasculopathies Nartural History Study, Young Genetic Stroke Alliance Biomarker studies and Minoryx Nexus Trial on childhood cerebral adrenoleukodystrophy. She holds scientific research agreements with Angea Biotherapeutics. She is/ has acted as consultant for Minoryx, Ionis, Biogen, Inozyme, Vertex, Bluebird bio, Atlas Ventures, Borea Therapeutics and Astellas Pharma.
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