Unraveling Etiological Indications and Therapeutic Implications of Familial Cerebral Cavernous Malformations in the Dawn of Gene Therapy for Monogenic Conditions.

Abstract

Cerebral Cavernous Malformations (CCMs) are vascular anomalies in the central nervous system that arise from both genetic and non-genetic factors, and can cause hemorrhage, seizures, and neurological deficits. Approximately 80% of CCMs are sporadic, while 20% are Familial (FCCMs), an autosomal dominant, monogenic disorder characterized by multiple lesions and severe clinical manifestations. Over the past three decades, linkage analyses have identified KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3 as major pathogenic genes in FCCMs. However, existing surgical and pharmacological treatments have not adequately prevented disease progression, underscoring the need for more effective strategies. Recent advancements in gene editing tools and delivery systems have transformed gene therapy from a laboratory concept to a clinical reality, offering renewed hope for FCCM patients. Given the multifactorial nature, complexity, and neurological comorbidities of FCCMs, exploring non-surgical gene therapies provides a promising approach for addressing these cerebrovascular lesions. This review summarizes the latest progress in gene editing for FCCMs and examines its therapeutic potential, while acknowledging both the promising benefits and the remaining uncertainties in this evolving field.