ASTROCYTIC MLC1 DEFICIENCY DRIVES BRAIN EDEMA AND THERMAL SUSCEPTIBILITY IN A MOUSE MODEL OF MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS

Megalencephalic leukoencephalopathy with subcortical cysts (MLC), also referred as Van der Knaap disease, is an ultra-rare inherited leukodystrophy associated with brain edema. Over 70% of patients harbor biallelic loss-of-function mutations in the astrocyte-specific gene MLC1, presenting with early-onset macrocephaly, epileptic seizures, muscle stiffness, and progressive motor impairment accompanied by mild cognitive deficits. Loss of MLC1 disrupts ion and water homeostasis, resulting in astrocytic endfeet swelling and impaired intercellular communication.
As no disease-modifying treatments currently exist, we explore gene therapy as a potential therapeutic strategy. Adeno-associated viral vectors (AAVs) expressing human MLC1 cDNA under the control of the human glial fibrillary acidic protein (GFAP) promoter (gfa2) were administered intravenously to 10-month-old Mlc1^-/- mice, seven months after symptom onset. This approach achieved sustained astrocytic expression of MLC1, leading to a robust reduction of brain edema and significant improvement in motor performance.
Clinically, approximately 60% of MLC patients experience symptom exacerbation following febrile episodes, infections, or head trauma, which notably increases seizure susceptibility. Consistently, Mlc1^-/- mice display similar outcomes when exposed to high temperatures compared to healthy controls. Hence, we are exploring hyperthermia as a tool to elucidate the mechanisms underlying this impaired astrocytic response to thermal stress in MLC.
Altogether, our results demonstrate the safety and long-term efficacy of glial-directed gene expression. Importantly, these findings support the feasibility of late-stage therapeutic intervention and provide a strong foundation for clinical translation in MLC. Ongoing studies aimed at identifying novel biomarkers and therapeutic response will further refine the evaluation of prospective MLC treatments.