Precision mutant-selective PI3Kα inhibition attenuates cerebral cavernous malformations

Activating PIK3CA mutations contribute to lesion growth in a subset of cerebral cavernous malformation (CCM) cases. STX-478 is an allosteric, mutant-selective PI3Kα inhibitor, but its activity in CCM is unclear. We evaluated STX-478 in a mouse model driven by combined endothelial expression of PIK3CA(H1047R) and MAP3K3(I441M). At postnatal day 5 (P5), C57BL/6J pups were injected with endothelial-tropic AAV-BR1 vectors encoding these mutations or with control AAV. Baseline MRI was obtained at P14 before treatment: mice received STX-478 (20 mg/kg intravenously every other day) or vehicle for two weeks, yielding four experimental groups. MRI and tissue analyses were performed at P28. Compared with vehicle-treated model mice, STX-478-treated model mice had lower summed susceptibility-weighted imaging (SWI) focus counts, smaller histological lesion areas, reduced hemosiderin deposition, and lower phosphorylated AKT (p-AKT) fluorescence intensity. Body weight increased in all groups during treatment. These findings support attenuation of the experimental CCM phenotype after baseline assessment, without establishing regression of individual lesions. Reduced hemosiderin deposition represents a haemorrhage-related histological finding rather than a direct measure of haemorrhage frequency. This study provides a preclinical rationale for further evaluation of mutant-selective PI3Kα inhibition in PIK3CA-mutant CCM, including dose optimisation, pharmacokinetic assessment, longer-term safety studies, and validation in additional models.