Delivery of ATSP-7041 by Minimally Invasive Nasal Depot (MIND) to Target Diffuse Intrinsic Pontine Glioma

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor with limited therapeutic progress due to its infiltrative brainstem location, blood-brain barrier (BBB), and resistance to systemic agents. We present a novel strategy for targeted central nervous system (CNS) delivery of ATSP-7041, a stapled peptide dual inhibitor of human double minute 2 (HDM2) and X (HDMX), using the minimally invasive nasal depot (MIND) technique. In p53-wild-type, PPM1D-mutant DIPG neurospheres (BT869), ATSP-7041 exhibited ∼125-fold greater antitumor activity than the HDM2-selective antagonist RG7388, consistent with elevated HDMX expression. MIND delivery in mice achieved sustained ATSP-7041 distribution across brain regions, including the pons, with peak levels at 72 hours and persistence for up to 14 days. In a patient-derived orthotopic xenograft model of DIPG, a single MIND-administered ATSP-7041 depot reduced tumor burden and prolonged survival compared with controls. This feasibility study provides proof of concept for on-target p53 reactivation in DIPG using a BBB-penetrant dual HDM2/HDMX inhibitor delivered by the MIND platform. The findings support a translational path for ALRN-6924, the clinical analogue of ATSP-7041, in DIPG and potentially other brain tumors that retain wild-type p53 but remain incurable because of drug resistance and restricted CNS access.