Expression of Small Peptide (SP7737) Stops mTORopathies-related Seizures
Abstract number :
1.4
Submission category :
8. Non-ASM/Non-Surgical Treatments (Hormonal, alternative, etc.)
Year :
2025
Submission ID :
96
Source :
www.aesnet.org
Presentation date :
12/6/2025 12:00:00 AM
Published date :
Authors :
Mi Jiang, MD – University of Michigan
Presenting Author: Yu Wang, MD, PhD – University of Michigan
Tao Yang, PhD – University of Michigan
Rajat Benerjee, PhD – University of Michigan
Jiwei Zhang, MD, PhD – University of Michigan
Rationale: Somatic mutations in the mechanistic target of rapamycin (mTOR) pathway genes have been frequently identified in patients with focal cortical dysplasia type II (FCDII), the most common underlying pathologies in children with drug-resistant epilepsies (DRE) (1). Although often curative, destructive lesionectomy could only be offered to less than one-fourth of patients. New therapeutic development to treat FCDII has significantly lagged behind our staggering advances in understanding of mTORopathies at genetic and cellular levels. For example, oral Rapalogs have been proposed as the prevision medicine but only showed equivocal benefits due to its systemic side effects, low blood brain barrier (BBB) penetration, and of feed-back loop activation.
Methods: We first used in-utero electroporation (IUE) of the human pathogenic RHEB mutant (P37L) or mTOR mutant (S2215Y) to establish mouse models of mTORopathies. We then applied a conditional co-expression IUE system to gate the expression of a small peptide (SP7737), a micro-peptide that negatively modulates MTORC1, at postnatal day (PND) 10, 21, 35, and 60 to test its therapeutic efficacy at different disease stages. Finally, we screened a AAV capsid that was rationally designed with direct evolution for cortical excitatory neurons and stereotactically injected the SP7737-expressing virus in the dysplastic cortex to test its clinical translatability.
Results: Mice with RHEBp.P37L or MTORp.S2215Y IUE displayed the pathological signatures in the human dysplastic cortex and developed frequent clinical seizures. SP7737effectively inhibited mTOR hyperactivation in neurons, rescued cytomegaly, re-engaged neuronal migration and restored cortical lamination, and stopped seizures. In addition, the stereotactic injection of novel AAV expressing SP7737 significantly improved the clinical seizure outcome in FCDII mice.
Conclusions: Our findings suggest that the SP7737 is a promising universal therapeutic target for mTORopathies.
Funding: NIH R01NS136181
Non-ASM