AAV9-Mediated PTEN Gene Therapy Rescues Hepatic Pathology and Neuroanatomical Abnormalities in a Murine Model of PTEN Hamartoma Tumour Syndrome.

Background/

Objectives

PTEN Hamartoma Tumour Syndrome (PHTS) is a rare inherited disorder caused by germline PTEN mutations, presenting with cancer predisposition and neurodevelopmental abnormalities, including macrocephaly. PTEN functions as a tumour suppressor by regulating the PI3K/AKT/mTOR pathway and contributes to cellular adhesion, migration, and genomic stability. As no curative therapy exists, gene therapy represents a promising avenue to correct the underlying genetic defect.

Methods

In this study we evaluated the therapeutic potential of AAV9-mediated PTEN gene delivery in a PtenΔ5/+ mouse model, which is predominantly characterized by progressive lymphoid hyperplasia leading to lymph node tumour development, as well as hepatic focal lesions and macrocephaly.

Results

Systemic vector delivery did not improve lymph node enlargement which represents the predominant disease phenotype in the PtenΔ5/+ mice at the doses tested, due to restricted vector biodistribution, but it did effectively rescue the hepatic lesions, including steatosis and steatohepatitis-like changes. Mechanistically, AAV-mediated PTEN expression significantly reduced elevated p-AKT levels, indicating attenuated hyperactivation of the PI3K/AKT/mTOR pathway. Additionally, intracranial delivery of the same vector in PtenΔ5/+ mouse neonates ameliorated macrocephaly without apparent adverse effects.

Conclusions

These findings highlight the therapeutic potential of AAV9-mediated PTEN gene therapy in PHTS, particularly for hepatic and neuroanatomical manifestations. Optimization of vector biodistribution and transduction efficiency will be critical for clinical translation.