PTEN Research today announced the launch of ‘PTEN Connect’, a new clinical trial of the mTOR inhibitor everolimus designed to evaluate whether the medicine can improve social abilities in people with PTEN Hamartoma Tumor Syndrome (PHTS or ‘PTEN Syndrome’). Enrollment is expected to begin in late 2026.

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Antonio Hardan, MD

Antonio Hardan, MD

Scientific rationale

PTEN Hamartoma Tumor Syndrome is caused by loss-of-function variants in the PTEN gene, which normally acts as a brake on the PI3K–AKT–mTOR cell-growth pathway. When PTEN function is reduced or lost, individuals can experience a broad range of manifestations that vary greatly in nature and severity from person to person. Neurological features commonly include macrocephaly (enlarged head) and learning difficulties, and around 25% of people with PTEN Syndrome meet diagnostic criteria for autism spectrum disorder (ASD). Emerging data further suggest that social difficulties are frequent in people with PTEN Syndrome, affecting more than 50% of individuals.

Everolimus is an oral mTOR inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of certain manifestations of Tuberous Sclerosis Complex (TSC) in addition to other indications. Both TSC and PTEN Syndrome involve overactivation of the same cellular pathway, providing a mechanistic rationale for evaluating everolimus in PTEN Syndrome. In a previous clinical trial (NCT02991807) involving 46 people with PTEN Syndrome, everolimus was well tolerated and showed several signals of activity, including changes in the social difficulties experienced by participants with PHTS. The PTEN Connect study is designed to explore these findings further in a larger and more focused trial.

About the PTEN Connect study

This randomized, double-blind, placebo-controlled study will be conducted under the leadership of Antonio Hardan, MD, professor of psychiatry and behavioral sciences at Stanford Medicine, together with PTEN Syndrome expert clinical centres including Boston Children’s Hospital and Cleveland Clinic, as part of the Developmental Synaptopathies Consortium (DSC).

Participants aged 5–45 years will be randomly assigned to receive either everolimus or placebo (a pill with no active medicine) for an initial double-blind period of 6 months. (This means for the first 6 months neither the person with PTEN Syndrome nor their doctor will know what treatment is being given). At the end of this period, all participants will be offered the opportunity to receive 6 months of treatment with everolimus, regardless of which treatment they originally received. The study will evaluate changes in social abilities and other key outcomes that are important to individuals with PTEN Syndrome and their families. Further details of the study can be found at: https://clinicaltrials.gov/study/NCT07218575

What this means for patients and families

For many families, social and communication difficulties can be highly challenging aspects of living with PTEN Syndrome. By focusing specifically on social abilities, PTEN Connect aims to understand whether targeting the PI3K–AKT–mTOR pathway with everolimus could offer a new therapeutic option for people with PHTS.

Study funding

This project is supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award 1R01FD008531-01A1 (Principal investigator Antonio Hardan) totaling $2.6m (44%) funded by FDA/HHS and $3.3m (56 %) funded by non-government source(s). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.

Support from non-government sources will be provided by PTEN Research and Novartis Pharmaceuticals Corporation.

Additional information and how to participate

Families and people with PTEN Syndrome who are interested in learning more about the PTEN can visit the study website or contact the team at PTENConnect@stanford.edu.

Notes for editors

About PTEN Hamartoma Tumor Syndrome (PHTS)

PHTS is a rare, inherited or spontaneous genetic condition caused by pathogenic variants in the PTEN gene. In addition to neurobehavioral manifestations, PHTS can cause vascular anomalies (abnormal growth of veins), gastrointestinal polyps, and benign skin lesions (hamartomas). People with PHTS also have a significantly elevated lifetime risk of several cancers, including breast, thyroid, and endometrial cancer, and there are currently no health-authority-approved treatments specific to PHTS.

About PTEN Research Foundation

PTEN Research (www.PTENresearch.org) is an English-registered charity (No. 1173589), founded in 2017 with the mission to fund and facilitate research leading to new treatments for people with PHTS. The Foundation’s goal is to have transformative therapies available as treatment options within 10 years.

About the Developmental Synaptopathies Consortium (DSC)

The Developmental Synaptopathies Consortium (U54NS092090, principal investigator Mustafa Sahin) is part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN) and is supported by the RDCRN Data Management and Coordinating Center (DMCC) (U2CTR002818).

Trial commencement is subject to site activation, institutional review board (IRB) and regulatory approvals and other regulatory processes. Everolimus is not currently approved for the treatment of PTEN Syndrome/PHTS by the FDA or other regulatory authorities.

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