Shh Signaling in Brain AVMs: Novel Player & Therapeutic Target (SHAM)

Sonic Hedgehog Signaling: Novel Player and Potential Therapeutic Target in Brain Arteriovenous Malformations

The present study, entitled "SHAM Study," is a prospective observational translational study aimed at investigating the molecular mechanisms underlying brain arteriovenous malformations (AVMs). In particular, the study seeks to explore the role of the Sonic Hedgehog (Shh) signaling pathway, which has recently been hypothesized as a potential key player in pathological angiogenesis and in the maintenance of the malformative nidus.

The study will be conducted through the analysis of brain tissues obtained exclusively as residual material from neurosurgical procedures performed for clinical indications. Under no circumstances will additional procedures be carried out or modifications made to the patients' therapeutic pathway for research purposes. Samples will include tissues from adult patients undergoing AVM resection and, as controls, non-pathological brain tissues derived from surgeries performed for other indications, such as drug-resistant epilepsy.

The methodological approach involves the isolation of endothelial cells from collected samples and their characterization using multi-omics techniques, including transcriptomic analysis, microRNA profiling, and quantitative proteomics. The resulting data will be integrated through advanced bioinformatics analyses in order to identify specific molecular patterns, altered pathways, and potential biomarkers. Particular attention will be given to the evaluation of Shh pathway activation and its interactions with other signaling systems involved in AVM pathogenesis.

The collected biological material may also be used, subject to specific informed consent, for preclinical studies conducted on animal models, with the aim of further investigating the identified pathogenetic mechanisms and assessing their functional relevance. Such activities will be carried out in compliance with current regulations on animal experimentation and subject to approval by the relevant authorities.

The primary objective of the study is to identify significant differences in gene expression between endothelial cells derived from AVMs and control brain tissue. Secondary objectives include the identification of integrated molecular profiles (RNA, microRNA, and proteins), the correlation of these profiles with patients' clinical and radiological characteristics, and the identification of potential therapeutic targets.

The study is designed so as not to entail additional risks for participants, as it is based exclusively on the use of biological material that would otherwise be discarded. All subjects will be enrolled only after providing written informed consent. Data will be processed in pseudonymized form in compliance with current regulations on personal data protection.

The total expected duration is 36 months, and the study is part of a targeted research project aimed at generating new knowledge with potential translational impact, laying the groundwork for the future development of targeted therapeutic strategies.

Study duration and number of patients:

The overall duration of the study will be 36 months. Enrollment will begin immediately after ethical approval and will be completed by month 24.

A total of 30-45 adult patients are expected to be enrolled, including 20-30 undergoing resection of brain arteriovenous malformations and 10-15 patients undergoing neurosurgical procedures for drug-resistant epilepsy, from whom non-pathological cortical tissue will be obtained.

Study Overview

• Status: Not yet recruiting
• Conditions: Brain Arteriovenous Malformations (AVMs)

• Study Type: Observational
• Enrollment (Estimated): 45

Contacts and Locations

Study Locations

• Italy
  • Rome
    • Rome, Rome, Italy, 00168
      • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
      • Contact: Roberto Pola, Professor, MD; Phone Number: +39 0630151; Email: roberto.pola@policlinicogemelli.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Adults ≥18 years undergoing neurosurgical intervention with resection of AVM or non-pathological cortical tissue (controls).

Description

Inclusion Criteria:

• Adult patients aged 18 years or older undergoing neurosurgical resection who provide written informed consent for research use of residual tissue.

Exclusion Criteria:

• Tissue with extensive necrosis or contamination, lack of valid consent, or known infectious agents that preclude safe handling.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
AVM group (cases); Adult patients undergoing neurosurgical resection of brain arteriovenous malformations for clinically indicated reasons. Residual AVM tissue obtained during surgery will be used for molecular analyses.
Control group; Adult patients undergoing neurosurgical procedures for drug-resistant epilepsy or other clinical indications, from whom non-pathological brain tissue is resected as part of standard care. Residual tissue will be used as control.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differential endothelial gene expression between AVM and control tissues.	Endothelial differential gene expression measured as log2 fold change and adjusted p value from bulk RNA seq.	Up to 34 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MicroRNA and proteomic profiles, pathway activity scores, histological markers, and clinical correlations.	MicroRNA abundance (normalized counts); protein abundance (LFQ intensity); pathway activity scores (Shh, Notch, VEGF, TGF β/ALK1, MAPK); histological metrics (percent positive area; mean staining intensity for Shh, Gli1, CD31, α SMA).	Up to 34 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Single-cell analyses, integrated biomarkers, and potential therapeutic targets.	Identification of single-cell transcriptional clusters and inferred cell-type composition, where single-cell data are available. Identification of integrated multi-omics biomarker panels based on concordant transcriptomic and proteomic signals. Identification of candidate druggable targets prioritized through network centrality analyses and cross-platform validation.	Up to 36 months

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): August 1, 2029

Study Registration Dates

• First Submitted: June 24, 2026
• First Submitted That Met QC Criteria: June 24, 2026
• First Posted (Actual): June 30, 2026

Study Record Updates

• Last Update Posted (Actual): June 30, 2026
• Last Update Submitted That Met QC Criteria: June 24, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: 27587

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No