Intranasal AAV9-PHP.eB Gene Therapy in Cerebral Palsy (CP) & Hypoxic Ischemic Encephalopathy (HIE)

Official title

Healing Hope International Multinational Observational Registry Evaluating Intranasal 15-Gene AAV9-PHP.eB Therapy and Functional Outcomes in Participants With Cerebral Palsy & Chronic Hypoxic-Ischemic Encephalopathy (HIE) (GEN-HOPE Study)

Overview

This international study, organized by Healing Hope International, is an observational registry designed to collect real-world data on participants living with chronic hypoxic ischemic encephalopathy (HIE) who receive an emerging intranasal gene therapy based on the AAV9-PHP.eB viral vector. The investigational therapy delivers a panel of 15 restorative genes that support brain repair, reduce inflammation, promote myelination, and improve neural communication. It is administered intranasally in one or three sessions by participating international clinical teams. Because the therapy is already being offered abroad, this registry does not assign treatment but instead follows participants who have received it as part of their existing medical care. The GEN HOPE Study aims to understand how this gene therapy affects movement, cognition, spasticity, and seizure frequency over time. Families and clinicians will share outcomes such as changes in gross motor function (GMFM-66/88), cognitive assessments (Bayley or WISC tests), and quality-of-life measures. Information on safety, laboratory results, MRI findings, and caregiver-reported experiences will also be collected. By combining data from multiple countries, the registry seeks to evaluate whether this novel gene based approach can meaningfully improve daily function and comfort for participants with chronic HIE. Results will guide future clinical trial development and help define safe and effective standards of care for regenerative neurologic therapies.

Detailed description

The GEN HOPE Study is a multinational, real world observational registry coordinated by Healing Hope International to characterize reported safety events and functional outcomes in participants with chronic hypoxic ischemic encephalopathy (HIE), a condition commonly presenting as cerebral palsy, who have received intranasal 15-gene AAV9-PHP.eB gene therapy outside the United States.

This registry does not assign or direct any medical intervention. Instead, it prospectively collects standardized clinical and caregiver reported data from participating international sites where the therapy is already being used under local medical supervision. The aim is to document the naturalistic course of recovery following treatment and to generate evidence that may inform the design of future controlled trials.

The investigational therapy uses an AAV9-PHP.eB viral vector optimized for central nervous system delivery through the nasal mucosa. The 15 gene panel encodes factors related to neuronal plasticity, white matter repair, antiinflammatory modulation, metabolic and vascular support, and cellular longevity. Dosing schedules vary by site (single session or three session delivery), and some centers administer short-term rapamycin as an adjunctive immunomodulator.

Participants aged 2-65 years who have documented chronic HIE, stable baseline medical status, and caregiver consent to share outcome data. Key assessments include gross motor function (GMFM-66/88), cognitive and language evaluations (Bayley-III/IV or WISC-V), spasticity and seizure frequency, and quality-of-life and caregiver burden metrics. Whenever available, MRI/DTI data and laboratory monitoring are recorded. Follow-up intervals occur at approximately 3, 6, 12, 18, and 24 months post-treatment.

Data are analyzed using target-trial emulation and propensity-weighted methods to estimate treatment effects compared with matched external controls receiving standard care. The primary outcome is change in GMFM-66/88 score at 12 months. Secondary outcomes include cognitive performance, seizure burden, quality of life, and safety parameters.

All information is deidentified and stored in a secure international database compliant with data protection and ethical governance standards. Oversight is provided by an independent Data and Safety Monitoring Board (DSMB) with expertise in neurology, statistics, and gene-therapy safety.

The GEN HOPE Study seeks to accelerate understanding of gene based neurorestorative strategies and to establish a transparent evidence base supporting compassionate use access, long-term safety monitoring, and eventual clinical trial harmonization for participants affected by HIE worldwide.

Primary outcome measures

• Change in Gross Motor Function Measure (GMFM-66/88) Score From Baseline to 12 Months [Time frame: Baseline to 12 months after treatment]

Secondary outcome measures (6)

• Change in Cognitive Performance (Bayley Scales) From Baseline [Time frame: Baseline to 12 months and 24 months]
• Change in Seizure Frequency [Time frame: Baseline to 12 months and 24 months]
• Change in Spasticity Using the Modified Ashworth Scale (MAS) [Time frame: Baseline to 12 months]
• Change in Quality of Life (PedsQL Caregiver-Reported Score) [Time frame: Baseline to 12 months and 24 months]
• Change in MRI/DTI Biomarkers of White-Matter Integrity [Time frame: Baseline to 12 months]
• Change in Cognitive Performance (WISC-V) From Baseline [Time frame: Baseline to 12 months and 24 months]

Eligibility criteria

Inclusion criteria

• Age 2 to 65 years, at the time of enrollment.
• Documented diagnosis of chronic hypoxic-ischemic encephalopathy (HIE), confirmed by medical history, MRI findings, or neonatal records.
• Stable medical condition for at least 6 months prior to enrollment (no major surgeries or hospitalizations related to HIE within that period).
• Baseline Gross Motor Function Measure (GMFM-66 or GMFM-88) score between 40% and 70%, representing moderate functional impairment.
• Completion or active receipt of intranasal 15-gene AAV9-PHP.eB therapy at a participating international clinical site under local physician supervision.
• Parent(s) or legal guardian(s) willing and able to provide written informed consent for participation in the observational registry and data sharing.
• Access to clinical follow-up and ability to participate in scheduled assessments or data submissions at 3, 6, 12, 18, and 24 months after treatment.

Exclusion criteria

• Active systemic infection, immune deficiency, or ongoing use of immunosuppressive agents (other than short-term rapamycin used per treating physician's protocol).
• Known positive anti-AAV9 neutralizing antibody titer at baseline exceeding threshold values that may preclude effective vector transduction (if testing performed locally).
• Uncontrolled seizure activity exceeding five episodes per day at baseline despite medical therapy.
• Known or suspected malignancy, severe hepatic or renal dysfunction, or other conditions that would confound safety monitoring.
• Previous gene therapy or investigational stem cell therapy within the past 12 months.
• Known pregnancy or breastfeeding in post-pubertal female participants.
• Any condition that, in the opinion of the local investigator or registry sponsor, may interfere with participation, data reliability, or patient safety.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-only

Study locations

Mexico · 1 center

• Stem Solutions — Monterrey

Publications

• Lindvall O, Bjorklund A. Cell replacement therapy: helping the brain to repair itself. NeuroRx. 2004 Oct;1(4):379-81. doi: 10.1602/neurorx.1.4.379. No abstract available. PMID 15717041
• Douglas-Escobar M, Weiss MD. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 2015 Apr;169(4):397-403. doi: 10.1001/jamapediatrics.2014.3269. PMID 25685948

Identifiers

NCT: NCT07264166 · HHI-HIE-OBS-2025-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗