Gene Therapy Study for Children With CLN5 Batten Disease

Study Overview
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Brief Summary
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This is a prospective, non-randomized, open-label, dose escalation study of a single administration of gene therapy in children who are 3 to 9 years old with Neuronal Ceroid Lipofuscinosis (Batten) Subtype 5 (CLN5) disease.

Detailed Description
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The study is a first in human (FIH) open-label, dose escalation study designed to assess the safety and efficacy of administration of an adeno-associated viral vector serotype 9 (AAV9) carrying the gene encoding human ceroid-lipofuscinosis neuronal protein 5 (CLN5) in subjects with CLN5 Batten disease. The study treatment will be delivered via intracerebroventricular (ICV) and intravitreal (IVT) injection on the same day. Each participant will be followed for safety and efficacy for 5 years after treatment. Efficacy assessments in this study will evaluate motor, language, visual and cognitive function.

Official Title
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A Phase 1/2 Intracerebroventricular and Intravitreal Administration of NGN-101 for Treatment of Neuronal Ceroid Lipofuscinosis (NCL) Subtype 5 (CLN5) Disease

Conditions
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Neuronal Ceroid Lipofuscinosis CLN5

Intervention / Treatment
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* Genetic: NGN-101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age from 3 to 9 years (Child) Molecular genetic diagnosis of the CLN5 gene Confirmed clinical diagnosis of CLN5 disease Impaired motor and/or language function and/or impaired visual acuity Written informed consent from parent or legal guardian and assent from study participant, if appropriate Able to comply with protocol required assessments (laboratory sample collection, lumbar puncture (LP), nerve conduction studies (NCS), magnetic resonance imaging (MRI), etc.), which may require sedation or general anesthesia Able to walk with or without assistance (assistance may include a walker, braces, or with one hand held) Agree to reside within a 1-hour drive of the study site for at least 6 months following treatment (or a safely drivable distance for the study participant and caregivers according to investigator's discretion) Exclusion Criteria Has another neurologic disease or illness that may have caused cognitive decline before study entry Known pathogenic or clinically suspected variant in a seizure associated genetic mutation besides CLN5 Any active infections or severe infections within the 30 days prior to study treatment administration Presence of a concomitant medical condition that precludes intracerebroventricular (ICV) injection, lumbar puncture (LP), or use of anesthetics needed for study-related procedures Presence of any concomitant medical conditions that preclude intravitreal (IVT) administration Has status epilepticus that lasts longer than 5 minutes or having more than 1 seizure within a 5-minute period, without returning to a normal level of consciousness between episodes within 12 weeks before study treatment Total anti-AAV9 antibody titer greater than 1:400 Any anticipated need for major surgery in the next 24 months Participation in an Investigational New Drug, Investigational Device Exemption, or equivalent clinical study in the past 6 months Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered Participation in other investigational studies and non-interventional studies that have similar study assessments as this protocol while the study participant is enrolled in this study with the exception of sister studies sponsored by Neurogene History of or current chemotherapy, radiotherapy, or other immunosuppressive therapy within the past 3 months Use of prohibited medications Immunizations of any kind in the 45 days prior to study treatment Requiring daytime or nighttime ventilatory support at the time of Screening Any item which would exclude the study participant from being able to undergo brain magnetic resonance imaging (MRI) according to local institutional policy Known allergies or hypersensitivities to the required immunosuppression regime

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 9 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation cohort study of NGN-101 administered by intracerebroventricular (ICV) infusion and intravitreal (IVT) injection; cohorts will be assigned sequentially.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>The study treatment is a recombinant serotype 9 adeno-associated virus encoding a codon-optimized human CLN5 transgene (hCLN5opt). | Genetic: NGN-101<br>* Participants with confirmed mutations in the CLN5 gene who meet all the inclusion and none of the exclusion criteria will be treated with a single intracerebroventricular (ICV) dose and a single intravitreal (IVT) dose of the study treatment.<br>|
| Experimental: Cohort 2<br>The study treatment is a higher dose of recombinant serotype 9 adeno-associated virus encoding a codon-optimized human CLN5 transgene (hCLN5opt). | Genetic: NGN-101<br>* Participants with confirmed mutations in the CLN5 gene who meet all the inclusion and none of the exclusion criteria will be treated with a single intracerebroventricular (ICV) dose and a single intravitreal (IVT) dose of the study treatment.<br>|
| Experimental: Cohort 3<br>The study treatment is a higher dose of recombinant serotype 9 adeno-associated virus encoding a codon- optimized human CLN5 transgene (hCLN5opt). | Genetic: NGN-101<br>* Participants with confirmed mutations in the CLN5 gene who meet all the inclusion and none of the exclusion criteria will be treated with a single intracerebroventricular (ICV) dose and a single intravitreal (IVT) dose of the study treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Emergent Adverse Events (TEAEs) | Incidence, type, severity, and frequency of TEAEs | 5 years (multiple visits) | 
| Incidence of Serious Adverse Events (SAEs) | Incidence, type, severity, and frequency of SAEs | 5 years (multiple visits) | 
| Incidence of clinical laboratory abnormalities | Incidence, type, severity, and frequency of clinical laboratory abnormalities | 5 years (multiple visits) | 
| Incidence of new nerve conduction study (NCS) abnormalities | Incidence, type, severity, and frequency of new nerve conduction study (NCS) abnormalities | 5 years (multiple visits) | 
| Incidence of new physical and neurologic exam abnormalities | Incidence, type, severity, and frequency of new physical and neurologic exam abnormalities | 5 years (multiple visits) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hamburg Scale, Motor and Language domain scores | Change from baseline in Hamburg Scale, Motor and Language domain scores (each domain is rated from 0 to 3, with 3 reflecting normal function for age and 0 reflecting complete loss of function) | 5 years (multiple visits) | 
| Change in Spectral Domain-Optical Coherence Tomography (SD-OCT) | Change from baseline in SD-OCT parameters including Ellipsoid Zone (EZ) defect area measurements, macular volume and thickness, retinal nerve fiber layer thickness, and ganglion cell layer thickness | 5 years (multiple visits) | 
| Change in Unified Batten Diseases Rating Scale (UBDRS) | Change from baseline in total score and individual domains of the Unified Batten Diseases Rating Scale (UBDRS; total score 0 to 277, with higher scores indicating worse function) | 5 years (multiple visits) | 
| Change in Caregiver global impression of change | Caregiver global impression of change throughout the study | 5 years (multiple visits) | 
| Change in visual acuity measurements | Change from baseline in visual acuity measured using Teller acuity cards, Lea symbol chart, Landolt C chart, or low contrast visual acuity (measure to be used will depend on subject's level of cognitive and visual function) | 5 years (multiple visits) | 
| Change in color vision | Change from baseline in color vision measured using Ishihara color blindness testing | 5 years (multiple visits) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NCL, Batten Disease, Neuronal Ceroid Lipofuscinosis Disease, Neuronal Ceroid Lipofuscinosis Subtype 5 Disease, Gene Therapy, Gene Transfer, CLN5, CLN