Gene Therapy for Neuronal Ceroid Lipofuscinosis

(CLN7 Trial)

Overseen By Souad Messahel, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Benjamin Greenberg

Must not be taking: Antibiotics, Antiepileptics, Chemotherapy, others

Disqualifiers: Neurodegenerative disease, Viral infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 91

Duration: 1 day

4 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1 open-label, single-administration of gene therapy agent AAV9/CLN7, administered intrathecally into the lumbar spinal cord region of pediatric patients with CLN7 Batten disease. This study consists of a one-time injection of AAV9/CLN7. There are two Cohorts with a low dose and a high dose. The primary objective for this clinical study is to evaluate safety. The secondary objective is to determine the efficacy of AAV9/CLN7. The secondary outcome measures include motor, cognition and intelligence assessments. The exploratory outcome measures include visual impairment assessment, cognitive evaluations, Brain magnetic resonance imaging (MRI), electroencephalogram (EEG), electrocardiogram (ECG) and echocardiogram (ECHO).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but new antiepileptic medications should not be started within 90 days of the infusion. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment AAV9/CLN7 for Neuronal Ceroid Lipofuscinosis?

Research on similar gene therapies, like AAV9/MFSD8 for CLN7 disease, shows that it can improve symptoms, extend lifespan, and is safe in animal models. This suggests that AAV9/CLN7 might also be effective for treating Neuronal Ceroid Lipofuscinosis. ^{1 2 3 4 5}

Is AAV9/CLN7 gene therapy safe for humans?

In preclinical studies, AAV9/CLN7 gene therapy was found to be safe and well tolerated in animal models, including mice and rats. While human trials are still needed, these results are promising for its safety profile. ^{1 3 4 6 7}

How is the AAV9/CLN7 treatment different from other treatments for neuronal ceroid lipofuscinosis?

The AAV9/CLN7 treatment is unique because it uses gene therapy to address the underlying genetic cause of CLN7 Batten disease, an ultra-rare condition with no existing treatments that can stop its progression. This therapy involves delivering a corrected version of the MFSD8 gene using a viral vector, which has shown promising results in preclinical models by improving symptoms and extending lifespan. ^{1 3 4 5 8}

Research Team

Benjamin Greenberg, MD

Principal Investigator

University of Texas Southwestern Medical Center

Eligibility Criteria

This trial is for children aged 1-18 with CLN7 Batten disease, a specific genetic disorder. Participants should have mild to moderate symptoms and be able to perform certain language or motor tasks. They must not require chronic ventilatory support or have other serious health issues that could interfere with the study.

Inclusion Criteria

Platelet count < 100,000/mm3

Any other abnormal lab values that are clinically significant per PI's discretion

Patients selected to be included in this study will have no more than moderate severity of the disease and will have to meet the following criteria; Not dependent on chronic invasive ventilatory support AND have either Expressive language sub test on Mullen and/or Vineland consistent with an age equivalent score of a 2 year 0 month old. This means they should have 20-50 words (all comprehensible) in their vocabulary and putting 2-3 words phrases in a sentence or, Patients can complete and obtain a score of 2-3 on GMFM sub domain E (Walking, Running & jumping) item 67 (ie With 2 hands held can walk 10 steps forward)

Exclusion Criteria

Inability to tolerate anesthesia or study procedures

I started a new epilepsy medication within the last 90 days.

Abnormal lab values that are clinically significant: Platelet count < 100,000/mm3

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a one-time intrathecal injection of AAV9/CLN7 gene therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of motor, cognition, and intelligence

24 months

Multiple visits at Days 90, 180, 360, and 720

Treatment Details

Interventions

• AAV9/CLN7

Trial Overview The trial tests a gene therapy called AAV9/CLN7 given as a one-time spinal injection in two different doses. It aims to assess the safety of this treatment and its effectiveness on motor skills, cognition, vision, and brain function in kids with CLN7 disease.

Participant Groups

Group I: AAV9/CLN7 Experimental Treatment 1 Intervention

AAV9/CLN7 is an intrathecally administered AAV9-based gene therapy vector that expresses the fully functional form of MFSD8 under the control of a synthetic promoter. AAV9/CLN7 is designed to achieve stable, potentially life-long expression of MFSD8 in non-dividing cells. The first participant will receive a low dose of 5X1014 vg, subsequent participants will receive a higher dose of 1x1015 vg of the AAV9/CLN7 agent.

Who Is Running the Clinical Trial?

Benjamin Greenberg

Lead Sponsor

Trials

1

Recruited

4+

Findings from Research

In a mouse model of CLN8 disease, a single neonatal injection of a gene therapy vector (scAAV9) was found to be safe and well tolerated, leading to long-lasting expression of the human CLN8 gene and significant improvements in disease symptoms over a period of 24 months.

This gene therapy not only reduced the disease's behavioral and histopathological effects but also extended the lifespan of treated mice from 10 months to over 24 months, marking a major advancement in potential treatments for CLN8 disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease. Johnson, TB., White, KA., Brudvig, JJ., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Neurological deterioration in late infantile neuronal ceroid lipofuscinosis. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

CLN7 gene therapy: hope for an ultra-rare condition. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Gene therapy for late infantile neuronal ceroid lipofuscinosis: neurosurgical considerations. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease. [2020]