Batten CLN6 Gene Therapy

Study Description

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Brief Summary:

The proposed clinical trial is the first human, open-label, single dose study of self-complementary AAV9 carrying the CLN6 gene delivered one-time intrathecally inserted by a lumbar puncture into Batten CLN6 Disease subjects. One cohort of patients with Batten CLN6 Disease, with confirmed diagnosis, will undergo gene transfer. A minimum of twelve patients will be enrolled into the cohort.

Condition or disease	Intervention/treatment	Phase
Batten Disease; CLN6	Drug: scAVV9.CB.CLN6	Phase 1; Phase 2

Detailed Description:

The proposed clinical trial is the first human, open-label, single dose study of self-complementary AAV9 carrying the CLN6 gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter (scAAV9.CB.CLN6) delivered one-time through an intrathecal catheter inserted by a lumbar puncture into the interspinous into the subarachnoid space of the lumbar thecal sac. All twelve patients will receive a dose equivalent to (1.5 x10^13 vg). This will be administered premixed with 2.5 mL of the contrast Omnipaque™ at a concentration of 180 mgI/mL of the contrast via a 10 mL syringe and a Spinal Needle. If no clinically significant improvement without toxicity is observed, the possibility of adding an additional escalation cohort at a higher dose will be discussed with the FDA, DSMB and relevant oversight regulatory agencies.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	12 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase I/IIa Gene Transfer Clinical Trial for Variant Late Infantile Neuronal Ceroid Lipofuscinosis, Delivering the CLN6 Gene by Self-Complementary AAV9
Study Start Date :	March 2016
Estimated Primary Completion Date :	March 2019
Estimated Study Completion Date :	March 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Cohort 1; Twelve (n=12) Batten CLN6 subjects will receive a single injection of scAAV9.CB.CLN6 via intrathecal delivery. Subjects will receive a total dose of 1.5 x 10^13 vg.	Drug: scAVV9.CB.CLN6; Twelve subjects with diagnosis of CLN6 disease will receive scAVV9.CB.CLN6 administered by intrathecal injection.

Outcome Measures

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Primary Outcome Measures :

1. Development of unacceptable toxicity, defined as the occurrence of any one Grade III or higher, unanticipated, treatment-related toxicity. [ Time Frame: 2 years ]
   This is evaluated based on the development of unacceptable toxicity, defined as the occurrence of any one Grade III or higher, unanticipated, treatment-related toxicity.

Secondary Outcome Measures :

1. Magnetic resonance imaging to document progression of the disease. [ Time Frame: Baseline and 24 months ]
   Volumetric imaging to monitor progression of the disease. The investigators will utilize 3D MP-RAGE scan, which is a T1-weighted volumetric scan of the whole brain. Investigators will also include T2 weighted Gradient Echo and diffusion- weighted axial images.
2. Cognitive testing [ Time Frame: Baseline, 6 months, 12 months, 24 months ]
   A retrospective review of cases indicates that language delay and cognitive regression are the earliest manifestations of the disease. The investigators will perform Stanford-Binet for mild, asymptomatic patients.
3. Cognitive testing [ Time Frame: Baseline, 6 months, 12 months, 24 months ]
   A retrospective review of cases indicates that language delay and cognitive regression are the earliest manifestations of the disease. The investigators will perform Mullen scales of Early learning for mild to moderate patients.
4. Language Delay [ Time Frame: Baseline, 6 months, 12 months, 24 months ]
   The investigators will use the Preschool Language scale -5 to monitor language.
5. Visual Failure [ Time Frame: ERG: Baseline, Day 30, 12 months, 24 months OCT: Baseline and 24 months ]
   This will be assessed via electroretinograms (ERG) or ocular computerized tomography.
6. EEG Monitoring [ Time Frame: Baseline, 12 months, 24 months ]
   24 hour EEG long term monitoring to monitor progression of encephalopathy and epileptiform activity.

Eligibility Criteria

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Ages Eligible for Study:	1 Year and older (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Diagnosis of CLN6 disease determined by genotype available at Screening
• Quantitative clinical assessment of the Hamburg motor-language aggregate score at Screening on CLN2 disease motor-language scale, as defined in the Ratings Assessment Guideline.
• Age ≥1 year
• Written informed consent from parent or legal guardian and assent from subject, if appropriate.
• Ability to comply with protocol required assessments (laboratory sample collection, EEG, ECG, MRI, etc.

Exclusion Criteria:

• Another inherited neurologic disease, e.g., other forms of CLN or seizures unrelated to CLN2 disease (patients with febrile seizures may be eligible)
• Another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) before screening
• Active viral infection
• Has received stem cell or bone marrow transplantation for CLN6 disease
• Contraindications for spinal tap procedure (e.g., spina bifida, meningitis, impairment, or clotting abnormalities)
• Contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain)
• Episode of generalized motor status epilepticus within 4 weeks before the First Dose visit
• Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before the First Dose visit (enrollment may be postponed)
• Has received any investigational medication within 30 days before the first infusion of study drug
• Patients with Anti-AAV9 antibody titers ≥ 1:50 as determined by ELISA binding immunoassay.
• Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's wellbeing, safety, or clinical interpretability
• Pregnancy any time during the study; a female subject judged by the investigator to be of childbearing potential will be tested for pregnancy
• Abnormal laboratory values considered clinically significant (GGT > 3XULN, Bilirubin ≥ 3.0 mg/dL , Creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm)

Contacts and Locations

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Contacts

Contact: Alana Mahley, BS	614-355-2606	Alana.Mahley@nationwidechildrens.org

Locations

United States, Ohio
Nationwide Children's Hosptial	Recruiting
Columbus, Ohio, United States, 43205
Contact: Alana Mahley, BS 614-355-2606 alana.mahley@nationwidechildrens.org
Contact: Katie Church, MSW 614-722-6961 kathleen.church@nationwidechildrens.org
Principal Investigator: Jerry R Mendell, MD
Sub-Investigator: Emily de los Reyes, MD

Sponsors and Collaborators

Nationwide Children's Hospital

Gray Foundation

Investigators

Principal Investigator:	Jerry R Mendell, MD	Director, Center for Gene Therapy

More Information

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Additional Information:

Center for Gene Therapy, The Research Institute at Nationwide 

Gene Therapy Clinical Studies at Nationwide 

Responsible Party:	Jerry R. Mendell, Principal Investigator, Center for Gene Therapy, Nationwide Children's Hospital
ClinicalTrials.gov Identifier:	NCT02725580 History of Changes
Other Study ID Numbers:	IRB15-00963
First Posted:	April 1, 2016
Last Update Posted:	August 9, 2018
Last Verified:	August 2018

Keywords provided by Jerry R. Mendell, Nationwide Children's Hospital:

Neuronal ceroid lipofuscinosis; NCL; Gene Transfer; Gray Foundation

Additional relevant MeSH terms:

Neuronal Ceroid-Lipofuscinoses; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Genetic Diseases, Inborn	Lipidoses; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases