Safety and Efficacy of Mutation-targeted Precision Genetic Therapy for Ataxia-Telangiectasia (A-T)

Official title

A Phase 1/2 Study of Antisense Oligonucleotide Therapy for Treatment of Ataxia-Telangiectasia

Overview

This project aims to evaluate the safety and efficacy of precision genetic therapy for patients with Ataxia-telangiectasia (A-T), a rare neurodegenerative disease caused by mutations in the ATM gene. The investigators will conduct a clinical trial to study the safety and efficacy of intrathecal administration of atipeksen, a targeted genetic therapy that restores ATM gene function in A-T individuals bearing the recurrent ATM c.7865C\>T variant. The aim of this study is to delay or forestall progression of neurologic symptoms in A-T and improving quality of life. Success will provide an empirical foundation for advancing additional precision genetic therapies for A-T and other neurodegenerative conditions.

Detailed description

The goal of this protocol is to study the safety and efficacy of the investigational drug atipeksen, a mutation-specific antisense oligonucleotide (ASO), in individuals with ataxia telangiectasia (A-T). The first objective is to evaluate the safety of therapy with atipeksen, a 22-nucleotide oligonucleotide designed to ameliorate the effects of mis-splicing caused by a mutation in the ATM gene(NM\_000051.3), c.7865C\>T (p.Ala2622Val), when administered via intrathecal injection. The second objective is to determine if administration of intrathecal atipeksen can reduce or stabilize neurological decline using clinical and physiological biomarkers. The primary endpoint will be serial clinical neurologic assessments using the Ataxia-Telangiectasia Neurological Examination Toolkit (A-T NEST) and a structured version of the Ataxia-Telangiectasia Clinical Global Impression of Change (A-T CGI). Secondary endpoints will include videotaped clinical neurological examinations, movement pattern analyses using wearable actigraphy, and standard scales administered by PT, OT, and neuropsychology. Exploratory endpoints include serial brain imaging with volumetric analyses, neurofilament light chain, alpha-fetoprotein, and growth parameters.

Interventions

• Drug Antisense oligonucleotide targeting the ATM gene
  Atipeksen is a fully modified PS-2'MOE splice-switching antisense oligonucleotide that is designed to restore normal splicing patterns in patients with the ATM c.7865C\>T mutation.

Primary outcome measures

• Neurological function as measured by the AT-NEST scale [Time frame: At Baseline and every 12 weeks up to ten years]
• Ataxia-Telangiectasia Structured Clinical Global Impression of Change (A-T CGI) [Time frame: At Baseline and every 12 weeks up to ten years]

Secondary outcome measures (8)

• Motor performance as measured by the Bruininks-Oseretsky Test of Motor Proficiency 2nd edition [Time frame: Baseline and every 6 months up to 10 years]
• Performance and goal satisfaction as measured by the Canadian Occupational Performance Measure (COPM) [Time frame: Baseline and every 6 months up to 10 years]
• Performance in activities of daily living as measured by the Pediatric Evaluation of Disability Inventory Computer Adaptive Test [Time frame: Baseline and every 6 months up to 10 years]
• Visual-motor function as measured by the Beery-Buktenica Developmental Test of Visual Motor Integration [Time frame: Baseline and every 6 months up to 10 years]
• Neurodevelopmental function, as measured by the Leiter International Performance, third edition [Time frame: Baseline and yearly up to 10 years]
• Neurodevelopmental function, as measured Wechsler Intelligence Scale for Children, fifth edition [Time frame: Baseline and yearly up to 10 years]
• Neurodevelopmental function, as measured by the Vineland Adaptive Behavior Scale [Time frame: Baseline and yearly up to 10 years]
• Motor performance through digital wearable actigraphs [Time frame: Baseline and every 12 weeks up to 10 years]

Eligibility criteria

INCLUSION/EXCLUSION CRITERIA:

Who can take part:

• People with classic A-T confirmed by genetic testing
• Must have a specific ATM gene change (c.7865C>T)
• Must also have another ATM change that causes A-T

Who cannot take part:

People with health problems that make lumbar puncture unsafe:

• Blood clotting or bleeding problems
• Brain conditions raising pressure inside the head
• Serious heart or breathing problems
• Infection near the lower back

Other things doctors will check:

• Overall health and stability
• Any medicines that might cause problems
• Past difficulties with lumbar punctures
• Any other safety concerns

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Boston Children's Hospital — Boston

Publications

• Kim J, Woo S, de Gusmao CM, Zhao B, Chin DH, DiDonato RL, Nguyen MA, Nakayama T, Hu CA, Soucy A, Kuniholm A, Thornton JK, Riccardi O, Friedman DA, El Achkar CM, Dash Z, Cornelissen L, Donado C, Faour KNW, Bush LW, Suslovitch V, Lentucci C, Park PJ, Lee EA, Patterson A, Philippakis AA, Margus B, Berde CB, Yu TW. A framework for individualized splice-switching oligonucleotide therapy. Nature. 2023 J PMID 37438524

Identifiers

NCT: NCT07215416 · IRB P00050954

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗