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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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.

Первичные конечные точки

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

Вторичные конечные точки (8)

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

Критерии участия

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Boston Children's Hospital — Boston

Публикации

• 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

Идентификаторы

NCT: NCT07215416 · IRB P00050954

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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