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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phase 1/2 Study of Antisense Oligonucleotide Therapy for Treatment of Ataxia - Telangiectasia | Experimental | Individuals with genetically confirmed, classic ataxia telangiectasia with at least one copy of the ASO-amenable ATM variant NM_000051.3:c.7865C>T;p.Ala2622Val, will receive the ASO at the same dose. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Antisense oligonucleotide targeting the ATM gene | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Neurological function as measured by the AT-NEST scale | The Ataxia-Telangiectasia Neurological Examination Toolkit (AT-NEST) is a test designed specifically for people with Ataxia-Telangiectasia (A-T). It helps doctors and researchers understand how the brain and nerves are working. The test looks at six main areas:
| At Baseline and every 12 weeks up to ten years |
| Ataxia-Telangiectasia Structured Clinical Global Impression of Change (A-T CGI) | The Ataxia-Telangiectasia Clinical Global Impression of Change (AT-CGI) is a tool used to track how A-T progresses over time. It looks at five main areas of the disease: Ataxia (balance and coordination problems) Dysarthria (difficulty speaking) Repetitive movements / Dysmetria (trouble controlling movements) Movement disorders Eye movements Each area is scored from 0 to 4, for a total of 20 points. Higher scores mean more severe symptoms, while lower scores indicate better function. | At Baseline and every 12 weeks up to ten years |
| Measure | Description | Time Frame |
|---|---|---|
| Motor performance as measured by the Bruininks-Oseretsky Test of Motor Proficiency 2nd edition | The Bruininks-Oseretsky Test of Motor Proficiency 2nd edition (BOT-2) is a simple way for therapists to check how your child is developing movement skills. It looks at:
|
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INCLUSION/EXCLUSION CRITERIA:
Who can take part:
Who cannot take part:
People with health problems that make lumbar puncture unsafe:
Other things doctors will check:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Arya Newington | Contact | 617-919-7499 | Arya.Newingham@childrens.harvard.edu |
| Name | Affiliation | Role |
|---|---|---|
| Timothy Yu, MD, PhD | Boston Childrens Hostpital | Study Director |
| Christelle Achkar, MD | Boston Children's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boston Children's Hospital | Recruiting | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37438524 | Background | 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 Jul;619(7971):828-836. doi: 10.1038/s41586-023-06277-0. Epub 2023 Jul 12. |
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| ID | Term |
|---|---|
| D001260 | Ataxia Telangiectasia |
| ID | Term |
|---|---|
| D020754 | Spinocerebellar Ataxias |
| D002524 | Cerebellar Ataxia |
| D002526 | Cerebellar Diseases |
| D001927 | Brain Diseases |
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| Baseline and every 6 months up to 10 years |
| Performance and goal satisfaction as measured by the Canadian Occupational Performance Measure (COPM) | The Canadian Occupational Performance Measure (COPM) is a test done by an occupational therapist to understand what daily activities are most important to a person and how well they feel they can do them. During the test, the person picks up to five activities they find difficult or want to improve. For each activity, they rate:
| 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 | The Pediatric Evaluation of Disability Inventory - Computer Adaptive Test (PEDI-CAT) is a questionnaire filled out by parents or caregivers. It helps us understand how a child is doing in everyday life. It looks at four areas:
| Baseline and every 6 months up to 10 years |
| Visual-motor function as measured by the Beery-Buktenica Developmental Test of Visual Motor Integration | The Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI) is a test often given by occupational therapists to see how well a child's eyes and hands work together. During the test, the child copies shapes and designs that get harder as the test goes on. Sometimes the child may also be asked to find differences between pictures or match patterns. The results show:
This helps parents and therapists see how the child's coordination and fine motor skills are compared to others their age. | Baseline and every 6 months up to 10 years |
| Neurodevelopmental function, as measured by the Leiter International Performance, third edition | The Leiter International Performance Scale-3 (Leiter-3) is a test that measures thinking and problem-solving skills. It is especially helpful for children or adults who have speech, language, or learning difficulties, or for those who do not speak English. The test looks at areas such as:
This helps show how a person's thinking skills compare to others their age. | Baseline and yearly up to 10 years |
| Neurodevelopmental function, as measured Wechsler Intelligence Scale for Children, fifth edition | he Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) is a test that measures different areas of a child's thinking and learning. It looks at skills such as:
The test gives a Full Scale IQ (FSIQ) score, which shows a child's overall level of thinking skills. Higher scores mean stronger abilities. | Baseline and yearly up to 10 years |
| Neurodevelopmental function, as measured by the Vineland Adaptive Behavior Scale | The Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) is a test that measures how a child or adult manages everyday life skills, also called adaptive behaviors.It looks at areas such as:
| Baseline and yearly up to 10 years |
| Motor performance through digital wearable actigraphs | Digital actigraphs are small motion sensors that track how a person moves during daily life. They are often used in people with movement disorders, like ataxia and ataxia-telangiectasia. In this study, participants will wear one sensor on the wrist and one on the ankle for one week at a time. The information collected will show how a person moves during everyday activities. These results will then be compared to others with ataxia-telangiectasia who are not receiving treatment. | Baseline and every 12 weeks up to 10 years |
| D002493 |
| Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D020752 | Neurocutaneous Syndromes |
| D001259 | Ataxia |
| D020820 | Dyskinesias |
| D009461 | Neurologic Manifestations |
| D013684 | Telangiectasis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D000081207 | Primary Immunodeficiency Diseases |
| D049914 | DNA Repair-Deficiency Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |