Drug repurposing screen for the rare disease ataxia-telangiectasia
Ataxia Telangiectasia (A-T) is a rare, autosomal recessive genetic disorder characterized by a variety of symptoms, including progressive neurodegeneration, telangiectasia, immunodeficiency, and an increased susceptibility to cancer. It is caused by bi-allelic mutations impacting a gene encoding a s...
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | SLAS Discovery |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2472555224000625 |
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| author | Namrata Jayanth Gurvan Mahé Matthew Campbell Mike Lipkin Shushant Jain Rhea van de Bospoort Jennifer Thornton Brad Margus David F. Fischer |
| author_facet | Namrata Jayanth Gurvan Mahé Matthew Campbell Mike Lipkin Shushant Jain Rhea van de Bospoort Jennifer Thornton Brad Margus David F. Fischer |
| author_sort | Namrata Jayanth |
| collection | DOAJ |
| description | Ataxia Telangiectasia (A-T) is a rare, autosomal recessive genetic disorder characterized by a variety of symptoms, including progressive neurodegeneration, telangiectasia, immunodeficiency, and an increased susceptibility to cancer. It is caused by bi-allelic mutations impacting a gene encoding a serine/threonine kinase ATM (Ataxia Telangiectasia Mutated), which plays a crucial role in DNA repair and maintenance of genomic stability. The disorder primarily affects the nervous system, leading to a range of neurological issues, including cerebellar ataxia. The cause of neurodegeneration due to mutations in ATM is still an area of investigation, and currently there is no known treatment to slow down or stop the progression of the neurological problems.In this collaboration of the A-T Children's Project (ATCP) with Charles River Discovery, we successfully developed a high-throughput assay using induced pluripotent stem cells (iPSC) from A-T donors to measure DNA damage response (DDR). By measuring the changes in levels of activated phosphorylated CHK2 (p-CHK2), which is a downstream signaling event of ATM, we were able to identify compounds that restore this response in the DDR pathway in A-T derived patient cells. Over 6,000 compounds from small molecule drug repurposing libraries were subsequently screened in the assay developed, leading to identification of several promising in vitro hits.Using the assay developed and the identified hits opens avenues to investigate potential therapeutics for A-T. |
| format | Article |
| id | doaj-art-c33ea9794dbc46d382eb85d70f7ac867 |
| institution | Kabale University |
| issn | 2472-5552 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | SLAS Discovery |
| spelling | doaj-art-c33ea9794dbc46d382eb85d70f7ac8672025-01-23T05:27:25ZengElsevierSLAS Discovery2472-55522025-01-0130100200Drug repurposing screen for the rare disease ataxia-telangiectasiaNamrata Jayanth0Gurvan Mahé1Matthew Campbell2Mike Lipkin3Shushant Jain4Rhea van de Bospoort5Jennifer Thornton6Brad Margus7David F. Fischer8Charles River Laboratories, Leiden, The NetherlandsCharles River Laboratories, Leiden, The NetherlandsCharles River Laboratories, Saffron Walden, UKCharles River Laboratories, Saffron Walden, UKCharles River Laboratories, Leiden, The NetherlandsCharles River Laboratories, Leiden, The NetherlandsA-T Children's Project, Florida, USAA-T Children's Project, Florida, USACharles River Laboratories, Saffron Walden, UK; Corresponding author at: Chesterford Research Park, Saffron Walden CB10 1XL, UKAtaxia Telangiectasia (A-T) is a rare, autosomal recessive genetic disorder characterized by a variety of symptoms, including progressive neurodegeneration, telangiectasia, immunodeficiency, and an increased susceptibility to cancer. It is caused by bi-allelic mutations impacting a gene encoding a serine/threonine kinase ATM (Ataxia Telangiectasia Mutated), which plays a crucial role in DNA repair and maintenance of genomic stability. The disorder primarily affects the nervous system, leading to a range of neurological issues, including cerebellar ataxia. The cause of neurodegeneration due to mutations in ATM is still an area of investigation, and currently there is no known treatment to slow down or stop the progression of the neurological problems.In this collaboration of the A-T Children's Project (ATCP) with Charles River Discovery, we successfully developed a high-throughput assay using induced pluripotent stem cells (iPSC) from A-T donors to measure DNA damage response (DDR). By measuring the changes in levels of activated phosphorylated CHK2 (p-CHK2), which is a downstream signaling event of ATM, we were able to identify compounds that restore this response in the DDR pathway in A-T derived patient cells. Over 6,000 compounds from small molecule drug repurposing libraries were subsequently screened in the assay developed, leading to identification of several promising in vitro hits.Using the assay developed and the identified hits opens avenues to investigate potential therapeutics for A-T.http://www.sciencedirect.com/science/article/pii/S2472555224000625Drug repurposing screenHTSDNA damageRare diseaseAtaxia-telangiectasiaNeurodegeneration |
| spellingShingle | Namrata Jayanth Gurvan Mahé Matthew Campbell Mike Lipkin Shushant Jain Rhea van de Bospoort Jennifer Thornton Brad Margus David F. Fischer Drug repurposing screen for the rare disease ataxia-telangiectasia SLAS Discovery Drug repurposing screen HTS DNA damage Rare disease Ataxia-telangiectasia Neurodegeneration |
| title | Drug repurposing screen for the rare disease ataxia-telangiectasia |
| title_full | Drug repurposing screen for the rare disease ataxia-telangiectasia |
| title_fullStr | Drug repurposing screen for the rare disease ataxia-telangiectasia |
| title_full_unstemmed | Drug repurposing screen for the rare disease ataxia-telangiectasia |
| title_short | Drug repurposing screen for the rare disease ataxia-telangiectasia |
| title_sort | drug repurposing screen for the rare disease ataxia telangiectasia |
| topic | Drug repurposing screen HTS DNA damage Rare disease Ataxia-telangiectasia Neurodegeneration |
| url | http://www.sciencedirect.com/science/article/pii/S2472555224000625 |
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