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ATM is a master regulator of DNA damage responses and loss of ATM function is accompanied by persistent activation of PARP1 leading to depletion of intracellular NAD+ and dysfunction of a series of cellular signalling pathways dependent on NAD+, providing a mechanistic rationale for NAD+ augmentation therapy. We performed a clinical trial of NAD+ augmentation with nicotinamide riboside (NR) over 24 months in A-T patients where we observed improved coordination and eye movements in A-T patients. Here, by using peripheral blood mononuclear cells, we performed longitudinal transcriptome profiling to define molecular signatures of A-T and to assess pathway-level responses to NR supplementation. A-T patients exhibited reproducible transcriptomic alterations involving immune, vascular, and inflammatory pathways. NAD+ augmentation was associated with suppression of interferon response genes and modulation of networks correlated with neurological improvement. These findings establish systemic molecular signatures of A-T and identify potential blood-based biomarkers that reflect disease processes and therapeutic response, supporting the use of NAD+ augmentation as a disease-modifying strategy in A-T by dampening interferon signalling.<\/jats:p>","DOI":"10.3390\/ijms27135652","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:09:17Z","timestamp":1782270557000},"page":"5652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Transcriptional Profiling Shows Dampening of Interferon Gene Signatures by NAD+ Augmentation in Ataxia-Telangiectasia"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4446-9445","authenticated-orcid":false,"given":"Veronica","family":"Suaste","sequence":"first","affiliation":[{"name":"Department of Biosciences, University of Oslo, 0317 Oslo, Norway"},{"name":"Department of 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