Long-term nicotinamide riboside use in patients with ataxia telangiectasia showed safety, improved motor coordination, and eye movements, suggesting potential disease attenuation.
A recently published single-arm, open-label clinical trial showed that among patients with ataxia telangiectasia (A-T), long-term use of nicotinamide riboside (NR) was safe, with associated improvements in motor coordination and eye movements when compared with historical controls. Researchers concluded that disease progression may be attenuated through this approach, although further investigation is needed in larger studies.
Senior author Hilde Loge Nilsen, PhD, professor at the Oslo University Hospital, and colleagues assessed the safety and benefits of long-term NR supplementation in 13 patients with A-T over a 2-year period. In addition to safety, the study used 4 clinical assessments to evaluate neurological and motor function: the A-T Neurological Examination Toolkit (A-T NEST), International Cooperative Ataxia Rating Scale (ICARS) test, Scale for the Assessment and Rating of Ataxia (SARA), and Gait Scale (GS).
Among the 13 enrolled patients, 10 completed 18 months of treatment, 7 of which were children and 3 adults. Four of these patients received weekly subcutaneous immunoglobulins as well. At 18 months, improvement in neuromotor scores were observed in all ages, including individuals in the age group (6-9 years) that experiences the most rapid neuromotor decline, and “surprisingly” also in the oldest participants, the study authors noted. Over this time, patients had an average increase of 4.7 points on A-T NEST total score (P = .036), with only 1 individual who didn’t demonstrate improvement.
Despite not reaching statistical significance, patients did still see average ICARS total scores drop from 62.8 at baseline to 54.4 at 18 months. Changes in the total scores were driven mostly by improvements in the coordination subscores. After NR supplementation, patients showed a reduction in SARA coordination subscore from 8.4 to 6.6 over the 18-month period (P <.001) and a reduction in ICARS coordination score of 3.3 points (P = .014). in the A-T NEST movement disorders subscore, only 1 participant scored lower after 18 months, with a reduction of 1.7 (P = .111).
At 24 months, patients demonstrated improvements in within-group marginal mean scores for all neuromotor outcomes whereas marginal means for historical controls remained relatively unchanged from baseline. Results continued to show significant improvements in the A-T NEST eye coordination test by 1.51 (95% CI, 0.51-2.50; P = .003) and an increase in A-T NEST total score by 6.02 (95% CI, –0.41 to 12.45; P = .066), albeit not significant. Looking at individual trajectories, all but 1 intervention group participant improved over the study period for both A-T NEST scores.
Over the study period, treated participants demonstrated significant improvements in SARA total score by –2.32 (95% CI, –4.01 to –0.63; P = .007) and coordination score by –2.21 (95% CI, –3.15 to –1.27; P <.001) in comparison with historical controls. Looking only at the intervention group, model-estimated means at 24 months showed improved ICARS total scores by −3.67 (95% CI −5.84 to −1.50), coordination by −3.21 (95% CI −4.55 to −1.88), and oculomotor scores by −0.19 (95% CI −0.77 to 0.39) when adjusted for baseline values.
Previously, research showed that chronic activation of PARP1, in an alternative DNA damage response pathway, leads to depletion of intracellular scores of NAD in ATM knockout cells, the pathogenic variant of A-T. Consistent with animal findings, NAM levels were higher in patients with A-T compared with age-matched controls. Following NAD concentrations individually showed stabilization between 2- and 6-fold over baseline levels. Additionally, there was no change in neurofilament light levels during the treatment.
In terms of safety, there were no observed clinically meaningful changes in biomarkers related to liver or kidney function throughout the 2-year treatment period. Additionally, AFP levels, a commonly used biomarker of A-T progression, remained stable throughout NR supplementation. Furthermore, NR supplementation did not cause notable adverse events nor significant elevation of biomarkers of dysregulated liver, kidney, or blood sugar during the study period. There were no consistent changes in any hematological or immunological parameters, including no cases of thrombocytopenia.