Patient-reported outcomes and functional assessments of patients with Alkaptonuria in a 3-year Nitisinone treatment trial.

Autor: Spears KR; Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, United States., Rossignol F; Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, United States., Perry MB; Rehabilitation Medicine Department, NIH Clinical Center, United States., Kayser MA; Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, United States., Suwannarat P; Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, United States., O'Brien KE; Office of the Clinical Director, NHGRI, United States., Bryant JC; Office of the Clinical Director, NHGRI, United States., Greenwood WF; Cycle Pharmaceuticals Limited, United Kingdom., Fuller S; Cycle Pharmaceuticals Limited, United Kingdom., Gahl WA; Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, United States., Introne WJ; Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, United States. Electronic address: wintrone@mail.nih.gov.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2024 Sep-Oct; Vol. 143 (1-2), pp. 108562. Date of Electronic Publication: 2024 Aug 03.
DOI: 10.1016/j.ymgme.2024.108562
Abstrakt: Alkaptonuria is a rare disorder of tyrosine catabolism caused by deficiency of homogentisate 1,2-dioxygenase that leads to accumulation of homogentisic acid (HGA). Deposition of HGA-derived polymers in connective tissue causes progressive arthropathy of the spine and large joints, cardiac valvular disease, and genitourinary stones beginning in the fourth decade of life. Nitisinone, a potent inhibitor of the upstream enzyme, 4-hydroxyphenylpyruvate dioxygenase, dramatically reduces HGA production. As such, nitisinone is a proposed treatment for alkaptonuria. A randomized clinical trial of nitisinone in alkaptonuria confirmed the biochemical efficacy and tolerability of nitisinone for patients with alkaptonuria but the selected primary outcome did not demonstrate significant clinical benefit. Given that alkaptonuria is a rare disease with slow progression and variable presentation, identifying outcome parameters that can detect significant change during a time-limited clinical trial is challenging. To gain insight into patient-perceived improvements in quality of life and corresponding changes in physical function associated with nitisinone use, we conducted a post-hoc per protocol analysis of patient-reported outcomes and a functional assessment. Analysis revealed that nitisinone-treated patients showed significant improvements in complementary domains of the 36-Item Short-Form Survey (SF-36) and 6-min walk test (6MWT). Together, these findings suggest that nitisinone improves both quality of life and function of patients with alkaptonuria. The observed trends support nitisinone as a therapy for alkaptonuria.
Competing Interests: Declaration of competing interest KRS, FR, MBP, MAK, PS, KEO, JCB, WAG, and WJI have no conflicts of interest to declare. WFG and SF are employees of Cycle Pharmaceuticals Limited. Partial research support was received from Cycle Pharmaceuticals Limited through a cooperative research and development agreement with the NIH.
(Published by Elsevier Inc.)
Databáze: MEDLINE
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