Classical homocystinuria: From cystathionine beta-synthase deficiency to novel enzyme therapies.

Autor: Bublil EM; Orphan Technologies Ltd., Rapperswil, 8640, Switzerland., Majtan T; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Electronic address: tomas.majtan@cuanschutz.edu.
Jazyk: angličtina
Zdroj: Biochimie [Biochimie] 2020 Jun; Vol. 173, pp. 48-56. Date of Electronic Publication: 2019 Dec 16.
DOI: 10.1016/j.biochi.2019.12.007
Abstrakt: Genetic defects in cystathionine beta-synthase (CBS), a key enzyme of organic sulfur metabolism, result in deficiency of CBS activity and a rare inborn error of metabolism called classical homocystinuria (HCU). HCU is characterized by massive accumulation of homocysteine, an intermediate of methionine metabolism, and multisystemic clinical symptoms. Current treatment options for HCU are very limited and often inefficient, partially due to a low patient compliance with very strict dietary regimen. Novel therapeutic approaches are needed to cope with the toxic accumulation of homocysteine and restoration of a healthy metabolic balance. Human CBS is a complex intracellular multimeric enzyme that relies on three cofactors (heme, pyridoxal-5'-phosphate and S-adenosylmethionine) for proper function. Engineering and chemical modification of human CBS yielded OT-58, a first-in-class enzyme therapy candidate for HCU. Pre-clinical testing of OT-58 showed its substantial efficacy in lowering plasma and tissue concentrations of homocysteine, improving metabolic balance and correcting clinical symptoms of HCU. In addition, OT-58 showed great safety and toxicity profile when administered to non-human primates. Overwhelmingly positive and extensive pre-clinical package propelled OT-58 into a first-in-human clinical trial, which started on January 2019. In a meantime, other enzyme therapies based on modified human cystathionine gamma-lyase or erythrocyte-encapsulated bacterial methionine gamma-lyase have shown efficacy in decreasing plasma homocysteine in HCU mice. In addition, gene therapy approaches using adenovirus or minicircle DNA have been evaluated in HCU. In this review, we summarize the current efforts developing novel therapies for HCU to address a high unmet medical need among HCU patients.
Competing Interests: Declaration of competing interest EMB is an employee of Orphan Technologies, a private pharmaceutical company developing OT-58 enzyme therapy for classical HCU. TM and EMB are inventors on patents related to OT-58 (US patents 9,034,318 and 9,243,239). TM provides ad hoc consulting services to Orphan Technologies Ltd.
(Copyright © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
Databáze: MEDLINE
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