期刊
BIOMACROMOLECULES
卷 18, 期 6, 页码 1747-1761出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.biomac.7b00154
关键词
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资金
- American Heart Association [16SDG30040000]
- Orphan Technologies Ltd.
- Colorado CTSA Grant from NCATS/NIH [UL1 TR001082]
Homocystinuria due to loss of cystathionine betasynthase (CBS) causes accumulation of homocysteine and depletion of cysteine. Current treatments are suboptimal, and thus the development of an enzyme replacement therapy based on PEGylated human truncated CBS (PEG-CBS) has been initiated. Attenuation of potency was observed, which necessitated a screen of several PEG-CBS conjugates for their efficacy to correct and maintain the plasma metabolite profile of murine homocystinuria after repeated administrations interrupted with washouts. We found that CBS coupling with maleimide PEG inconsistently modified the enzyme. In contrast, the PEG-CBS conjugate with 20 kDa N-hydroxysuccinimide-PtG showed very little loss of potency likely due to a reproducible PEGylation resulting in species modified with five PEGs per subunit on average. We developed assays suitable for monitoring the extent of CBS PEGylation and demonstrated a sustainable partial normalization of homocystinuria upon continuous PEG-CBS administration via osmotic pumps. Taken together, we identified the PEG-CBS conjugate suitable for manufacturing and clinical development.
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