Target-Cell-Directed Bioengineering Approaches for Gene Therapy of Hemophilia A.

ABSTRACT: Potency is a key optimization parameter for hemophilia A gene therapy product candidates. Optimization strategies include promoter engineering to increase transcription, codon optimization of mRNA to improve translation, and amino-acid substitution to promote secretion. Herein, we describe both rational and empirical design approaches to the development of a minimally sized, highly potent AAV-fVIII vector that incorporates three unique elements: a liver-directed 146-nt transcription regulatory module, a target-cell-specific codon optimization algorithm, and a high-expression bioengineered fVIII variant. The minimal synthetic promoter allows for the smallest AAV-fVIII vector genome known at 4,832 nt, while the tissue-directed codon optimization strategy facilitates increased fVIII transgene

SUBMITTER: Brown HC 

PROVIDER: S-EPMC5852392 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature