Improved Titer and Gene Transfer by Lentiviral Vectors Using Novel, Small β-Globin Locus Control Region Elements.

Molecular therapy : the journal of the American Society of Gene Therapy 2020 Jan 08

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β-globin lentiviral vectors (β-LV) have faced challenges in clinical translation for gene therapy of sickle cell disease (SCD) due to low titer and sub-optimal gene transfer to hematopoietic stem and progenitor cells (HSPCs). To overcome the challenge of preserving efficacious expression while increasing vector performance, we used published genomic and epigenomic data available through ENCODE to redefine enhancer element boundaries of the β-globin locus control region (LCR) to construct novel ENCODE core sequences. These novel LCR elements were used to design a β-LV of reduced proviral length, termed CoreGA-AS3-FB, produced at higher titers and possessing superior gene transfer to HSPCs when compared to the full-length parental β-LV at equal MOI. At low vector copy number, vectors containing the ENCODE core sequences were capable of reversing the sickle phenotype in a mouse model of SCD. These studies provide a β-LV that will be beneficial for gene therapy of SCD by significantly reducing the cost of vector production and extending the vector supply. Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Citation

Richard A Morgan, Mildred J Unti, Bamidele Aleshe, Devin Brown, Kyle S Osborne, Colin Koziol, Paul G Ayoub, Oliver B Smith, Rachel O'Brien, Curtis Tam, Eric Miyahira, Marlene Ruiz, Jason P Quintos, Shantha Senadheera, Roger P Hollis, Donald B Kohn. Improved Titer and Gene Transfer by Lentiviral Vectors Using Novel, Small β-Globin Locus Control Region Elements. Molecular therapy : the journal of the American Society of Gene Therapy. 2020 Jan 08;28(1):328-340