4. β-Deliverin: A Small Molecule for Improving Gene Transfer to Hematopoietic Stem Cells and Probing Mechanisms of Lentiviral Vector Restriction

Timberlake, Nina; Ozog, Stosh; D'Souza, Saritha S.; Slukvin, Igor I.; Catz, Sergio D.; Snyder, Scott A.; Torbett, Bruce E.

doi:10.1016/s1525-0016(16)32813-1

Cited by 2 publications

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“…The cell transduction efficiency of LVs is difficult to control and predict, even with purified vectors, and is seemingly highly dependent on patient samples 8, 54, 55. Finding agents to enhance the frequency of hematopoietic cell transduction is being considered,56, 57 but higher transduction efficacy on the fraction of cells highly permissive to transduction may considerably increase the VCN per transduced cells and the risk for insertional mutagenesis 58 . Heterozygous β 0 /β + -thalassemia carriers are healthy.…”

Section: Discussionmentioning

confidence: 99%

Ex Vivo Selection of Transduced Hematopoietic Stem Cells for Gene Therapy of β-Hemoglobinopathies

et al. 2018

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Although gene transfer to hematopoietic stem cells (HSCs) has shown therapeutic efficacy in recent trials for several individuals with inherited disorders, transduction incompleteness of the HSC population remains a hurdle to yield a cure for all patients with reasonably low integrated vector numbers. In previous attempts at HSC selection, massive loss of transduced HSCs, contamination with non-transduced cells, or lack of applicability to large cell populations has rendered the procedures out of reach for human applications. Here, we fused codon-optimized puromycin N-acetyltransferase to herpes simplex virus thymidine kinase. When expressed from a ubiquitous promoter within a complex lentiviral vector comprising the β-globin gene, viral titers and therapeutic gene expression were maintained at effective levels. Complete selection and preservation of transduced HSCs were achieved after brief exposure to puromycin in the presence of MDR1 blocking agents, suggesting the procedure's suitability for human clinical applications while affording the additional safety of conditional suicide.

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Section: Discussionmentioning

confidence: 99%

Ex Vivo Selection of Transduced Hematopoietic Stem Cells for Gene Therapy of β-Hemoglobinopathies

et al. 2018

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“…Furthermore, TB2 is a lot more efficient than TB1 in promoting lentiviral transduction, and Tat-Scrambled is inefficient, but all of these peptides contain the same number of cationic charges. All of these features are rather reminiscent of a recently described transduction enhancer called ␤-Deliverin (27). ␤-Deliverin seems to promote viral adhesion/fusion by modulating endosomal maturation and trafficking.…”

Section: Beclin-derived Peptides Promote Viral Transductionmentioning

confidence: 96%

Peptides derived from evolutionarily conserved domains in Beclin-1 and Beclin-2 enhance the entry of lentiviral vectors into human cells

Majdoul

Cosette

Seye

et al. 2017

Journal of Biological Chemistry

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Autophagy-related proteins such as Beclin-1 are involved in an array of complex processes, including antiviral responses, and may also modulate the efficiency of gene therapy viral vectors. The Tat-Beclin-1 (TB1) peptide has been reported as an autophagy-inducing factor inhibiting the replication of pathogens such as HIV, type 1 (HIV-1). However, autophagy-related proteins are also essential for the early steps of HIV-1 infection. Therefore, we examined the effects of the Beclin-1 evolutionarily conserved domain in TB1 on viral transduction and autophagy in single-round HIV infection or with nonreplicative HIV-1-derived lentiviral vectors. TB1 enhanced transduction with various pseudotypes but without inducing the autophagy process. TB1 augmented the transduction of human CD34+ hematopoietic stem/progenitor cells while maintaining their capacity to engraft into humanized mice. TB1 was as effective as other transduction additives and functioned by enhancing the adhesion and fusion of viral particles with target cells but not their aggregation. We also found that the N-terminal L1 loop was critical for TB1 transduction-enhancing activity. Interestingly, the Tat-Beclin-2 (TB2) peptide, derived from the human Beclin-2 protein, was even more potent than TB1 in promoting viral transduction and infection. Taken together, our findings suggest that the TB1 and TB2 peptides enhance the viral entry step. Tat-Beclin peptides therefore represent a new family of viral transduction enhancers for potential use in gene therapy.

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4. β-Deliverin: A Small Molecule for Improving Gene Transfer to Hematopoietic Stem Cells and Probing Mechanisms of Lentiviral Vector Restriction

Cited by 2 publications

References 0 publications

Ex Vivo Selection of Transduced Hematopoietic Stem Cells for Gene Therapy of β-Hemoglobinopathies

Ex Vivo Selection of Transduced Hematopoietic Stem Cells for Gene Therapy of β-Hemoglobinopathies

Peptides derived from evolutionarily conserved domains in Beclin-1 and Beclin-2 enhance the entry of lentiviral vectors into human cells

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