Adeno-Associated Virus and Hematopoietic Stem Cells: The Potential of Adeno-Associated Virus Hematopoietic Stem Cells in Genetic Medicines

Abstract

Adeno-associated virus (AAV)-based vectors have transformed into powerful elements of genetic medicine with proven therapeutic efficacy and a good safety profile. Over the years, efforts to transduce hematopoietic stem cells (HSCs) with AAV2 vectors have, however, been challenging. While there was evidence that AAV2 delivered vector genomes to primitive, quiescent, multipotential, self-renewing, in vivo engrafting HSCs, transgene expression was elusive. In this study, we review the evolution of AAV transduction of HSC, starting with AAV2 vectors leading to the isolation of a family of naturally occurring AAVs from human CD34 + HSC, the AAVHSC. The stem cell-derived AAVHSCs have turned out to have remarkable potentials for genetic therapies well beyond the hematopoietic system. AAVHSCs have tropism for a wide variety of peripheral tissues, including the liver, muscle, and the retina. They cross the blood-brain barrier and transduce cells of the central nervous system. Preclinical gene therapy studies underway using AAVHSC vectors are discussed. We review the notable ability of AAVHSCs to mediate efficient, seamless homologous recombination in the absence of exogenous nuclease activity and discuss the therapeutic implications. We also discuss early results from an AAVHSC-based clinical gene therapy trial that is underway for the treatment of phenylketonuria. Thus, the stem cell-derived AAVHSC, offer a multifaceted platform for in vivo gene therapy and genome editing for the treatment of inherited diseases.

Advances in HIV Gene Therapy

“…The modification of target cells with the gene of interest can face various challenges. For example, adeno-associated virus vectors do not effectively transduce HSCs due to blocks to nuclear entry, uncoating and second-strand synthesis [ 110 ]. Pseudotyping lentiviral vectors with a VSV-G envelope leads to broad cell tropism although primary human resting T cells, and CD34+ cells are not effectively transduced due to a lack of or inadequate expression of the LDLR receptor, through which it gains entry into the cell [ 111 ].…”

The Role of Recombinant AAV in Precise Genome Editing

“…We have recently shown that AAV editing vectors belonging to clade F mediate exclusively HR-based, highly accurate and seamless, and efficient genome editing in human cells and mice without the requirement for exogenous nucleases ( Figure 2D ) ( Smith et al, 2018 ). These vectors include a family of novel, naturally occurring AAVs isolated from healthy human hematopoietic stem cells (HSCs), termed AAVHSC ( Smith et al, 2014 ; Chatterjee et al, 2020 ). AAVHSC editing was found to be precise and efficient, with no on-target insertion/deletion mutations and no evidence of genomic scarring or incorporation of residual viral sequences, including the ITRs.…”

Novel vectors and approaches for gene therapy in liver diseases

“…It has been shown that AAVHSC-mediated gene insertion can correct the disease phenotype in a PKU mouse model. 93 A phase I/II clinical trial has recently been initiated using AAVHSC15 in patients with late-onset PKU ( Table 1 ).…”