Key result
Self-inactivating alpharetroviral vectors provided functional correction of the X-CGD phenotype up to wild-type levels in human CD34+ cells without causing aberrant splicing.
Why the study?
Does SIN alpharetroviral vector-mediated gene therapy provide functional correction and a safe integration profile in X-CGD models?
Does SIN alpharetroviral vector-mediated gene therapy provide functional correction and a safe integration profile in X-CGD models?
SIN alpharetroviral vectors provide functional correction of X-CGD in preclinical models without the aberrant splicing seen with lentiviral vectors, suggesting a favorable safety profile for gene therapy.
Supports preclinical development of SIN alpharetroviral vectors for X-CGD; leaves open clinical translation and long-term safety.
Comparative integrome analysis has revealed that the most neutral integration pattern among retroviruses is attributed to alpharetroviruses. We chose X-linked chronic granulomatous disease (X-CGD) as model to evaluate the potential of self-inactivating (SIN) alpharetroviral vectors for gene therapy of monogenic diseases. Therefore, we combined the alpharetroviral vector backbone with the elongation factor-1α short promoter, both considered to possess a low genotoxic profile, to drive transgene (gp91(phox)) expression. Following efficient transduction transgene expression was sustained and provided functional correction of the CGD phenotype in a cell line model at low vector copy number. Further analysis in a murine X-CGD transplantation model revealed gene-marking of bone marrow cells and oxidase positive granulocytes in peripheral blood. Transduction of human X-CGD CD34+ cells provided functional correction up to wild-type levels and long-term expression upon transplantation into a humanized mouse model. In contrast to lentiviral vectors, no aberrantly spliced transcripts containing cellular exons fused to alpharetroviral sequences were found in transduced cells, implying that the safety profile of alpharetroviral vectors may extend beyond their neutral integration profile. Taken together, this highlights the potential of this SIN alpharetroviral system as a platform for new candidate vectors for future gene therapy of hematopoietic disorders.
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Kaufmann et al. (2012) studied X-linked chronic granulomatous disease (X-CGD). Self-inactivating (SIN) alpharetroviral vectors vs. Lentiviral vectors was evaluated on Functional correction of the CGD phenotype and aberrant splicing. Self-inactivating alpharetroviral vectors provided functional correction of the X-CGD phenotype up to wild-type levels in human CD34+ cells without causing aberrant splicing.
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