In Vivo Transduction by Intravenous Injection of a Lentiviral Vector Expressing Human ADA into Neonatal ADA Gene Knockout Mice: A Novel Form of Enzyme Replacement Therapy for ADA Deficiency

Abstract

Using a mouse model of adenosine deaminase-deficient severe combined immune deficiency syndrome (ADA-deficient SCID), we have developed a noninvasive method of gene transfer for the sustained systemic expression of human ADA as enzyme replacement therapy. The method of delivery is a human immunodeficiency virus 1-based lentiviral vector given systemically by intravenous injection on day 1 to 2 of life. In this article we characterize the biodistribution of the integrated vector, the expression levels of ADA enzyme activity in various tissues, as well as the efficacy of systemic ADA expression to correct the ADA-deficient phenotype in this mouse model. The long-term expression of enzymatically active ADA achieved by this method, primarily from transduction of liver and lung, restored immunologic function and significantly extended survival. These studies illustrate the potential for sustained in vivo production of enzymatically active ADA, as an alternative to therapy by frequent injection of exogenous ADA protein.

Prolonged Adherence of Human Immunodeficiency Virus-Derived Vector Particles to Hematopoietic Target Cells Leads to Secondary Transduction In Vitro and In Vivo

“…Further, we demonstrated the detection of GFP by IHC and PCR in liver and spleen. Overall, the distribution of particles and resultant marking in these animals appear to be different from and less diffuse than those after IV injection of particles reported in other studies (7,13,26,28).…”

Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics

“…Moreover, it has to be mentioned that for immunotherapy, the lentiviral vectors are systemically administered, whereas in the case of gene therapy, the lentiviral vectors are most often administered in the Lentiviral vectors in cancer immunotherapy K Breckpot et al tissue of interest, resulting in transduction of these tissue-specific cells. [157][158][159][160][161] Second, when using ex vivo-transduced DC or targeting DC in vivo, terminally differentiated, nondividing cells are transduced as opposed to extensively proliferating cells in the SCID trial, thereby posing less of a risk for oncogenic transformations. Finally, when an immune response is induced in vivo, the effector cells will most likely kill cells that express the target antigen, including the transduced APC, thus, further reducing the risk for oncogenesis.…”

Lentiviral gene transfer to reduce atherosclerosis progression by long-term CC-chemokine inhibition

“…Modified lentivirus vectors can direct stable gene transfer by evasion of host immunosurveillance [15][16][17] through incorporation into the host genome and absence of viral gene expression. 18 However, efficient transduction rates in vivo are difficult to achieve, typically requiring delivery through the portal vein, 19 injection into the facial vein of neonates 16 or transplantation of transduced bone marrow.…”

“…18 However, efficient transduction rates in vivo are difficult to achieve, typically requiring delivery through the portal vein, 19 injection into the facial vein of neonates 16 or transplantation of transduced bone marrow. 17 More efficient in vivo transduction by lentiviral vectors is required to provide prolonged gene transfer with biologically important effects.…”