Schejtman, A;
Vetharoy, W;
Choi, U;
Rivat, C;
Theobald, N;
Piras, G;
Leon-Rico, D;
... Santilli, G; + view all
(2021)
Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47phox-Deficient Chronic Granulomatous Disease.
Human Gene Therapy
, 32
(17-18)
pp. 949-958.
10.1089/hum.2020.276.
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Abstract
Chronic granulomatous disease (CGD) is an inherited blood disorder that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with no adverse events related to the gene therapy procedure. We have recently developed a parallel lentiviral vector for p47-deficient CGD (p47phoxCGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardised pre-clinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumourigenesis, in human haematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34+ cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34+ cells derived from a p47phoxCGD patient were subjected to an optimised transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed NADPH oxidase production in vivo, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47phoxCGD.
| Type: | Article |
|---|---|
| Title: | Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47phox-Deficient Chronic Granulomatous Disease |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1089/hum.2020.276 |
| Publisher version: | https://doi.org/10.1089/hum.2020.276 |
| Language: | English |
| Additional information: | This Open Access article is distributed under the terms of the Creative Commons License [CC-BY] (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10124812 |
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