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Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side

1
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, The Netherlands
2
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands
3
Willem-Alexander Children’s Hospital, Leiden University Medical Center, 2333ZA Leiden, The Netherlands
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(6), 549; https://doi.org/10.3390/pharmaceutics12060549
Received: 30 April 2020 / Revised: 5 June 2020 / Accepted: 9 June 2020 / Published: 13 June 2020
(This article belongs to the Special Issue Cell-Based Drug-Delivery Platforms)
Recent clinical trials using patient’s own corrected hematopoietic stem cells (HSCs), such as for primary immunodeficiencies (Adenosine deaminase (ADA) deficiency, X-linked Severe Combined Immunodeficiency (SCID), X-linked chronic granulomatous disease (CGD), Wiskott–Aldrich Syndrome (WAS)), have yielded promising results in the clinic; endorsing gene therapy to become standard therapy for a number of diseases. However, the journey to achieve such a successful therapy is not easy, and several challenges have to be overcome. In this review, we will address several different challenges in the development of gene therapy for immune deficiencies using our own experience with Recombinase-activating gene 1 (RAG1) SCID as an example. We will discuss product development (targeting of the therapeutic cells and choice of a suitable vector and delivery method), the proof-of-concept (in vitro and in vivo efficacy, toxicology, and safety), and the final release steps to the clinic (scaling up, good manufacturing practice (GMP) procedures/protocols and regulatory hurdles). View Full-Text
Keywords: gene therapy; immunodeficiency; HSC; vector design; animal model; efficacy; safety; scaling up; regulations; GMP complaint gene therapy; immunodeficiency; HSC; vector design; animal model; efficacy; safety; scaling up; regulations; GMP complaint
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Garcia-Perez, L.; Ordas, A.; Canté-Barrett, K.; Meij, P.; Pike-Overzet, K.; Lankester, A.; Staal, F.J.T. Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side. Pharmaceutics 2020, 12, 549.

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