Abstract
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).
Highlights
Over the past 5 years, the gene therapy product market has substantially expanded
Release tests to assess microbial contamination and purity, safety (Replication competent lentivirus negative and residual plasmid negative) and potency of the Lentiviral Vector (LV) starting material are recommended for routine batch analysis
hematopoietic stem cells (HSCs) isolation procedures and used vectors are rather standardized in the field, it is important to keep basic research in parallel to their clinical use, allowing continuous optimization in Good Manufacturing Practice (GMP) compliant manufacturing and automated procedures as well as improving vector safety
Summary
Over the past 5 years, the gene therapy product market has substantially expanded. Several products have been approved by the FDA (U.S Food and Drug Administration Agency) and the EMA (European Medicines Agency) and have been granted market authorization. In 2016, the EMA approved the first ex-vivo gene therapy product using autologous hematopoietic stem cells, Strimvelis (GlaxoSmithKline), for the treatment of Adenosine deaminase (ADA) deficiency. Over 3000 clinical trials have been reported worldwide [1], with the majority addressing human cancer (CAR-T cells) and inherited monogenic diseases like primary immunodeficiencies [2]. Clinical trials with both self-inactivating (SIN) gamma-retroviruses and SIN-lentiviruses (10% of clinical trials) are currently ongoing for various primary immunodeficiencies like ADA Severe Combined Immunodeficiency (SCID) [3,4,5], X-linked SCID [6,7,8,9], Artemis SCID [10,11,12], Wiskott–Aldrich Syndrome (WAS) [13,14,15] or X-linked chronic granulomatous disease (CGD) [16,17] (Table 1).
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