Gene Therapy for Primary Immunodeficiency

Abstract

Over the past 3 decades, there has been significant progress in refining gene therapy technologies and procedures. Transduction of hematopoietic stem cells ex vivo using lentiviral vectors can now create a highly effective therapeutic product, capable of reconstituting many different immune system dysfunctions when reinfused into patients. Here, we review the key developments in the gene therapy landscape for primary immune deficiency, from an experimental therapy where clinical efficacy was marred by adverse events, to a commercialized product with enhanced safety and efficacy. We also discuss progress being made in preclinical studies for challenging disease targets and emerging gene editing technologies that are showing promising results, particularly for conditions where gene regulation is important for efficacy.

Future of Therapy for Inborn Errors of Immunity

“…Later trials discontinued enzyme replacement after gene correction and used non-myeloablative conditioning to improve engraftment. Strimvelis, the first ex vivo gene therapy product to receive regulatory approval in the world, was approved in Europe in 2016, based on data from 18 patients with ADA-SCID who were treated from 2000 to 2011 with a median follow-up of 7 years, showing 100% survival and evidence of long-term gene correction in T cells and maintenance of immune reconstitution [ 35 , 37 – 42 ]. Until recently, there had been no reports of insertional oncogenesis or leukemic proliferation observed in greater than 40 ADA patients treated with gamma-retroviral vector gene therapy, but it has been recently reported that a patient treated with Strimvelis for ADA-SCID was diagnosed with T cell leukemia and the cause is under investigation.…”

“…Until recently, there had been no reports of insertional oncogenesis or leukemic proliferation observed in greater than 40 ADA patients treated with gamma-retroviral vector gene therapy, but it has been recently reported that a patient treated with Strimvelis for ADA-SCID was diagnosed with T cell leukemia and the cause is under investigation. [ 35 ] The most recent trials, which are ongoing in the UK and US, are using a safer self-inactivating lentiviral vector with codon optimized cDNA for adenosine deaminase under control of an elongation factor (elongation factor 1α) promoter with continuation of ERT for one month after gene therapy. For up to 3 years of follow-up, the 30 treated patients have shown excellent efficacy and no associated genotoxicity.…”

“…Gene editing approaches create a DNA double-strand break, providing a substrate for the endogenous DNA repair pathways to either knock out genes or insert therapeutic DNA by providing a suitable donor containing sequence homologous to the cleaved ends, thereby conserving the native regulatory motifs surrounding the gene. [ 35 ] Zinc finger nucleases (ZFN), transcript activator-like effector nucleases (TALEN), and clustered regularly interspersed short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) are the currently available platforms available to accomplish gene editing Table 6 . The first trial of zinc finger nucleases (ZFN) in humans used ZFN to knock out CCR5 in T cells for patients with HIV, demonstrating that gene editing can be safe in T cells.…”

“…The first trial of zinc finger nucleases (ZFN) in humans used ZFN to knock out CCR5 in T cells for patients with HIV, demonstrating that gene editing can be safe in T cells. [ 35 ] TALEN and CRISPR are being used in immunotherapy products, such as CAR T cells. X-SCID HSC have been corrected using ZFN and non-integrating lentiviral vectors in a mouse model, and CRISPR/Cas9 along with adeno-associated virus type 6 (AAV6) homology donors are showing promise with levels as high as 50% gene correction in hematopoietic stem cells (HSC) [ 35 ].…”

A Novel Non-Coding Variant in DCLRE1C Results in Deregulated Splicing and Induces SCID Through the Generation of a Truncated ARTEMIS Protein That Fails to Support V(D)J Recombination and DNA Damage Repair

“…Currently, allogeneic hematopoietic stem cell transplantation (HSCT) remains the treatment of choice but the genetic subtype greatly impacts long-term survival and immune reconstitution (16). Therefore, for some SCID genetic defects, gene therapy studies using autologous stem cells seem to be promising as an alternative approach to cure disease as illustrated for ADA-, IL2RG-and ARTEMIS-SCID (17)(18)(19)(20)(21).…”