The rapidly evolving state of gene therapy

Abstract

Gene therapy is emerging as a viable option for clinical therapy of monogenic disorders and other genetically defined diseases, with approved gene therapies available in Europe and newly approved gene therapies in the United States. In the past 10 years, gene therapy has moved from a distant possibility, even in the minds of much of the scientific community, to being widely realized as a valuable therapeutic tool with wide‐ranging potential. The U.S. Food and Drug Administration has recently approved Luxturna (Spark Therapeutics Inc, Philadelphia, PA, USA), a recombinant adeno‐associated virus (rAAV) 2 gene therapy for one type of Leber congenital amaurosis 2 (1, 2). The European Medicines Agency (EMA) has approved 3 recombinant viral vector products: Glybera (UniQure, Amsterdam, The Netherlands), an rAAV vector for lipoprotein lipase deficiency; Strimvelis (Glaxo Smith‐Kline, Brentford, United Kingdom), an ex vivo gammaretrovirus‐based therapy for patients with adenosine deaminase‐deficient severe combined immune deficiency (ADA‐SCID); and Kymriah (Novartis, Basel, Switzerland), an ex vivo lentivirus‐based therapy to engineer autologous chimeric antigen‐receptor T (CAR‐T) cells targeting CD19–positive cells in acute lymphoblastic leukemia. These examples will be followed by the clinical approval of other gene therapy products as this field matures. In this review we provide an overview of the state of gene therapy by discussing where the field stands with respect to the different gene therapy vector platforms and the types of therapies that are available.— Gruntman, A. M., Flotte, T. R. The rapidly evolving state of gene therapy. FASEB J. 32, 1733–1740 (2018). http://www.fasebj.org

CRISPR/Cas9-Mediated TERT Disruption in Cancer Cells

“…One feasible strategy readily to be evaluated in preclinical models consists of using adeno-associated virus (AAV) to package CRISPR/Cas9 components that are driven by a tumor specific promoter to target essential tumor survival genes. For delivery, AAV is the dominant cargo used in gene therapy applications nowadays which recently gained the approval from the FDA [42]. To fit the packaging by AAV, saCas9 [43] or other small size gene editing nucleases are to be used.…”

Maternal antibody interference contributes to reduced rotavirus vaccine efficacy in developing countries

“…Continuous expression of antigen through vectored expression, administered early to release antigen for a longer period, could stimulate the infant immune system after matAbs drop to a noninterfering level [24,61]. However, gene therapy approaches are held to a higher safety standard due to the potential of vector integration into the genome [62], and further investigation is needed to determine if such an approach would be effective in the context of RV vaccination. While there are several possible approaches, further investigation is needed to determine if their ability to overcome matAb interference outweighs the risks to the infant.…”

CRISPR-to-Kill (C2K)–Employing the Bacterial Immune System to Kill Cancer Cells

“…An obvious limitation of the C2K approach as presented in this conceptual study is the lack of tumor specificity, which is, however, a common shortcoming of suicide systems. In fact, numerous approaches addressing this challenge have been developed and could be combined to ensure cancer-tissue specificity at different levels [ 34 , 35 ], e.g., delivery using targeted vectors [ 36 , 37 ], transcriptional and posttranscriptional targeting, e.g., using cell-specific promoters and/or miRNA target sequences [ 37 , 38 , 39 ], and/or application of switchable variants of Cas9 [ 40 ] and gRNA [ 41 ].…”