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Gene Therapy Clinical Trials for Adenosine Deaminase Deficiency/Severe Combined Immunodeficiency
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Eriinda M. Gordon, W. French Anderson
The primary concerns involving use of retroviral vectors for gene delivery were 1) the potential for the production of a pathological recombinant retrovirus, and 2) insertional mutagenesis leading to a malignancy. Preclinical studies of monkeys showed no evidence of pathology or cancer (Cornetta, et al., 1990, 1991.) Further, there were no side effects or pathology attributable to gene transfer noted in patients who participated in the gene marker (N2-TIL) study (Rosenberg et al., 1990; Anderson et al., 1992.)
Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
CGD carries a high mortality risk, especially due to infections. However, significant progress in the management of the disease now permits almost half of the patients to survive into the third decade. Treatment is based on prompt and aggressive investigation of any febrile episode in order to identify the responsible microorganism(s), and on continuous antimicrobial prophylaxis with trimethoprim-sulfamethoxazole (for bacterial infections) and itraconazole (for fungal infections). In addition, subcutaneous administration of IFN-γ has been shown to reduce occurrence of severe infections. However, the only definitive cure is represented by HCT, whose results are largely influenced by degree and duration of donor chimerism in the myeloid compartment, and by preexisting risk factors, such as lung aspergillosis. Results of HCT are better when the transplant is performed from an HLA-identical related donor. Use of a matched unrelated donor has been associated with increased risk of graft-versus-host disease, graft loss, and death. However, a successful outcome has been recently reported (including correction of inflammatory bowel disease) using reduced-intensity conditioning. Gene therapy has been attempted, but in the absence of conditioning, only modest and transient presence of gene-corrected phagocytes is achieved. Furthermore, myelodysplasia has been observed due to insertional mutagenesis.
Gene Transfer into Human Hematopoietic Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Serguei Kisselev, Tatiana Seregina, Richard K. Burt, Charles J. Link
Questions concerning the safety of integration of transgene into a host genome remain to be answered. The complete potential integration sites for retroviral cDNAs are unknown and thought to be mostly random. This random integration creates a number of concerns about insertional mutagenesis and integration of the transgene into either oncogenes or sequences coding the inhibitors of genes such as cyclin kinases (tumor suppressor genes) causing their disruption. These warnings are very real and serious in the context of recent reports concerning cases of acute T cell leukemia lymphoma (ATLL) that developed in two SCID children infused with common gamma chain gene transduced into autologous CD34+ cells.126 In both cases, insertion of the transgene occurred in the first intron of rhombotin 2 (LIM-only protein 2 (LMO2)) transcription factor gene. Previous studies of LMO2 physiology and function have revealed that ATLL development is closely associated with LMO2 translocations and over expression.127,12 The disruption of regulatory sequences of the gene by transgene insertion followed by its uncontrolled activation is the probable reason for leukemia development in these children. Preclinical data had previously demonstrated such risks. Acute myeloid leukemia development in mice transplanted with autologous bone marrow transduced by a mutant non functional nerve growth factor receptor (NGFR) gene used as a cell surface marker.129 Since risks do exist after stem cell transduction with integrating retroviral vectors, the development and application of vectors containing both a gene of interest and inducible suicide genes such as herpes simplex virus thymidine kinase (HSV-tk) as a safety feature are in development. The idea would be to eliminate transduced cells by activation of the suicide gene if leukemia developed. Other procedures to confirm insertion site prior to product release being discussed for human trials.
Advances in mRNA-based drug discovery in cancer immunotherapy
Published in Expert Opinion on Drug Discovery, 2022
Claudia Augusta Di Trani, Myriam Fernandez-Sendin, Assunta Cirella, Aina Segués, Irene Olivera, Elixabet Bolaños, Ignacio Melero, Pedro Berraondo
Adoptive T-cell therapy is currently the focus of well-deserved research and clinical attention. Adoptive T-cell transfer for cancer patients dates back to 1985 when Rosenberg et al. administered autologous T cells, ex-vivo expanded with IL-2, together with recombinant IL-2 inducing objective cancer regressions in 25 patients [64]. In the last decade, research on adoptive T-cell transfer has experienced an exponential growth, culminating in the recent regulatory approvals of chimeric antigen receptor (CAR) T cells for certain types of non-Hodgkin lymphoma, acute lymphoblastic leukemia, relapsed/refractory mantle cell lymphoma, and advanced multiple myeloma [65–69]. Retroviral/lentiviral transduction has been the method employed to genetically engineer therapeutic T lymphocytes. In spite of the fact that this strategy led to impressive clinical results, there are some limitations. The most relevant shortcomings are the potential risk of insertional mutagenesis and the possibility of off-target toxicities. One of the alternative strategies to develop safer T cell products is the transfection of T cells with messenger RNA because it is transient and non-integrative. Accordingly, there is no risks of insertional mutagenesis, and the potential side effects will be self-limiting. The transient nature of mRNA has been exploited to more safely express immunostimulatory molecules to increase the antitumor effect of tumor-specific T lymphocytes or to confer naïve T cells with tumor-specificity by expressing transgenic T cell receptors (TCR) or CARs (Figure 3).
An update on COVID-19 pandemic: the epidemiology, pathogenesis, prevention and treatment strategies
Published in Expert Review of Anti-infective Therapy, 2021
Hin Fung Tsang, Lawrence Wing Chi Chan, William Chi Shing Cho, Allen Chi Shing Yu, Aldrin Kay Yuen Yim, Amanda Kit Ching Chan, Lawrence Po Wah Ng, Yin Kwan Evelyn Wong, Xiao Meng Pei, Marco Jing Woei Li, Sze-Chuen Cesar Wong
RNA vaccines involve the introduction of RNA sequence encoding for the antigen to induce adaptive immune response [79]. RNA does not integrate into host genome. The risk of insertional mutagenesis and anti-vector immunity can be avoided [79]. However, introduction of RNA strand in the vaccine may elicit unintended immune response which raises safety concern of the vaccine. Delivering RNA vaccine effectively to the target tissue is challenging because RNA vaccines are temperature sensitive and are broken down easily [79]. An mRNA-based vaccine, mRNA-1273, co-developed Moderna and the Vaccine Research Center at the National Institutes of Health that expresses has entered phase III clinical trial (ClinicalTrials.gov: NCT04470427). It targets antigen in vivo and elicits antiviral response toward the spike proteins of SARS-CoV-2 after intramuscular injection to human bodies.
Merits of the ‘good’ viruses: the potential of virus-based therapeutics
Published in Expert Opinion on Biological Therapy, 2021
Qianyu Zhang, Wen Wu, Jinqiang Zhang, Xuefeng Xia
Nowadays, adenovirus, retrovirus, lentivirus, and adeno-associated virus (AAV) constitute over half of the vectors used in gene therapy (Source: Wiley Gene Therapy Clinical Trials Worldwide, http://www.abedia.com/wiley.) γ-retrovirus MLV (murine leukemia virus) was among the first viruses tested in human trials, which was intended for the therapy of ADA-SCID and X-SCID as mentioned above. Retroviruses possess high efficiency in the transduction of replicating cells, integration into host cell genome, and low incidence of immunogenicity, making the therapeutic gene expression permanent [56]. Owing to the fact that it might promote host proto-oncogene activation, much attention has been focused on addressing the insertional mutagenesis by the vectors. Techniques such as deleting the enhancer or promoter of the long terminal repeat (LTR) to develop self-inactivating (SIN) vectors have been developed [57]. Lentiviral vectors were subsequently developed which can transfer genes into nondividing cells. They allowed for a significant extension of the range of cell lines of therapeutic benefit. In 1996, the human immunodeficiency virus (HIV) was the first to be engineered into a lentiviral vector for both mitotic and nondividing cells [58]. Later, SIN lentiviral vectors have also been established to improve safety. Lentiviral vectors such as HIV tend to integrate in downstream regions within transcribed genes, which are significantly safer regions compared with promoter elements [59]. This could be translated toward improved clinical safety.