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Clinical Applications of Gene Therapy for Immuno-Deficiencies
Published in Yashwant Pathak, Gene Delivery, 2022
Khushboo Faldu, Sakshi Gurbani, Jigna Shah
ADA-SCID, a PID that lacks enzyme adenosine deaminase, causing immunodeficiency due to absenteeism of natural killer (NK), B, and T-cells, with fatal outcomes in infancy without alloHSCT therapy. HSC-GT clinical study established that transduction of T-lymphocytes was possible with the use of γRV vectors containing ADA enzyme. The treated patients produced ADA enzyme endogenously that resulted in improvement of the clinical phenotype [28, 29]. This method overcame the limitation of multiple transfusions of modified T-lymphocytes for the maintenance of therapeutic outcomes [29–31]. Busulfan conditioning improved ADA multilineage engraftment [32, 33] and reduced the number of patients requiring enzyme replacement therapy [34]. Strimvelis is the first HSC-GT, a SIN-γRV (self-inactivating (SIN) LTR modification of γ-retrovirus vector (γRV)) approved in 2016 in Europe for the treatment of adenosine deaminase-deficient SCID (ADA-SCID) who lack a suitable donor for alloHSCT [26], which is exclusively available in Milan, Italy, and requires patients globally to undertake a medical holiday to receive Strimvelis, as it is fresh cell product. When γRV vectors were utilized for X-linked SCID (X-SCID), they resulted in insertional mutagenesis [35–37] that led to the development of SIN-LV vectors that have an enhanced safety and efficiency profile when compared to γRV vectors [38]. HSC-GT is now considered one of the first-line therapies for ADA-SCID in Europe [39].
Pharmaceuticals: Some General Aspects
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Finally, Strimvelis (GlaxoSmithKline) that was granted orphan status on August 2005 should be mentioned as the second gene therapy approved by the EMA after Glybera for treating the ultrarare (about 15 patients per year in Europe) ADA-SCID (Severe Combined Immunodeficiency due to Adenosine Deaminase Deficiency). This inherited condition is caused by a mutation in the gene responsible for expressing the enzyme adenosine deaminase (ADA) essential for maintaining healthy lymphocytes to fight off infections. Strimvelis is produced from CD34+ cells extracted from the patient’s bone marrow cells; an ADA gene is inserted into these CD34+ cells by means of a genetically modified retrovirus. After the autologous CD34+ enriched cell fraction is given as an infusion into a vein in a dose depending on the bodyweight of the patient, CD34+ cells start to grow in the bone marrow and produce normal lymphocytes with the ability to synthesize functional ADA (EMA, 2016; Aiuti et al., 2017).
Nonclinical Safety Evaluation of Advanced Therapies
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Timothy K. MacLachlan, Kendall S. Frazier, Mercedes Serabian
Recently, data from pivotal clinical trials for a genetic form of severe combined immunodeficiency have led to the EMA recommending that the European Commission approve the therapy, called Strimvelis (Cicalese 2016)—a vector that also utilizes genomic integration. As these therapies mature to the late stage, more attention will be paid to having these profiles in place as a critical quality attribute of the product.
Gene therapy for primary immunodeficiencies: up-to-date
Published in Expert Opinion on Biological Therapy, 2021
A milestone for gene therapy was reached in 2016 in the first worldwide marketing approval of an ex vivo gene therapy product by the EMA [42]. Strimvelis ™ uses autologous patient HSCs transduced with γRV vector containing the ADA gene. The product is received as a fresh infusion following cytoreductive chemotherapy to allow for engraftment of gene-modified cells [12]. As this gene therapy drug product is fresh, patients are required to travel to a treatment center for ex vivo manipulation, conditioning, infusion, and recovery. Cryopreservation of gene therapy products will allow a product to be manufactured centrally and shipped to the patient, improving logistical accessibility and availability of gene therapy. Cryopreservation of transduced cells provides the additional benefit of giving greater control over the quality of the product and ensuring adequate transduction of cells [12].
Are UK hospital pharmacy departments ready for the rise of gene therapy medicinal products?
Published in Expert Opinion on Biological Therapy, 2018
NICE has issued final draft guidance recommending gene therapy for children with the genetically inherited disease, ADA-SCID, which is a severe immunodeficiency disorder in which babies are born with adenosine deaminase deficiency, which makes them vulnerable to infection and so have to be isolated in order to survive [10]. Patients with this deficiency usually have delays in development, chronic diarrhea, recurrent infections, and issues with thriving. ‘Strimvelis’ is the gene therapy treatment that is licensed, where patients will have to receive treatment in Milan. The treatment is an ‘ex vivo’ gene therapy treatment in which bone marrow cells from the patient are incubated with the gene therapy to genetically modify them so that they produce a correctly working ADA enzyme. The genetically modified cells are returned to the patient via an infusion. NICE is also reviewing how they will be assessing and appraising regenerative medicine and cell therapy products[11].
Layer-by-Layer technique as a versatile tool for gene delivery applications
Published in Expert Opinion on Drug Delivery, 2021
Dmitrii S. Linnik, Yana V. Tarakanchikova, Mikhail V. Zyuzin, Kirill V. Lepik, Joeri L. Aerts, Gleb Sukhorukov, Alexander S. Timin
Protocols for ex vivo gene transfer procedures of hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) have been successfully implemented into clinical translation [121,122]. Thus, Strimvelis, a product based on ex vivo retroviral transduction of hematopoietic stem cells, has been approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for the treatment of adenosine deaminase deficiency – severe combined immunodeficiency (ADA-SCID). Another example of this success is ex vivo gene modification of T cells, especially in CAR T-cell therapy, using either retroviral or lentiviral vectors. In addition, other types of somatic stem cells can be modified by genetic engineering and have shown promising results for therapeutic applications (Figure 4). It should be noted that the gene transfection of clinically relevant cell types is usually performed using viral vectors or non-viral physical methods, e.g. electroporation [123]. The clinical feasibility and safety should be highlighted as crucial aspects and at the same time, as the main challenges for the development of ex vivo gene modification of cells. Although lentiviral vectors are among the most efficient viral vectors, they can carry the risk of reactivation and continuous expression of viral genes. In addition, insertional mutations can result from the integration of the viral vector into the host genome [124]. Physical methods, including electroporation, gene gun, etc., always require an optimal protocol for transfection and can lead to serious toxicity. The use of non-viral chemical methods (e.g. liposomes, micelles, inorganic NPs) can be considered as an alternative way to perform gene modification of cells in a safe and effective manner. In this regard, LbL capsules offer promising non-viral gene delivery systems for cell modification. The use of LbL capsules for modification of human mesenchymal stem cells (hMSCs) has been described in several publications. In particular, our group first reported on the magnetization of hMSCs using magnetic multilayer microcapsules [125]. The modification of hMSCs by microcapsules was based on the simple co-incubation of hMSCs with microcapsules for 24 h, resulting in a high internalization efficiency of magnetic capsules by hMSCs, which makes them responsive to external magnetic fields, allowing to perform magnetic sorting. Furthermore, our group used this principle of magnetic manipulation of hMSCs with impregnated capsules to obtain a pure population of gene-transfected hMSCs using magnetic sorting [118]. In another study, Reibetanz et al. performed a fundamental investigation of the ability of induced pluripotent stem cells (iPSCs) to interact with LbL carriers and demonstrated the potential of LbL carriers for the manipulation of iPSCs, including gene modification [124].