Progress in gene therapy for primary immunodeficiencies using lentiviral vectors

Sauer, Aisha V.; Lorenzo, Biagio Di; Carriglio, Nicola; Aiuti, Alessandro

doi:10.1097/aci.0000000000000114

Cited by 28 publications

(17 citation statements)

References 89 publications

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“…In this system, it may be difficult to detect off-target effects in all modified cells. Even a single aberrantly gene-edited cell could clonally expand and give rise to malignancy, akin to previous gene therapy studies in SCIDX1 patients (51). A recent study of gene editing of non-viable human embryos showed a high incidence of off-target effects (52).…”

Section: In Vivo Gene Editing Including the Crispr Cas9 Systemmentioning

confidence: 88%

Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure

et al. 2016

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Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by mutations of the SERPING1 or the Factor 12 genes. It is potentially fatal, particularly if not identified at an early stage. Apart from androgens, which are contraindicated in children and in pregnant women, a range of effective, albeit very expensive treatments have recently become available for HAE patients. The cost of these new treatments is beyond the reach of most developing countries. At this time, there is no cure for the disorder. In spite of mutations of the SERPING1 gene, autoimmunity and infections are not prominent features of the condition. Here, we present the argument that HAE should be viewed primarily as a metabolic liver disorder. This conceptual paradigm shift will stimulate basic research and may facilitate new therapeutic approaches to HAE outlined in this paper. We suggest several novel potential treatment options for HAE from the perspectives of clinical immunology, molecular biology, and liver transplantation. Many of these offer the prospect of curing the disorder. The effectiveness of these options is rapidly improving in many cases, and their risks are decreasing. Given the very high costs of treating HAE, some of these curative options may become feasible in the next decade.

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Section: In Vivo Gene Editing Including the Crispr Cas9 Systemmentioning

confidence: 88%

Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure

et al. 2016

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“…Cell therapy has produced clinically extraordinary results, having saved hundreds of thousands of lives -especially those affected by congenital or acquired diseases of the hematopoietic tissue. 27,[69][70][71][72] This is most likely because there is the option of ablating diseased host tissue: bone marrow can be destroyed to various extents by radiation or cytotoxic agents, while skin or other epithelia can be surgically removed. These procedures create 'space' for donor cells (either allogeneic or autologous) and favour their engraftment, since they do not have to compete with resident diseased cells.…”

Section: Results and Challenges Of Cell And Gene Therapymentioning

confidence: 99%

Lancet Commission: Stem cells and regenerative medicine

et al. 2018

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“…Moreover, in contrast to observations in other PIDs, in none of the ADA‐SCID‐treated patients have SAEs been reported (Table ), even though integration hotspots in different proto‐oncogenes were identified. Due to the similarities of RV backbones used in the ADA‐SCID trial and in other trials where insertional oncogenesis events were generated, differences in either the therapeutic transgene or most probably in the nature of the disease should account for the safety associated to ADA‐SCID gene therapy. After the observation of the first SAEs in a number of PID patients, the gene therapy field rapidly progressed thanks to the development of safer therapeutic vectors.…”

Section: Gene Therapy In Primary Immunodeficienciesmentioning

confidence: 99%

“…Moreover, in contrast to observations in other PIDs, in none of the ADA-SCID-treated patients have SAEs been reported (Table 1), even though integration hotspots in different proto-oncogenes were identified. 5,6,25,27,34,35 Due to the similarities of RV backbones used in the ADA-SCID trial and in other trials where insertional oncogenesis events were generated, differences in either the therapeutic transgene or most probably in the nature of the…”

Section: Gene Therapy In Primary Immunodeficienciesmentioning

confidence: 99%

Advances in the gene therapy of monogenic blood cell diseases

et al. 2019

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Hematopoietic gene therapy has markedly progressed during the last 15 years both in terms of safety and efficacy. While a number of serious adverse events (SAE) were initially generated as a consequence of genotoxic insertions of gamma-retroviral vectors in the cell genome, no SAEs and excellent outcomes have been reported in patients infused with autologous hematopoietic stem cells (HSCs) transduced with self-inactivated lentiviral and gammaretroviral vectors. Advances in the field of HSC gene therapy have extended the number of monogenic diseases that can be treated with these approaches. Nowadays, evidence of clinical efficacy has been shown not only in primary immunodeficiencies, but also in other hematopoietic diseases, including beta-thalassemia and sickle cell anemia. In addition to the rapid progression of non-targeted gene therapies in the clinic, new approaches based on gene editing have been developed thanks to the discovery of designed nucleases and improved non-integrative vectors, which have markedly increased the efficacy and specificity of gene targeting to levels compatible with its clinical application. Based on advances achieved in the field of gene therapy, it can be envisaged that these therapies will soon be part of the therapeutic approaches used to treat life-threatening diseases of the hematopoietic system.

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Progress in gene therapy for primary immunodeficiencies using lentiviral vectors

Cited by 28 publications

References 89 publications

Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure

Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure

Lancet Commission: Stem cells and regenerative medicine

Advances in the gene therapy of monogenic blood cell diseases

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