Evolving Gene Therapy in Primary Immunodeficiency

Thrasher, Adrian J.; Williams, David A.

doi:10.1016/j.ymthe.2017.03.018

Cited by 68 publications

(48 citation statements)

References 114 publications

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“…For these patients, diagnosis can be delayed or difficult and the natural history of exceptionally rare underlying diseases is often unclear. In several PIDs, controversy surrounding optimum timing of Allo-HSCT remains, due to rarity of disease, lack of experience, emerging gene therapies, [14][15][16][17] and infrequent published outcome data due to the very low numbers in any 1 center.…”

Section: Introductionmentioning

confidence: 99%

Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency

Fox

Chakraverty

Burns

et al. 2018

Blood

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Section: Introductionmentioning

confidence: 99%

Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency

Fox

Chakraverty

Burns

et al. 2018

Blood

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“…Traditional treatments for PID consist of prophylaxis against infection, with antimicrobials and immunoglobulin, iatrogenic immunomodulation with high inherent risk associated with additional untargeted immunosuppression, and bone marrow transplantation in severe cases. Precision therapies now include targeted immunosuppression in cases of autoimmune/inflammatory manifestations and gene therapy to correct germline errors in autologous haematopoietic stem cells . These therapeutic approaches have the potential to dramatically improve the prognoses for patients with PID .…”

Section: Introductionmentioning

confidence: 99%

“…Precision therapies now include targeted immunosuppression in cases of autoimmune/inflammatory manifestations and gene therapy to correct germline errors in autologous haematopoietic stem cells. 6,7 These therapeutic approaches have the potential to dramatically improve the prognoses for patients with PID. [7][8][9] Precision treatments, as well with genetic family counselling and preimplantation diagnostics, are only possible with knowledge of the causal monogenic variant in patients, and recent progressions in diagnostics and treatments underline the importance of genomic investigations in the clinical care of patients with PID.…”

Section: Introductionmentioning

confidence: 99%

Clinical efficacy of a next‐generation sequencing gene panel for primary immunodeficiency diagnostics

et al. 2018

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Primary immunodeficiencies (PIDs) are rare monogenic inborn errors of immunity that result in impairment of functions of the human immune system. PIDs have a broad phenotype with increased morbidity and mortality, and treatment choices are often complex. With increased accessibility of next-generation sequencing (NGS), the rate of discovery of genetic causes for PID has increased exponentially. Identification of an underlying monogenic diagnosis provides important clinical benefits for patients with the potential to alter treatments, facilitate genetic counselling, and pre-implantation diagnostics. We investigated a NGS PID panel of 242 genes within clinical care across a range of PID phenotypes. We also evaluated Phenomizer to predict causal genes from human phenotype ontology (HPO) terms. Twenty-seven participants were recruited, and a total of 15 reportable variants were identified in 48% (13/27) of the participants. The panel results had implications for treatment in 37% (10/27) of participants. Phenomizer identified the genes harbouring variants from HPO terms in 33% (9/27) of participants. This study shows the clinical efficacy that genetic testing has in the care of PID. However, it also highlights some of the disadvantages of gene panels in the rapidly moving field of PID genomics and current challenges in HPO term assignment for PID.

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“…Thanks to the development of SIN‐LV and SIN‐RV, more than 100 patients with PIDs have been treated with these new vectors. Strikingly, no SAEs and excellent clinical outputs have been observed in these patients, suggesting that gene therapy will soon constitute a therapeutic alternative to HSCT for patients with PIDs …”

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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Evolving Gene Therapy in Primary Immunodeficiency

Cited by 68 publications

References 114 publications

Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency

Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency

Clinical efficacy of a next‐generation sequencing gene panel for primary immunodeficiency diagnostics

Advances in the gene therapy of monogenic blood cell diseases

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