Gene therapy for primary immunodeficiencies

Fox, Thomas A.; Booth, Claire

doi:10.1111/bjh.17269

Cited by 18 publications

(19 citation statements)

References 126 publications

(156 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Current approaches to gene therapy (GT) for primary immunodeficiencies use autologous stem cells harvested from an affected patient. These cells then undergo genetic transformation with the wildtype or normal gene, and are re-infused into the patient where they differentiate into immune cells that express the normal gene [39]. Gene therapy has been used to treat patients with T cell deficiencies such as IL2RG deficiency and ADA-SCID and can correct the immunologic defect [40].…”

Section: Gene Therapymentioning

confidence: 99%

The Treatment of Primary Immune Deficiencies: Lessons Learned and Future Opportunities

Paris,

Wall

2022

Clinic Rev Allerg Immunol

View full text Add to dashboard Cite

Primary immunodeficiency is a group of disorders associated with susceptibility to infectious agents and the development of various comorbidities. Many primary immunodeficiencies are complicated by immune dysregulation, autoinflammation, or autoimmunity which impacts multiple organ systems. Major advances in the treatment of these disorders have occurred over the last half-century, and deeper molecular understanding of many disorders combined with clinically available genetic testing is allowing for use of precision therapy for several primary immunodeficiencies. Patients with antibody deficiencies who rely on immunoglobulin replacement therapy now have many treatment options with products that are much safer and better tolerated compared to the past. Newborn screening for severe combined immunodeficiency, now implemented throughout the USA and in many countries worldwide, has lowered the age at which many patients are diagnosed with these diseases. Early diagnosis of severe combined immunodeficiency allows infants to proceed to definitive therapy such as stem cell transplantation or gene therapy prior to facing potentially life-threatening infections. While stem cell transplantation continues to carry significant risks, knowledge gained over recent decades is allowing for improved survival with less toxicity and less graft versus host disease.

show abstract

Section: Gene Therapymentioning

confidence: 99%

The Treatment of Primary Immune Deficiencies: Lessons Learned and Future Opportunities

Paris,

Wall

2022

Clinic Rev Allerg Immunol

View full text Add to dashboard Cite

show abstract

“…Recurrent infections (often severe, life-threatening infections) are the most common presenting complaint. An underlying IEI should be suspected in patients presenting with a wide variety of haematological and immunological symptoms at an earlier than expected age, which are refractory to conventional treatments or who have a relevant family history ( Fox and Booth, 2021 ). For severe combined immune deficiencies (SCID), survival past infancy is rare without a definitive treatment ( Cirillo et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…Autologous ex vivo haematopoietic stem cell gene therapy (HSC-GT) is in the advanced stages of clinical development for several IEIs. HSC-GT may potentially offer curative therapy whilst mitigating the immunological complications of alloHSCT ( Booth et al, 2016 ; Fox and Booth, 2021 ). The development of gene therapy using retroviral vectors and lentiviral vectors to transduce HSCs has had a turbulent history, which has been summarised in several recent reviews ( Booth et al, 2016 ; Kuo and Kohn, 2016 ; Kohn and Kuo, 2017 ; Fox and Booth, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…HSC-GT may potentially offer curative therapy whilst mitigating the immunological complications of alloHSCT ( Booth et al, 2016 ; Fox and Booth, 2021 ). The development of gene therapy using retroviral vectors and lentiviral vectors to transduce HSCs has had a turbulent history, which has been summarised in several recent reviews ( Booth et al, 2016 ; Kuo and Kohn, 2016 ; Kohn and Kuo, 2017 ; Fox and Booth, 2021 ). Early viral vectors resulted in insertional mutagenesis in several patients after transgene integration occurred close to proto-oncogenes leading to leukaemias and myelodysplasia in several patients in trials ( Howe et al, 2008 ; Braun et al, 2014 ; Dunbar et al, 2018 ; Fox and Booth, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…In response to the adverse events seen in retrovirus vector GT trials, the field focused on developing new vectors with an improved safety profile. Retroviral vectors use powerful viral promoters in the long terminal repeat (LTR) sequences to drive transgene expression and have a preference for integration in transcriptionally active genomic regions ( Scherdin et al, 1990 ; Fox and Booth, 2021 ). The development of self-inactivating (SIN)-retroviral-vectors incorporated mutations in the LTRs and less powerful mammalian promoters ( Gaspar et al, 2011 ; Hacein-Bey-Abina et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Gene Edited T Cell Therapies for Inborn Errors of Immunity

Fox

Houghton²,

Booth

2022

Front. Genome Ed.

View full text Add to dashboard Cite

Inborn errors of immunity (IEIs) are a heterogeneous group of inherited disorders of the immune system. Many IEIs have a severe clinical phenotype that results in progressive morbidity and premature mortality. Over 450 IEIs have been described and the incidence of all IEIs is 1/1,000–10,000 people. Current treatment options are unsatisfactory for many IEIs. Allogeneic haematopoietic stem cell transplantation (alloHSCT) is curative but requires the availability of a suitable donor and carries a risk of graft failure, graft rejection and graft-versus-host disease (GvHD). Autologous gene therapy (GT) offers a cure whilst abrogating the immunological complications of alloHSCT. Gene editing (GE) technologies allow the precise modification of an organisms’ DNA at a base-pair level. In the context of genetic disease, this enables correction of genetic defects whilst preserving the endogenous gene control machinery. Gene editing technologies have the potential to transform the treatment landscape of IEIs. In contrast to gene addition techniques, gene editing using the CRISPR system repairs or replaces the mutation in the DNA. Many IEIs are limited to the lymphoid compartment and may be amenable to T cell correction alone (rather than haematopoietic stem cells). T cell Gene editing has the advantages of higher editing efficiencies, reduced risk of deleterious off-target edits in terminally differentiated cells and less toxic conditioning required for engraftment of lymphocytes. Although most T cells lack the self-renewing property of HSCs, a population of T cells, the T stem cell memory compartment has long-term multipotent and self-renewal capacity. Gene edited T cell therapies for IEIs are currently in development and may offer a less-toxic curative therapy to patients affected by certain IEIs. In this review, we discuss the history of T cell gene therapy, developments in T cell gene editing cellular therapies before detailing exciting pre-clinical studies that demonstrate gene editing T cell therapies as a proof-of-concept for several IEIs.

show abstract

A CRISPR view of hematopoietic stem cells: Moving innovative bioengineering into the clinic

Worthington

Forsberg

2022

American J Hematol

View full text Add to dashboard Cite

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas genome engineering has emerged as a powerful tool to modify precise genomic sequences with unparalleled accuracy and efficiency. Major advances in CRISPR technologies over the last 5 years have fueled the development of novel techniques in hematopoiesis research to interrogate the complexities of hematopoietic stem cell (HSC) biology. In particular, high throughput CRISPR based screens using various “flavors” of Cas coupled with sequencing and/or functional outputs are becoming increasingly efficient and accessible. In this review, we discuss recent achievements in CRISPR‐mediated genomic engineering and how these new tools have advanced the understanding of HSC heterogeneity and function throughout life. Additionally, we highlight how these techniques can be used to answer previously inaccessible questions and the challenges to implement them. Finally, we focus on their translational potential to both model and treat hematological diseases in the clinic.

show abstract

Gene therapy for primary immunodeficiencies

Cited by 18 publications

References 126 publications

The Treatment of Primary Immune Deficiencies: Lessons Learned and Future Opportunities

The Treatment of Primary Immune Deficiencies: Lessons Learned and Future Opportunities

Gene Edited T Cell Therapies for Inborn Errors of Immunity

A CRISPR view of hematopoietic stem cells: Moving innovative bioengineering into the clinic

Contact Info

Product

Resources

About