Therapeutic gene editing of T cells to correct CTLA-4 insufficiency

Fox, Thomas A.; Houghton, Benjamin C.; Petersone, Lina; Waters, Erin; Edner, Natalie M.; McKenna, Alex; Preham, Olivier; Hinze, Claudia; Williams, Cayman; Albuquerque, Adriana S.; Kennedy, Alan; Pesenacker, Anne M.; Genovese, Pietro; Walker, Lucy S. K.; Burns, Siobhan O.; Sansom, David M.; Booth, Claire; Morris, Emma

doi:10.1126/scitranslmed.abn5811

Cited by 18 publications

(12 citation statements)

References 55 publications

(82 reference statements)

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“…Topal et al demonstrated that LV GT corrects the immune abnormalities in XIAP-deficient mice [45], a particularly appealing treatment given the poor HCT outcomes seen in XIAP patients who develop GVHD [46,47]. Fox et al recently developed a gene editing strategy that inserts the CTLA-4 cDNA into the first intron of the CTLA-4 genomic locus in human T cells and corrects the lymphoproliferation in in vivo mouse models [48]. T cell GT has several advantages over traditional GT using HSPCs, including a lower risk of insertional mutagenesis.…”

Section: Preclinical Gene Therapy Studies For Inborn Errors Of Immunitymentioning

confidence: 99%

Progress in the field of hematopoietic stem cell-based therapies for inborn errors of immunity

Arnold,

Pai

2023

Current Opinion in Pediatrics

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Purpose of review Hematopoietic stem cell-based therapies, including allogeneic hematopoietic cell transplantation (HCT) and autologous gene therapy (GT), have been used as curative therapy for many inborn errors of immunity (IEI). As the number of genetically defined IEI and the use of HCT and GT increase, valuable data on outcomes and approaches for specific disorders are available. We review recent progress in HCT and GT for IEI in this article. Recent findings Novel approaches to prevention of allogeneic complications and experience in adolescents and young adults have expanded the use of HCT. Universal newborn screening for severe combined immunodeficiency (SCID) has led to improved outcome after HCT. Analysis of outcomes of HCT and GT for SCID, Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD) reveal risk factors for survival, the impact of specific conditioning regimens, and vector- or disease-specific impacts on efficacy and safety. Preclinical studies of GT and gene editing show potential for translation to the clinic. Summary Emerging data on outcome after HCT for specific IEI support early evaluation and treatment, before development of co-morbidities. Data in large cooperative retrospective databases continues to yield valuable insights clinicians can use in patient selection and choice of therapy.

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Section: Preclinical Gene Therapy Studies For Inborn Errors Of Immunitymentioning

confidence: 99%

Progress in the field of hematopoietic stem cell-based therapies for inborn errors of immunity

Arnold,

Pai

2023

Current Opinion in Pediatrics

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“…approach has been demonstrated for X-SCID [45][46][47], X-CGD [48], CD40L [49 & ,50,51], CTLA4 [52], XLP [53], RAG1 [54,55] and Wiskott-Aldrich syndrome (WAS) [56]. With both approaches, endogenous gene regulation is kept intact resulting in physiological expression.…”

Section: Gene Editingmentioning

confidence: 99%

“…The last decade, several methods have been optimized to introduce the programmed nucleases efficiently to the cells [65], but the large size of the donor template makes most nonviral methods inadequate for the donor template. The most commonly used successful strategy has been delivery by AAV6 [45,47,48,49 ▪ ,51–53], an adeno-associated nonintegrating viral vector. The safety of this approach and the potential risk for AAV integration needs to be further evaluated before clinical translation [66 ▪ ].…”

Section: Gene Therapymentioning

confidence: 99%

“…In that case, the same approach would be applicable to all mutations. However, in contrast to delivery of the engineered nuclease, delivery of donor template is still challenging and has mostly been accomplished by use of nonintegrating viral vectors (AAV6) requiring additional safety studies [45,47,48,49 ▪ ,51–53,66 ▪ ].…”

Section: Challenges and Future Perspectivesmentioning

confidence: 99%

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Advances in gene therapy for inborn errors of immunity

Ott de Bruin,

Lankester,

Staal

2023

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of review Provide an overview of the landmark accomplishments and state of the art of gene therapy for inborn errors of immunity (IEI). Recent findings Three decades after the first clinical application of gene therapy for IEI, there is one market authorized product available, while for several others efficacy has been demonstrated or is currently being tested in ongoing clinical trials. Gene editing approaches using programmable nucleases are being explored preclinically and could be beneficial for genes requiring tightly regulated expression, gain-of-function mutations and dominant-negative mutations. Summary Gene therapy by modifying autologous hematopoietic stem cells (HSCs) offers an attractive alternative to allogeneic hematopoietic stem cell transplantation (HSCT), the current standard of care to treat severe IEI. This approach does not require availability of a suitable allogeneic donor and eliminates the risk of graft versus host disease (GvHD). Gene therapy can be attempted by using a viral vector to add a copy of the therapeutic gene (viral gene addition) or by using programmable nucleases (gene editing) to precisely correct mutations, disrupt a gene or introduce an entire copy of a gene at a specific locus. However, gene therapy comes with its own challenges such as safety, therapeutic effectiveness and access. For viral gene addition, a major safety concern is vector-related insertional mutagenesis, although this has been greatly reduced with the introduction of safer vectors. For gene editing, the risk of off-site mutagenesis is a main driver behind the ongoing search for modified nucleases. For both approaches, HSCs have to be manipulated ex vivo, and doing this efficiently without losing stemness remains a challenge, especially for gene editing.

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“…After their combination, the interaction between CTLA-4 and its ligand CD80/CD86 is blocked and the activation and proliferation of T cells enhance the tumor immune response. 41 , 42 However, the results of ipilimumab’s single use are not satisfactory. At present, it is believed that nivolumab plus ipilimumab has a very positive clinical effect in dMMR/MSI-H patients, such that 54.6% of them can objectively experience relief.…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitor-Based Combination Therapy for Colorectal Cancer: An Overview

Li¹,

Xu²

2023

IJGM

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Colorectal cancer (CRC) is one of the most common diseases in the world. Tumor immunotherapy is an innovative cancer treatment that acts by activating the human body's autoimmune system. Immune checkpoint block has been shown to be effective in DNA deficient mismatch repair/microsatellite instability-high CRC. However, the therapeutic effect for proficient mismatch repair/ microsatellite stability patients still requires further study and optimization. At present, the main CRC strategy is to combine other therapeutic methods, such as chemotherapy, targeted therapy, and radiotherapy. Here, we review the current status and the latest progress of immune checkpoint inhibitors in the treatment of CRC. At the same time, we consider therapeutic opportunities for transforming cold to hot, as well as perspectives on possible future therapies, which may be in great demand for drug-resistant patients.

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Therapeutic gene editing of T cells to correct CTLA-4 insufficiency

Cited by 18 publications

References 55 publications

Progress in the field of hematopoietic stem cell-based therapies for inborn errors of immunity

Progress in the field of hematopoietic stem cell-based therapies for inborn errors of immunity

Advances in gene therapy for inborn errors of immunity

Immune Checkpoint Inhibitor-Based Combination Therapy for Colorectal Cancer: An Overview

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