Overview of the current status of gene therapy for primary immune deficiencies (PIDs)

doi:10.1016/j.jaci.2020.05.024

Journal of Allergy and Clinical Immunology

Volume 146, Issue 2, August 2020, Pages 229-233

https://doi.org/10.1016/j.jaci.2020.05.024 Get rights and content

Over 3 decades, gene therapy has advanced from a logical idea to becoming a clinical reality for several of the most severe primary immune deficiencies, as well as other inherited disorders. The first gene therapy medicines have been licensed for marketing and several more are advancing toward that goal to make them widely available, beyond clinical trials. Although common platforms of cells, vectors, or editing reagents are used for these disorders, each individual genetic cause of an immune deficiency requires its own vector or editing tools and a package of preclinical data on efficacy and safety to initiate clinical trials. One-by-one, gene therapy for primary immune deficiencies is being brought to the clinic and hopefully will provide safe and effective therapies.

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Cited by (7)

Challenges for gene editing in common variable immunodeficiency disorders: Current and future prospects
2024, Clinical Immunology
The original CRISPR Cas9 gene editing system and subsequent innovations offers unprecedented opportunities to correct severe genetic defects including those causing Primary Immunodeficiencies (PIDs). Common Variable Immunodeficiency Disorders (CVID) are the most frequent symptomatic PID in adults and children. Unlike many other PIDs, patients meeting CVID criteria do not have a definable genetic defect and cannot be considered to have an inborn error of immunity (IEI). Patients with a CVID phenotype carrying a causative mutation are deemed to have a CVID-like disorder consequent to an IEI. Patients from consanguineous families often have highly penetrant early-onset autosomal recessive forms of CVID-like disorders. Individuals from non-consanguineous families may have autosomal dominant CVID-like disorders with variable penetrance and expressivity.
This essay explores the potential clinical utility as well as the current limitations and risks of gene editing including collateral genotoxicity. In the immediate future the main application of this technology is likely to be the in vitro investigation of epigenetic and polygenic mechanisms, which are likely to underlie many cases of CVID and CVID-like disorders. In the longer-term, the CRISPR Cas9 system and other gene-based therapies could be utilized to treat CVID-like disorders, where the underlying IEI is known.
Inborn Errors of Immunity
2023, Primary Care - Clinics in Office Practice
Development and clinical translation of ex vivo gene therapy
2022, Computational and Structural Biotechnology Journal
Citation Excerpt :
Notably, however, introducing SIN-LV system with some added regulatory elements resistant to epigenetic modification was recently exploited, which has shown some promising therapeutic results in several patients with severe X-linked CGDs (NCT02234934, NCT01855685) [91]. In short, the multiple clinical trials for treating SCIDs demonstrated the curative potential of gene therapy and the lesson learned from tackling SCIDs not only provided valuable guidance but also generated momentum for pursuing the translational research for a variety of PIDs [23,68,70,71,92,93]. The properties of multipotency and readiness for in vitro manipulation and repopulation have placed HSCs at the frontline of genetically engineering ex vivo therapy (indicated in Fig. 1).
Retroviral gene therapy has emerged as a promising therapeutic modality for multiple inherited and acquired human diseases. The capability of delivering curative treatment or mediating therapeutic benefits for a long-term period following a single application fundamentally distinguishes this medical intervention from traditional medicine and various lentiviral/γ-retroviral vector-mediated gene therapy products have been approved for clinical use. Continued advances in retroviral vector engineering, genomic editing, synthetic biology and immunology will broaden the medical applications of gene therapy and improve the efficacy and safety of the treatments based on genetic correction and alteration. This review will summarize the advent and clinical translation of ex vivo gene therapy, with the focus on the milestones during the exploitation of genetically engineered hematopoietic stem cells (HSCs) tackling a variety of pathological conditions which led to marketing approval. Finally, current statue and future prospects of gene editing as an alternative therapeutic approach are also discussed.
Next-generation sequencing for inborn errors of immunity
2021, Human Immunology
Citation Excerpt :
The most important point to remember is that while a molecular diagnosis can substantially alter the treatment or management strategy of an IEI, a lack of it should not prevent appropriate clinical management with the available knowledge and information. For a handful of IEIs, and certain others in the pipeline, gene therapy treatments are either available clinically, in research trials or clinical trials [109,110]. For such treatments, a molecular diagnosis is a necessity, and the number of IEIs treated with either gene therapy or gene editing will likely increase with the passage of time, and improvement in laboratory methodologies, however, the cost of these remains prohibitive to most patients, and it is not uniformly available across the globe.
Inborn errors of immunity (IEIs) include several hundred gene defects affecting various components of the immune system. As with other constitutional disorders, next-generation sequencing (NGS) is a powerful tool for the diagnosis of these diseases. While NGS can provide molecular confirmation of disease in a patient with a suspected or classic phenotype, it can also identify new molecular defects of the immune system, expand gene-disease phenotypes, clarify mechanism of disease, pattern of inheritance or identify new gene-disease associations. Multiple clinical specialties are involved in the diagnosis and management of patients with IEI, and most have no formal genetic training or expertise. To effectively utilize NGS tools and data in clinical practice, it is relevant and pragmatic to obtain a modicum of knowledge about genetic terminology, the variety of platforms and tools available for high-throughput genomic analysis, the interpretation and implementation of such data in clinical practice. There is considerable variability not only in the technologies and analytical tools used for NGS but in the bioinformatics approach to variant identification and interpretation. The ability to provide a molecular basis for disease has the potential to alter therapeutic management and longer-term treatment of the disease, including developing personalized approaches with molecularly targeted therapies. This review is intended for the clinical specialist or diagnostic immunologist who works in the area of inborn errors of immunity, and provides an overview of the need for genetic testing in these patients (the “why” aspect), the various technologies and analytical approaches, bioinformatics tools, resources, and challenges (the “how” aspect), and the clinical evidence for identifying which patients might be best served by such testing (the “when” aspect).
The New “Wholly Trinity” in the Diagnosis and Management of Inborn Errors of Immunity
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Citation Excerpt :
In such cases, the decision to pursue definitive treatment, such as HCT or allogenic thymus implantation, should be based on clinical and immunological criteria (Figure 2). Gene therapy, by its very nature, can only be performed in the context of a confirmed molecular defect.58-60 In the examples provided here, it is clear that each condition identified by NBS SCID requires a coordinated plan for diagnosis and subsequent treatment, because they did not manifest in a typical manner and defied conventional approaches to evaluation.
The field of immunology has a rich and diverse history, and the study of inborn errors of immunity (IEIs) represents both the “cake” and the “icing on top of the cake,” as it has enabled significant advances in our understanding of the human immune system. This explosion of knowledge has been facilitated by a unique partnership, a triumvirate formed by the physician who gathers detailed immunological and clinical phenotypic information from, and shares results with, the patient; the laboratory scientist/immunologist who performs diagnostic testing, as well as advanced functional correlative studies; and the genomics scientist/genetic counselor, who conducts and interprets varied genetic analyses, all of which are essential for dissecting constitutional genetic disorders. Although the basic principles of clinical care have not changed in recent years, the practice of clinical immunology has changed to reflect the prodigious advances in diagnostics, genomics, and therapeutics. An “omic/tics”-centric approach to IEI reflects the tremendous strides made in the field in the new millennium with recognition of new disorders, characterization of the molecular underpinnings, and development and implementation of personalized treatment strategies. This review brings renewed attention to bear on the indispensable “trinity” of phenotypic, genomic, and immunological analyses in the diagnosis, management, and treatment of IEIs.
How to evaluate for immunodeficiency in patients with autoimmune cytopenias: Laboratory evaluation for the diagnosis of inborn errors of immunity associated with immune dysregulation
2020, Hematology (United States)

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Reviews and feature articleOverview of the current status of gene therapy for primary immune deficiencies (PIDs)

Am J Med Sci

Blood

Mol Ther

Blood

Blood

Lancet Haematol

Cell Stem Cell

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Science

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N Engl J Med

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Science

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N Engl J Med

Gene therapy in a patient with sickle cell disease

N Engl J Med

Correction of adenosine deaminase deficiency in cultured human T and B cells by retrovirus-mediated gene transfer

Proc Natl Acad Sci U S A

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Science

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Sci Transl Med

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Reviews and feature article
Overview of the current status of gene therapy for primary immune deficiencies (PIDs)