In Utero Gene Therapy for Primary Immunodeficiencies

Mardy, Anne H.; Norton, Mary E.

doi:10.1097/grf.0000000000000652

Cited by 3 publications

(3 citation statements)

References 95 publications

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“…Regarding the treatment perspectives, it is noteworthy that many IEI monogenic diseases appear to be good candidates for gene therapy, e.g., X-linked SCID and X-linked GCD, ADA-SCID and Wiskott-Aldrich Syndrome, and several clinical trials have already been accomplished (107). The transition from engineered viral vectors to gene editing approaches, coupled with advances in hematopoietic stem cell transplantation, may bring new perspectives to this field of therapeutic research (17,107), Furthermore, the possibility of in utero gene therapy is already on our horizon (17).…”

Section: Discussionmentioning

confidence: 99%

“…The majority of IEI present early in life, and a significant proportion of them, particularly the most severe ones, manifest in the first months of life, some even in the neonatal period (5)(6)(7)(8)(9)(10). Nevertheless, a few reports on intrauterine manifestations of IEI have been published, frequently represented by cases of hydrops fetalis in individuals in whom an IEI-related mutation was later identified in the family (7,9,(11)(12)(13)(14)(15)(16)(17). Commonly, infectious manifestations were the first and dominant features described in IEI patients but have not been reported in intrauterine life.…”

Section: Introductionmentioning

confidence: 99%

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Inborn Errors of Immunity With Fetal or Perinatal Clinical Manifestations

et al. 2022

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In this article we revised the literature on Inborn Errors of Immunity (IEI) keeping our focus on those diseases presenting with intrauterine or perinatal clinical manifestations. We opted to describe our findings according to the IEI categories established by the International Union of Immunological Societies, predominantly addressing the immunological features of each condition or group of diseases. The main finding is that such precocious manifestations are largely concentrated in the group of primary immune regulatory disorders (PIRDs) and not in the group of classical immunodeficiencies. The IEI categories with higher number of immunological manifestations in utero or in perinatal period are: (i) diseases of immune dysregulation (HLH, IPEX and other Tregopathies, autosomal recessive ALPS with complete lack of FAS protein expression) and (ii) autoinflammatory diseases (NOMID/CINCA, DIRA and some interferonopathies, such as Aicardi-Goutières syndrome, AGS, and USP18 deficiency). Regarding the other IEI categories, some patients with Omenn syndrome (an atypical form of SCID), and a few X-linked CGD patients present with clinical manifestations at birth associated to immune dysregulation. The most frequent clinical features were hydrops fetalis, intrauterine growth retardation leading to fetal loss, stillbirths, and prematurity, as in HLH and IPEX. Additionally, pseudo-TORCH syndrome was observed in AGS and in USP18 deficiency. The main goal of our review was to contribute to increasing the medical awareness of IEI with intrauterine and perinatal onset, which has obvious implications for diagnosis, treatment, and genetic counseling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inborn Errors of Immunity With Fetal or Perinatal Clinical Manifestations

et al. 2022

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“…There are numerous reports showing that in utero therapies are becoming a reality for a multitude of conditions employing diverse modalities such as stem cell transplantation (e.g., BOOSTB4 for severe osteogenesis imperfecta type IV), intra-amniotic drug administration (e.g., ER004 for Xlinked hypohidrotic ectodermal dysplasia), in utero enzyme replacement therapy (IURET, e.g., for lysosomal storage diseases), and potentially, gene therapy and gene editing. 23 It has been demonstrated that in severely ill newborns, the sooner the treatment is initiated, the better the results. 21 What could be sooner than prenatal diagnosis?…”

Section: Patients Who Prefer Comprehensive Prenatal Detection Of As M...mentioning

confidence: 99%

International Society for Prenatal Diagnosis 2022 debate 3—Fetal genome sequencing should be offered to all pregnant patients

2022

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Prenatal trio exome sequencing (ES) has become integrated into the care for pregnant women when the fetus has structural anomalies. Details regarding optimizing indications for prenatal exome sequencing, its detection rates with different categories of fetal anomalies, and principles of interpretation of pathogenicity of sequence variants are still under investigation. However, there is now growing consensus about its benefits for finding the cause of fetal structural anomalies.What is not established, is whether exome or genome sequencing (GS) has a place in the care of all pregnant women. This report is a summary of the debate on this topic at the 26th International Conference on Prenatal Diagnosis and Therapy. Both expert debaters considered the advantages and disadvantages. Advantages include the ability to diagnose serious childhood conditions without a prenatally observable phenotype, which creates the potential of early treatments. Disadvantages include difficulties with variant classification, counseling complexities, healthcare cost, and the burden on healthcare systems and families, in particular with the discovery of adult-onset disorders or variants of uncertain significance. Although both debaters weighed the balance of these conflicting arguments differently, they agreed that more research is needed to further explore the clinical utility and ethical aspects of GS for all pregnant women. Key points What is already known about this topic?� Prenatal exome sequencing (pES) has a significant incremental diagnostic yield over karyotype and chromosomal microarray (CMA) in cases with structural fetal anomalies.� Emerging evidence shows that genome sequencing (GS) has a higher diagnostic yield for single nucleotide variants (SNVs) and expansion mutations compared to ES, as well as superior detection of copy number variants (CNVs) compared to CMA. What does this study add?� The debaters discuss potential benefits and pitfalls of offering pGS to all pregnant patients.

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Development and clinical translation of ex vivo gene therapy

Liu

et al. 2022

Computational and Structural Biotechnology Journal

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In Utero Gene Therapy for Primary Immunodeficiencies

Cited by 3 publications

References 95 publications

Inborn Errors of Immunity With Fetal or Perinatal Clinical Manifestations

Inborn Errors of Immunity With Fetal or Perinatal Clinical Manifestations

International Society for Prenatal Diagnosis 2022 debate 3—Fetal genome sequencing should be offered to all pregnant patients

Development and clinical translation of ex vivo gene therapy

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