Curative gene therapies for rare diseases

Maldonado, Rocio; Jalil, Sami; Wartiovaara, Kirmo

doi:10.1007/s12687-020-00480-6

Cited by 18 publications

(16 citation statements)

References 47 publications

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“…23 Potential future therapies could include targeting the ubiquitylation pathways, UBA1 gene editing to alter the mutant clone, or allogeneic bone marrow transplantation to replace affected progenitor cells. 24,25 Tables Table 1. Summary of clinical presentation and pertinent laboratory studies. x), also illustrated by an MPO immunostain (E, 400 x, representative pictures from patient 2).…”

Section: Discussionmentioning

confidence: 99%

A clinical, histopathological, and molecular study of two cases of VEXAS syndrome without a definitive myeloid neoplasm

et al. 2022

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VEXAS (vacuoles, E1 enzyme, X- linked, autoinflammatory, somatic) syndrome is caused by somatic mutations in UBA1 and is identified using a genotype-driven method. This condition connects unrelated men with adult-onset inflammatory syndromes in association with hematologic manifestations of peripheral cytopenia and bone marrow myeloid dysplasia. While bone marrow vacuolization restricted to myeloid and erythroid precursors has been identified in VEXAS patients, the detailed clinical and histopathological features of peripheral blood and bone marrows remain unclear. The current case report describes the characteristic hematologic findings in patients with VEXAS, including macrocytic anemia, thrombocytopenia, marked hypercellular marrow with granulocytic hyperplasia, megaloblastic changes in erythroid precursors, and the absence of hematogones in addition to prominent vacuoles in myeloid and erythroid precursor cells. Characterizing the clinical and hematologic features helps to raise awareness and improve diagnosis of this novel, rare, but potentially under-recognized disease. Prompt diagnosis expands the general knowledgeable and understanding of this disease, and optimal management might prevent patients from developing complications related to this refractory inflammatory syndrome and improve the overall clinical outcome.

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Section: Discussionmentioning

confidence: 99%

A clinical, histopathological, and molecular study of two cases of VEXAS syndrome without a definitive myeloid neoplasm

et al. 2022

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“…This method significantly simplifies and enhances the work of researchers and biobanks, providing a cleaner and more efficient way to convert A⋅T base pairs to G⋅C base pairs, which could potentially correct a large portion of human pathogenic SNPs ( Gaudelli et al., 2017 ) or even enable targeted exon skipping ( Winter et al., 2019 ). Considering the several CRISPR-based technologies available ( Anzalone et al., 2020 ) and the rapid advance of gene therapy toward clinics ( Maldonado et al., 2020 ), we envision a near future where all pathogenic SNPs are efficiently base edited, DSB-free, and without PAM limitations. Similarly, hiPSC research also dynamically evolves, getting closer to delivering cell and tissue therapy applications.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous high-efficiency base editing and reprogramming of patient fibroblasts

et al. 2021

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Summary Human induced pluripotent stem cells (hiPSCs) allow in vitro study of genetic diseases and hold potential for personalized stem cell therapy. Gene editing, precisely modifying specifically targeted loci, represents a valuable tool for different hiPSC applications. This is especially useful in monogenic diseases to dissect the function of unknown mutations or to create genetically corrected, patient-derived hiPSCs. Here we describe a highly efficient method for simultaneous base editing and reprogramming of fibroblasts employing a CRISPR-Cas9 adenine base editor. As a proof of concept, we apply this approach to generate gene-edited hiPSCs from skin biopsies of four patients carrying a Finnish-founder pathogenic point mutation in either NOTCH3 or LDLR genes. We also show LDLR activity restoration after the gene correction. Overall, this method yields tens of gene-edited hiPSC monoclonal lines with unprecedented efficiency and robustness while considerably reducing the cell culture time and thus the risk for in vitro alterations.

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“…After 30 years of official clinical trials, the total number of completed and ongoing gene therapy clinical trials exceeds 4000 90 with at least 22 gene therapies approved by drug regulatory agencies globally. 91 Based on the pipeline and the clinical success rates of products, the FDA predicts approving 10 to 20 cell and gene therapy products every year by 2025.…”

Section: Considerations For Successful Implementation Of Gene Therapy...mentioning

confidence: 99%

Gene Therapy and Hemophilia: Where Do We Go from Here?

Bolous¹,

Bhatt²,

Bhakta³

et al. 2022

JBM

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Gene therapy for hemophilia using adeno-associated virus (AAV) derived vectors can reduce or eliminate patients’ disease-related complications and improve their quality of life. Broad implementation globally will lead to societal gains and foster health equity. Several vector products each for factor IX (FIX) or factor VIII (FVIII) deficiency are in advanced clinical development. Safety data are reassuring. Efficacy data for up to 8 and 5 years, respectively, vary considerably among vector types and among individuals, but indicate significant reduction in bleeds and factor use. Products will soon be approved for marketing. This review highlights the relevant considerations for implementation of hemophilia gene therapy, specifically across a broad range of socioeconomic backgrounds globally, based on recent publications and our own experience. We address the current efficacy and safety data and relevant aspects of vector immunology. We then discuss pertinent implementation steps including pre-implementation and readiness assessments, considerations on cost, cost-effectiveness and payment models, approaches to education and informed consent, and the operational needs as well as the need for monitoring of health outcomes and implementation outcomes. To prevent a lag or complete lack of establishing access to this life-changing therapy option for all patients with hemophilia worldwide, adaptable pathways supported by collaborative and international efforts of all stakeholders are needed.

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Curative gene therapies for rare diseases

Cited by 18 publications

References 47 publications

A clinical, histopathological, and molecular study of two cases of VEXAS syndrome without a definitive myeloid neoplasm

A clinical, histopathological, and molecular study of two cases of VEXAS syndrome without a definitive myeloid neoplasm

Simultaneous high-efficiency base editing and reprogramming of patient fibroblasts

Gene Therapy and Hemophilia: Where Do We Go from Here?

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