Development of Gene Editing Strategies for Human <b>β</b>-Globin (HBB) Gene Mutations

Kalkan, Batuhan Mert; Kala, Ezgi Yagmur; Yuce, Melek; Alpaslan, Medine Karadag; Kocabaş, Fatih

doi:10.1101/2020.01.16.908319

Cited by 4 publications

(5 citation statements)

References 45 publications

(28 reference statements)

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“…In a humanized mouse model for HbSS SCD, investigators have achieved an average of 14.8% (1%-35.4%, n = 9) allele correction in repopulating HSCs, with improvement of hemolytic anemia (97). Direct correction of the SCD codon will likely improve with protocols and technologies designed to enhance the rates of HDR in HSCs and/or select for those that are genetically corrected (98)(99)(100)(101)(102)(103)(104).…”

Section: Autologous Genetic Therapies For Scdmentioning

confidence: 99%

Genetic therapies for the first molecular disease

Doerfler¹,

Sharma²,

Porter³

et al. 2021

Journal of Clinical Investigation

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in order to disseminate cures more broadly. Initially, such therapies will occur in high-income countries where advanced tertiary care centers provide cell manufacturing and medical support. Delivery of autologous HSCT therapies to the vast majority of individuals with SCD, who reside mainly in low-and middle-income countries, will be facilitated by reduced-toxicity in vivo approaches that selectively modify HSCs via intravenous or bone marrow injection of targeted delivery vehicles such as engineered nanoparticles or nonintegrating viral vectors (206)(207)(208). The NIH and the Gates Foundation are collaborating to develop gene-based cures for SCD on a global scale (209). We are confident that this endeavor will succeed, although it will require time and advancing technologies. In the meantime, autologous HSCT for SCD must be considered as an essential component of a larger, multifaceted effort that also includes widespread newborn screening, institution of preventative therapies such as immunization, prophylactic penicillin and hydroxyurea, better drugs, allogeneic HSCT, and optimized infrastructures for delivering both basic and advanced medical care.

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Section: Autologous Genetic Therapies For Scdmentioning

confidence: 99%

Genetic therapies for the first molecular disease

Doerfler¹,

Sharma²,

Porter³

et al. 2021

Journal of Clinical Investigation

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show abstract

“…Recientemente, ha crecido el interés por emplear la técnica CRISPR/cas 9 como procedimiento terapéutico en la corrección del gen β-globina mutado 54,55 . La edición de la mutación β S por reparación de ADN dirigida por homología ["Homology Directed Repair" (HDR)], se puede conseguir por medio de nucleasas con zinc o CRISPR/Cas9, para escindir el locus β S , por otra parte, genomas virales u oligonucleótidos monocatenarios actúan como moldes donantes HDR 56 . La plataforma CRISPR/Cas9 utiliza una única endonucleasa y un solo ARN guía (ARNg) para inducir la ruptura de ADN (doble cadena) de secuencia específica.…”

Section: Terapia Génicaunclassified

“…La plataforma CRISPR/Cas9 utiliza una única endonucleasa y un solo ARN guía (ARNg) para inducir la ruptura de ADN (doble cadena) de secuencia específica. Cuando esto acompaña a un molde de reparación, permite reparar el gen mutado 56,57 .…”

Section: Terapia Génicaunclassified

Anemia falciforme: una revisión sobre el genotipo de la enfermedad, haplotipos, diagnóstico y estudios asociados

Díaz-Matallana¹,

Márquez-Benítez²,

Martínez-Lozano³

et al. 2021

Rev. méd. Chile

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Disease genotype, haplotypes, diagnosis and associated studies in sickle cell anemiaSickle cell anemia is a type of hemoglobinopathy characterized by a specific mutation in the beta globin gene with the consequent generation of an unstable hemoglobin that crystallizes in a state of hypoxia. This causes a change in the structure of the red blood cell, which ends up producing vaso-occlusion with the corresponding clinical complications for the patient. Worldwide, various diagnostic tests have been developed that allow the appropriate approach to the affected patient. These include techniques for the determination of hemoglobin and the use of molecular markers, among others. There are new therapeutic alternatives to the use of hydroxyurea and L-glutamine, such as the use of gene therapy tools. The most recent experimental trials are exploring gene editing techniques.

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“…While HSCs form the basis of bone marrow transplantation, they also hold promise for gene therapy studies (Kalkan et al, 2020). HSC transplantation is used in the treatment of leukemia, lymphoma, some solid cancers, autoimmune diseases and genetic conditions such as Sickle Cell Anemia or Mediterranean Anemia (Rameshwar et al, 2011;Zheng et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Pluripotin facilitates the expansion of hematopoietic stem cells, but restricts the growth of fibroblasts and the proliferation of mesenchymal stem cells from the bone marrow

Turan

Kocabaş

2021

Preprint

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Hematopoietic stem/progenitor cell (HSPC) quiescence modulators play a key role in the modulation of HSPC numbers. Targeting HSPC modulators with small molecules could contribute to the cell cycle entry and expansion of HSPC. To this end, we have investigated the effect of two small molecules Pluripotin and CHIR-99021 on HSPC expansion. Both Pluripotin and CHIR-99021 have been shown to result in a 3-fold rise in the murine pool of HSPC in a dose-dependent compartment after 7 days of treatments. In addition, we investigated the influence of Pluripotin treatment on the ex vivo expansion of human umbilical cord blood and bone marrow mononuclear cells. In specific, Pluripotin treatment increased human CD34 + and ALDHbr HSPC content up to 3-fold compared to control. In addition, human CD133 + HSPC cell content was increased to 5-fold following treatment with Pluripotin. Intriguingly, we find that Pluripotin treatment inversely changes bone marrow-derived mesenchymal stem cell (MSC) proliferation and lowers fibroblast growth although there is no effect on adipose-derived MSCs. CHIR-99021 treatment did not have any effect in proliferation of MSCs or fibroblasts. In conclusion, Pluripotin-induced stem cell expansion is unique to HSPCs that can be used to expand HSPCs and reduce unwanted fibroblast or MSC growth in the primary ex vivo cultures.

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Development of Gene Editing Strategies for Human β-Globin (HBB) Gene Mutations

Cited by 4 publications

References 45 publications

Genetic therapies for the first molecular disease

Genetic therapies for the first molecular disease

Anemia falciforme: una revisión sobre el genotipo de la enfermedad, haplotipos, diagnóstico y estudios asociados

Pluripotin facilitates the expansion of hematopoietic stem cells, but restricts the growth of fibroblasts and the proliferation of mesenchymal stem cells from the bone marrow

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