Genetic therapies for sickle cell disease

Esrick, Erica B.; Bauer, Daniel E.

doi:10.1053/j.seminhematol.2018.04.014

Cited by 31 publications

(21 citation statements)

References 112 publications

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“…Preliminary outcome data are currently available for 21 patients treated on four gene therapy trials (Cavazzana et al , ; Ribeil et al , ; Esrick & Bauer, ; Kanter et al , ; Malik et al , ; Mapara et al , )(Table II). All patients treated with LentiGlobin BB305 ( n = 18) had a stable increase in vector‐derived Hb.…”

Section: Haploidentical Transplantation Versus Gene Therapymentioning

confidence: 99%

“…The theoretical advantage to site‐specific gene correction is the reduction in off‐target insertion, the requirement for only transient delivery of the engineered nuclease and repair template to achieve correction, and the lack of permanent insertion of foreign DNA into the genome. Treating cells with CRISPR/Cas9 and a β‐globin donor gene for repair may result, however, in multiple genetic outcomes, ranging from healthy (both alleles corrected) to β‐thalassaemia major (both alleles disrupted) (Esrick & Bauer, ). As precise correction in long‐term HSCs is not yet efficient and editing results in reduction in engrafting HSCs (Dever et al , ; Hoban et al , ), transplantation of mixed culture could be clinically problematic and possible unintended consequences should be addressed before clinical trials.…”

Section: Haploidentical Transplantation Versus Gene Therapymentioning

confidence: 99%

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Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

2020

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Summary Haematopoietic stem cell transplantation (HSCT) is curative in sickle cell disease (SCD); however, the lack of available matched donors makes this therapy out of reach for the majority of patients with SCD. Alternative donor sources such as haploidentical HSCT expand the donor pool to nearly all patients with SCD, with recent data showing high overall survival, limited toxicities, and effective reduction in acute and chronic graft‐versus‐host disease (GVHD). Simultaneously, multiple gene therapy strategies are entering clinical trials with preliminary data showing their success, theoretically offering all patients yet another curative strategy without the morbidity and mortality of GVHD. As improvements are made for alternative donors in the allogeneic setting and as data emerge from gene therapy trials, the optimal curative strategy for any individual patient with SCD will be determined by many critical factors including efficacy, transplant morbidity and mortality, safety, patient disease status and preference, cost and applicability. Haploidentical may be the preferred choice now based mostly on availability of data; however, gene therapy is closing the gap and may ultimately prove to be the better option. Progress in both strategies, however, makes cure more attainable for the individual with SCD.

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Section: Haploidentical Transplantation Versus Gene Therapymentioning

confidence: 99%

Section: Haploidentical Transplantation Versus Gene Therapymentioning

confidence: 99%

Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

2020

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“…These findings have led to a considerable effort to target BCL11A to achieve HbF induction in patients with the bhemoglobin disorders. These efforts include gene therapy-based delivery of shRNAs targeting BCL11A and efforts to target an erythroid enhancer of BCL11A using genome editing approaches (Esrick & Bauer, 2018 this pathway and identify more broadly effective therapeutic approaches for HbF induction in these diseases. Collectively, the study of HbF regulation has encompassed the full journey from variation to function and has now moved into the translational realm in an attempt to cure human diseases.…”

Section: Population-based Genetic Studies Of Hematopoiesis and Their mentioning

confidence: 99%

“…These findings have led to a considerable effort to target BCL11A to achieve HbF induction in patients with the β‐hemoglobin disorders. These efforts include gene therapy‐based delivery of shRNAs targeting BCL11A and efforts to target an erythroid enhancer of BCL11A using genome editing approaches (Esrick & Bauer, ). In addition, groups have begun to perturb this pathway and identify more broadly effective therapeutic approaches for HbF induction in these diseases.…”

Section: Introductionmentioning

confidence: 99%

The genetics of human hematopoiesis and its disruption in disease

2019

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Hematopoiesis, or the process of blood cell production, is a paradigm of multi‐lineage cellular differentiation that has been extensively studied, yet in many aspects remains incompletely understood. Nearly all clinically measured hematopoietic traits exhibit extensive variation and are highly heritable, underscoring the importance of genetic variation in these processes. This review explores how human genetics have illuminated our understanding of hematopoiesis in health and disease. The study of rare mutations in blood and immune disorders has elucidated novel roles for regulators of hematopoiesis and uncovered numerous important molecular pathways, as seen through examples such as Diamond‐Blackfan anemia and the GATA2 deficiency syndromes. Additionally, population studies of common genetic variation have revealed mechanisms by which human hematopoiesis can be modulated. We discuss advances in functionally characterizing common variants associated with blood cell traits and discuss therapeutic insights, such as the discovery of BCL11A as a modulator of fetal hemoglobin expression. Finally, as genetic techniques continue to evolve, we discuss the prospects, challenges, and unanswered questions that lie ahead in this burgeoning field.

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“…Hoy en día, el trasplante halogénico de células madre hematopoyéticas modificadas genéticamente, constituye una opción terapéutica relativamente curativa para algunos pacientes, puesto que contribuye a la remisión de las crisis vaso-oclusivas y a la estabilización o mejoría de las anormalidades neurológicas y pulmonares [15]. Este procedimiento abre las puertas a una única corrección desprovis-Universidad de Manizales -Facultad de Ciencias de la Salud ta de efectos secundarios autoinmunes, por lo que es un procedimiento prometedor para el campo de la terapéutica, sin embargo, es una alternativa que sigue en etapa de prueba [15,16,17,18,19].…”

Section: Introductionunclassified

Anemia de Células Falciformes: Correlación Clínico-Patológica

Saavedra¹

2019

archmed

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La anemia de células falciformes es la alteración hematológica heredada más común a nivel mundial. Esta dada por la presencia de hemoglobinas anormales (HbS y sus diferentes genotipos) a raíz de una mutación en las cadenas de globina. La tríada clínica consiste en eventos vaso-oclusivos, anemia hemolítica crónica y asplenia funcional. Hoy en día se ha documentado toda clase de complicaciones asociadas a la enfermedad, entre las cuales se encuentran: accidentes cerebrovasculares, infarto agudo de miocardio, hipertensión pulmonar, tromboembolismos venosos, infecciones, necrosis de la papila renal, enfermedad renal crónica, ulceraciones en miembros inferiores, enfermedades del aparato hepatobiliar y necrosis ósea avascular. Es de vital importancia la realización de un correcto enfoque clínico y terapéutico de los pacientes con anemia de células falciformes de modo que sea posible la prevención y tratamiento oportuno de las complicaciones asociadas a esta condición.

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Genetic therapies for sickle cell disease

Cited by 31 publications

References 112 publications

Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

The genetics of human hematopoiesis and its disruption in disease

Anemia de Células Falciformes: Correlación Clínico-Patológica

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