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Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy.

ABSTRACT: Genome editing produces genetic modifications in somatic cells, offering novel curative possibilities for sickle cell disease and β-thalassemia. These opportunities leverage clinical knowledge of hematopoietic stem cell transplant and gene transfer. Advantages to this mode of ex vivo therapy include locus-specific alteration of patient hematopoietic stem cell genomes, lack of allogeneic immune response, and avoidance of insertional mutagenesis. Despite exciting progress, many aspects of this approach remain to be optimized for ideal clinical implementation, including the efficiency and specificity of gene modification, delivery to hematopoietic stem cells, and robust and nontoxic engraftment of gene-modified cells. This review highlights genome editing as compared to other genetic therapies, the differences between editing strategies, and the clinical prospects and challenges of implementing genome editing as a novel treatment. As the world's most common monogenic disorders, the β-hemoglobinopathies are at the forefront of bringing genome editing to the clinic and hold promise for molecular medicine to address human disease at its root.

SUBMITTER: Rosanwo TO

PROVIDER: S-EPMC8571174 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy.

Rosanwo Tolulope O TO Bauer Daniel E DE

Molecular therapy : the journal of the American Society of Gene Therapy 20211008 11

Genome editing produces genetic modifications in somatic cells, offering novel curative possibilities for sickle cell disease and β-thalassemia. These opportunities leverage clinical knowledge of hematopoietic stem cell transplant and gene transfer. Advantages to this mode of ex vivo therapy include locus-specific alteration of patient hematopoietic stem cell genomes, lack of allogeneic immune response, and avoidance of insertional mutagenesis. Despite exciting progress, many aspects of this app ...[more]

PMID: 34628053

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Project description:BackgroundIn vitro models of prostate cancer (PCa) are not always reliable to evaluate anticancer treatment efficacy. This limitation may be overcome by using viable tumor slice material. Here we report on the establishment of an optimized ex vivo method to culture tissue slices from patient-derived xenografts (PDX) of prostate cancer (PCa), to assess responses to PCa treatments.MethodsThree PDX models were used that are characterized by different androgen receptor (AR) expression and different homology directed DNA repair capacities, due to a breast cancer associated two (BRCA2) wild-type or mutated status. Tumors were removed from mice, sliced using a vibratome and cultured for a maximum of 6 days. To test the sensitivity to androgen antagonist, tumor slices from the AR-expressing and AR-negative PDX tumors were treated with the anti-androgen enzalutamide. For sensitivity to DNA repair intervention, tumors slices from BRCA2 wild-type and mutated PDXs were treated with the poly (ADP-ribose) polymerase-1 inhibitor olaparib. Treatment response in these tumor slices was determined by measuring slice morphology, cell proliferation, apoptosis, AR expression level, and secretion of prostate specific antigen (PSA).ResultsWe compared various culture conditions (support materials, growth media, and use of a 3D smooth rocking platform) to define the optimal condition to maintain tissue viability and proliferative capacity up to least 6 days. Under optimized conditions, enzalutamide treatment significantly decreased proliferation, increased apoptosis, and reduced AR-expression and PSA secretion of AR-expressing tumor slices compared to AR-negative slices, that did not respond to the intervention. Olaparib treatment significantly increased cell death in BRCA2 mutated tumors slices as compared to slices from BRCA2 wild type tumors.ConclusionsEx vivo treatment of PCa PDX tumor slices with enzalutamide and olaparib recapitulates responses previously observed in vivo. The faithful retention of tissue structure and function in this ex vivo model offers an ideal opportunity for treatment efficacy screening, thereby reducing costs and numbers of experimental animals.

Dataset Information

Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy.

Publications

Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy.

Similar Datasets

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