H2020Индивидуална стипендия2018–2020

CXCR4THERAPY · IMPROVING HEMATOPOIETIC STEM CELL- BASED GENE THERAPY OUTCOME BY MODULATING CXCR4 EXPRESSION

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-06-01 → 2020-05-31
Финансиране от ЕС: 173 076 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Генната терапия при бета-таласемия и сърповидноклетъчна анемия се опитва да подобри работата на стволовите клетки чрез регулиране на рецептора CXCR4. Това е важно, за да се увеличи ефективността на трансплантацията и способността на коригираните клетки да заселват костния мозък.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

IMPROVING HEMATOPOIETIC STEM CELL- BASED GENE THERAPY OUTCOME BY MODULATING CXCR4 EXPRESSION

β-thalassemias and sickle cell disease (SCD) are caused by mutations in the β-globin gene (HBB) that result in the defective synthesis or the production of an abnormal variant of hemoglobin. Currently, the only curative option is allogeneic transplantation of hematopoietic stem cells (HSCs). Alternative strategies, based on lentiviral (LV) vector-mediated introduction of a functional copy of the HBB gene followed by autologous bone marrow (BM) transplantation, are currently explored. Despite that clinical data are promising, achieving a broad therapeutic benefit remains a major hurdle because of suboptimal gene correction and limited transplantation fitness of corrected HSCs. This proposal intended to confer an in vivo competitive advantage to transduced HSCs by modulating the expression levels of the chemokine receptor CXCR4 by means of two different approaches. On one hand, as increased CXCR4 levels enhance bone marrow (BM) homing, we aimed to develop an innovative LV-based strategy to transiently deliver CXCR4 into HSCs to improve their migration to the BM. Despite we could create LV particles capable to transiently transfer proteins on HSCs, CXCR4 was not functional under the tested experimental conditions and this prevented to demonstrate the feasibility of the proposed approach in vivo. On the other hand, as CXCR4 haploinsufficiency enhances proliferation of HSCs, we aimed to develop LV particles down-regulating CXCR4 expression to endow corrected HSCs with an increased BM repopulating capacity. We developed an artificial LV cassette capable to reduce CXCR4 expression in cell lines, but it failed to function in HSCs. Importantly, as the project was interrupted by an early grant termination, we could not further optimize the described LV systems.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

β-thalassemias and sickle cell disease (SCD) are caused by mutations in the β-globin gene (HBB) that result in the defective synthesis (β-thalassemias) or the production of an abnormal variant (SCD) of hemoglobin. Currently, the only curative option is allogeneic transplantation of hematopoietic stem cells (HSCs), but it is severely limited by conditioning toxicity and the restricted availability of compatible donors. Alternative strategies, based on lentiviral vector (LV)-mediated introduction of a functional copy of the HBB gene followed by autologous transplantation, are currently explored. Despite the fact that clinical data are promising, achieving a broad therapeutic benefit still remains a major hurdle because of inefficient gene correction and competition of the endogenous affected HSCs.In this proposal, I intend to confer an in vivo competitive advantage to transduced HSCs in terms of homing and engraftment efficiencies by modulating the expression levels of the chemokine receptor CXCR4 through two different approaches. On one hand, as increased CXCR4 levels enhance bone marrow (BM) homing, I will develop an innovative LV-based strategy to transiently deliver CXCR4 into HSCs to improve their migration to the BM. On the other hand, as CXCR4 haploinsufficiency enhances proliferation of homed HSCs, I will develop LVs down-regulating CXCR4 expression to endow corrected HSCs with an increased BM repopulating capacity. Thanks to these strategies, corrected HSCs will be able to out-compete non-corrected as well as endogenous affected HSCs, thus attaining therapeutic levels of engraftment even with a reduced number of corrected HSCs. In addition, this will contribute to use a milder conditioning regimen, normally required to eliminate endogenous affected HSCs, and thus reduce its toxicity, which preclude this treatment for patients with high disease burden. Noteworthy, this approach can potentially benefit many diseases amenable to HSC gene therapy.

Оригинален текст от CORDIS (на английски).

Участници

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisКоординаторФранция