CE17 - Recherche translationnelle en santé

Improving hematopoietic stem cell-based gene therapy for ß-hemoglobinopathies. – HemoLen

Submission summary

ß-thalassemias and sickle cell disease (SCD) are caused by mutations in the ß-globin gene (HBB) that result in defective synthesis (ß-thalassemias) or 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 availability of compatible donors. Lentiviral vector(LV)-mediated addition of a functional ß-globin gene is a promising alternative therapeutic option; however, inefficient delivery/expression of the transgene and competition between gene corrected and endogenous affected HSCs still remain major hurdles.
With this proposal, we will explore two novel alternative and possibly complementary strategies focusing on the modification of LVs for improving HSC-based gene therapy for ß-globin disorders.
On one hand, we will adapt LVs to provide an in vivo advantage to transduced HSCs in terms of homing and engraftment efficiencies by transient delivery of the chemokine receptor CXCR4. Thanks to this strategy, corrected HSCs will be able to out-compete noncorrected as well as endogenous affected HSCs, thus attaining therapeutic levels of engraftment even with a reduced number of ex vivo corrected HSCs. In addition, this approach could translate in milder conditioning regimen for patients - normally required to ameliorate transplant engraftment by eliminating endogenous affected HSCs - thus reducing its general tissue toxicity. Noteworthy, this approach can potentially benefit many diseases amenable to HSC-based gene therapy.
On the other hand, we will ameliorate the therapeutic potential of current LV-based gene replacement treatment by expressing the HBB transgene together with an artificial microRNA down-regulating the expression of the proteins causing disease manifestation (mutated ß-globin for SCD and excess of a-globin for ß-thalassemia). We expect that the combination of gene replacement and gene silencing strategies will allow better correction of patient HSCs with a lower LV copy number compared to state-of-the-art LV.
Finally, we will combine the proposed strategies to benefit from both improved HSC homing/engraftment and improved therapeutic efficacy of our LV-based gene addition/RNAi design for an all-round optimized curative genetic approach.
Thanks to these LV improvements, we expect to change the goal of current gene therapy clinical trial from an amelioration of clinical signs and reduction of blood transfusion to a complete cure of the disease.

Project coordination

Mario Amendola (Integrated genetic approaches in therapeutic discovery for rare)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


UMR_S951 Integrated genetic approaches in therapeutic discovery for rare

Help of the ANR 458,505 euros
Beginning and duration of the scientific project: October 2020 - 36 Months

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