New therapeutic approaches for sickle cell disease

 
Biree Andemariam, Willem Scheele, Victor Gordeuk, et al.
 
The authors of the abstract conclude: 
This 2nd interim analysis demonstrates that daily dosing of IMR-687, either alone or in combination with HU, was well-tolerated. Findings demonstrate a statistically significant increase in F-cells and an encouraging and dose-dependent increase in HbF percentage in patients in the high dose group after 24 weeks of monotherapy. PK data indicated that treatment with IMR-687 + HU did not result in changes in the HU PK and that there were no drug-drug interactions between IMR-687 and HU suggesting a role in combination therapy. The clinical data generated in this pre-specified interim analysis support further clinical development and testing of higher doses of IMR-687 as a potential disease modifying therapy for SCD. 
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Karsten Peppel, Michael Yan, Steven Lee, Jeffrey Bartlett, Jeffrey Ahlers
 
The authors of the abstract conclude: 
CAL-H-transduced CD34+ cells from SCD donors are able to differentiate ex vivo into mature RBCs containing sufficient HbF to prevent sickling under deoxygenated conditions. These data support the potential efficacy and safety of plerixafor-mobilized CAL-H-transduced HSPCs as a durable gene therapy for patients with SCD and the further clinical development of CSL200.
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Jack Heath, Edouard de Dreuzy, Patricia Sousa, et al.
 
The authors of the abstract conclude: 
In summary, we have demonstrated successful on-target editing of mPB CD34+ cells derived from both healthy and SCD donors using a Cas12a RNP, which coincided with robust HbF induction and a phenotypic reduction of sickling in the SCD erythroid progeny. Editing at the distal CCAAT-box region of the HBG1 and HBG2 promoters using this RNP is also shown to be highly specific with no measurable off-target editing. These cells readily engrafted and reconstituted all blood cell lineages at levels comparable to unedited cells. Production has been scaled up from research to clinical scale in preparation for progressing EDIT-301 towards the clinic.
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Naja Nyffenegger, Anna Flace, Cédric Doucerain, Franz Dürrenberger, Vania Manolova
 
The authors of the abstract conclude: 

Our results clearly show that (i) VIT-2763 does not interfere with iron chelation treatment and (ii) the positive effects of VIT-2763 on erythropoiesis are not affected by iron chelation therapy. Thus, co-administration of the oral ferroportin inhibitor VIT-2763 and the iron chelator DFX is feasible and might offer the advantage of reversing established iron overload and improving erythropoiesis in β-thalassemia.  

References: 1Manolova V, et al. Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia. J Clin Invest. 2019.

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Vania Manolova, Naja Nyffenegger, Anna Flace, et al.
 
The authors of the abstract conclude: 
Iron restriction by the oral ferroportin inhibitor VIT-2763 has the potential to alleviate VO events and thereby improve hemodynamics in the SCD model, presumably by reducing hemolysis and vascular inflammation.