Treating hemoglobinopathies using gene-correction approaches: promises and challenges

Abstract

Hemoglobinopathies are genetic disorders caused by aberrant hemoglobin expression or structure changes, resulting in severe mortality and health disparities worldwide. Sickle cell disease (SCD) and β-thalassemia, the most common forms of hemoglobinopathies, are typically treated using transfusions and pharmacological agents. Allogeneic hematopoietic stem cell transplantation is the only curative therapy, but has limited clinical applicability. Although gene therapy approaches have been proposed based on the insertion and forced expression of wild-type or anti-sickling β-globin variants, safety concerns may impede their clinical application. A novel curative approach is nuclease-based gene correction, which involves the application of precision genome editing tools to correct the disease-causing mutation. This review describes the development and potential application of gene therapy and precision genome editing approaches for treating SCD and β-thalassemia. The opportunities and challenges in advancing a curative therapy for hemoglobinopathies are also discussed.

β-Thalassemia

“…73 Other approaches being investigated for gene therapy of the β-hemoglobinopathies include pharmacological or genetic induction of γ-globin production through interference with the BCL11A pathway or disruption of the BCL11A erythroid enhancer by CRISPR/CAS9 technology as well as zinc finger or transcription activator-like effector nuclease, and even using genome editing in attempts at repairing the defective HBB in hematopoietic stem cells. 74…”

Poly(Lactic-co-Glycolic Acid) Nanoparticle Delivery of Peptide Nucleic Acids In Vivo

“…While even more seminal demonstrations of gene correction/modification by PNA/DNAloaded PLGA NPs are described in the next section, it is worth examining some of the important considerations arising from the data summarized above: (1) Even with its associated toxicity, nucleofection remains a transfection protocol of choice in many applications of gene editing, including those involving the nuclease-based reagents that produce higher modification frequencies than those induced by PNA [28]. (2) Consequently, for many applications, the realistic goals are to modify stem cells ex vivo, select for the modified population, and transplant into patients [29,30]. Achieving any/all of these goals will require that treated cells survive long enough and in large enough quantities for additional manipulation post-treatment [29,30].…”

Biomedical applications of gene editing

“…symptomatic in nature. However, gene editing empowers researchers to overcome some of the fundamental challenges inherent to the treatment of cystic fibrosis (Harrison et al 2016), hemoglobinopathies (Cottle et al 2016;Tasan et al 2016), hemophilia (Park et al 2016), and Duchenne muscular dystrophy (DMD) (Robinson-Hamm and Gersbach 2016).…”