The Future of Gene Therapy for Transfusion-Dependent Beta-Thalassemia: The Power of the Lentiviral Vector for Genetically Modified Hematopoietic Stem Cells

Abstract

β-thalassemia, a disease that results from defects in β-globin synthesis, leads to an imbalance of β- and α-globin chains and an excess of α chains. Defective erythroid maturation, ineffective erythropoiesis, and shortened red blood cell survival are commonly observed in most β-thalassemia patients. In severe cases, blood transfusion is considered as a mainstay therapy; however, regular blood transfusions result in chronic iron overload with life-threatening complications, e.g., endocrine dysfunction, cardiomyopathy, liver disease, and ultimately premature death. Therefore, transplantation of healthy hematopoietic stem cells (HSCs) is considered an alternative treatment. Patients with a compatible human leukocyte antigen (HLA) matched donor can be cured by allogeneic HSC transplantation. However, some recipients faced a high risk of morbidity/mortality due to graft versus host disease or graft failure, while a majority of patients do not have such HLA match-related donors. Currently, the infusion of autologous HSCs modified with a lentiviral vector expressing the β-globin gene into the erythroid progenitors of the patient is a promising approach to completely cure β-thalassemia. Here, we discuss a history of β-thalassemia treatments and limitations, in particular the development of β-globin lentiviral vectors, with emphasis on clinical applications and future perspectives in a new era of medicine.

Benefits and Risks in Polypathology and Polypharmacotherapy Challenges in the Era of the Transition of Thalassaemia from a Fatal to a Chronic or Curable Disease

“…Several other products and gene editing techniques are under investigation and development. Many clinical trials for these agents are ongoing and full assessment of the results is expected in the next few years [178][179][180][188][189][190][191][192][193][194][195].…”

New Entity—Thalassemic Endocrine Disease: Major Beta-Thalassemia and Endocrine Involvement

“…Since the patients with intermediate BTH have different clinical presentations, EDs vary, and a subgroup of subjects was similar to patients with major BTH with regards to the profile of EDs [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Overall, short stature affects both children and adults; GH/IG...…”

“…Moreover, endocrine glands are particularly sensitive to iron deposits, hence the associated panel of hormonal imbalance is massive, representing a major challenge of the already complicated clinical course of the disease. The management strategies of TH include: transfusions, chelation agents against IO, hydroxyurea, splenectomy, stimulation of foetal Hb synthesis, and bone marrow/hematopoietic stem cell transplantation [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 16 , 17 , 18 ].…”

Reducing the transcriptional read‐through rate of a lentiviral vector for β‐thalassemia gene therapy

“…So far, lentiviral vector (LV) mediated gene and cell therapy for treating β-thalassemia has reached around 100 successful cases. 2 The most often used LV is Zynteglo (BB305), generated by Bluebird Bio. 3 The LVs are HIV-1 based with an inverse placed erythroid-specific β-globin expression cassette.…”

“…Of these patients, 60–80% bear severe β ‐thalassemia phenotypes, requiring regular red blood cell transfusion and conventional iron acanthosis treatment. So far, lentiviral vector (LV) mediated gene and cell therapy for treating β ‐thalassemia has reached around 100 successful cases 2 . The most often used LV is Zynteglo (BB305), generated by Bluebird Bio 3 .…”