Haematopoietic stem cell transplantation to treat hereditary blood cell disorders :
The first class of ailments to be successfully treated using gene therapy were inherited blood cell abnormalities. 1)Hemoglobinopathies, which affect red blood cells (sickle cell disease, thalassemia).
2) Inborn errors of immunity (IEI), which affect neutrophils, macrophages, or lymphocytes.
3) Lysosomal storage diseases and some leukodystrophies, which affect tissue resident macrophages and brain microglial cells.
4) conditions that result in impaired HSC function and genome stability (Fanconi Anemia) are examples of monogenic diseases that affect blood cell production or function.
Transplanting normal hematopoietic stem cells (HSC) from a suitable match healthy (allogeneic) donor that can engraft and create normal blood cells can cure many hereditary blood cell illnesses. After being pumped into the patient's bloodstream, the donor HSC settle in the bone marrow, where they create the missing blood cells that the body needs for the rest of their lives. Finding a donor who is a good match is essential for performing stem cell transplantation for blood cell disorders because it reduces the possibility of unfavorable immune responses between the recipient's and donor's immune cells, such as graft rejection or graft versus host disease. Due to advancements in tissue typing techniques over the past few decades, the results of HSC transplants have steadily improved.
Haematopoietic stem cell gene therapy (HSCGT)
For inherited blood disorders, hematopoietic stem cell gene therapy (HSCGT) uses the patient's own (autologous) HSC that have been gene corrected. This can be done in one of two ways: either by introducing a normal copy of the inherited defective gene using an integrating vector, or—more recently—by editing the defective gene to restore its function. Relatively high levels of engraftment of gene-corrected HSC can be obtained (25->90%) because HSC can be extracted from the body by bone marrow harvest or blood stem cell collection, gene changed ex vivo, and then reintroduced into the patient by intravenous infusion.
Successes
Using gene therapy to treat severe combined immune deficiency (SCID) was the first clinical success. The most severe kind of IEI in humans is called SCID. It is characterized by the loss of T and B lymphocyte activity, which leaves the child vulnerable to infections that can be fatal if treatment is not received. Allogeneic HSC transplantation is the first curative treatment for this genetic blood cell disorder, and bone marrow transplants from matched siblings are quite successful in regaining immunity . However, most SCID patients are treated with transplants from alternate donors, such as haplo-identical parents or well-matched unrelated donors, as they do not have a matched sibling donor. Compared to sibling donors, survival with prolonged immunity following these kinds of transplantation has been lower, but results are constantly increasing However, autologous gene therapy might offer a secure and efficient course of treatment.
Murine gamma-retrovirus vectors were used to successfully transfer the genes for ADA SCID (ADA) and XSCID (IL2RG) into patients' bone marrow HSC, resulting in clinically favorable immune reconstitution and good health . Nevertheless, six out of twenty XSCID patients experienced a significant leukemia-induced consequence two or more years following gene therapy , and one ADA SCID patient experienced this complication more recently.
Due to lentiviral vectors' increased efficacy in transducing human hematopoietic cells and less genotoxicity when compared to gamma-retroviral vectors, the field has switched towards their utilization. Indeed, the latest clinical outcomes utilizing lentiviral vectors for gene therapy for XSCID, ADA SCID, and Artemis SCID (DCLRE1C) have been outstanding.
The majority of sickle cell gene therapy strategies are founded on the clinical finding that elevated fetal hemoglobin expression reduces sickle cell disease severity. This is because elevated fetal hemoglobin slows down the rate at which deoxyhemoglobin S aggregates . The particular amino acid Q87 in the γ-globin chain of fetal hemoglobin is what prevents HbS from aggregating. Clinical benefits have been demonstrated with lentivirus vectors expressing "anti-sickling genes" (γ-globin transgene or β-globin substituted with the Q87 amino acid from γ-globin) that prevent sickle hemoglobin from aggregating. These vectors significantly reduce acute complications associated with sickle cell disease . Other methods reduced the mRNA for the γ-globin repressor by using a short hairpin RNA.
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