Sickle cell disease is a monogenic disorder that occurs due to point mutation at position 6 of Beta globin chain of hemoglobin molecule in which valine is being substitute for glutamic acid. Homozygous individuals suffer severe crisis when subjected under low oxygen tension which is usually fatal.
Studies have shown that sickle cell disease is successfully treated in mice via gene therapy. The mice-which have essentially the same defect that causes sickle cell disease in humans-through the use of a viral vector well made, to express the production of fetal hemoglobin (Hbf), which normally ceases to be produced by an individual shortly after birth. In humans, the use of hydroxyurea to stimulate the production of Hbf has long been shown to temporarily alleviate the symptoms of sickle cell disease. The researchers demonstrated this method of gene therapy to be more permanent means to increase the production of the therapeutic Hbf,thus a good intervention for adult sicklers.
Other uses of Gene therapy includes;
Use of gene therapy in chronic granulomatous disease and SICKLE CELL
Chronic granulomatous disease (Bridges-Good or Quie syndrome) is a diverse group of hereditary disease in which certain cells of the immune system have difficulty forming the reactive oxygen compounds (mostly superoxide radical used to kill certain ingested pathogens this leads to the formation of granulomata in many organs. This disorder can be treated by using a vector based on the spleen forming virus (Sffv) since its enhancer-promoter combination is particularly active in myeloid cells.
Early clinical trail in patient with chronic granulomatous disease (CGD) resulted in prolonged production of gene-corrected granulocyte but the numbers were inadequate to correct the disease phenotype (Maluh et al., 1997). However, recently 2 young adult patients with this disorder who received genetically modified cells after partial myelobalation had clearance of severe infection and clinical improvement associated with engraftment of genetically corrected repopulating cells (Chinen et al, 2007).
Initially, approximately 15%-20% of the granulocytes in these two patients were genetically corrected. Molecular analysis demonstrated that this increased in the number of genetically corrected cells reflected clonal dominance engendered by insertional activation of one or more of the proto-oncogenes, MDSI-EVIL, PRDM16 or SETBPI (Ott et al., 2006).
Suicide gene therapy for graft versus-host disease
Graft versus host disease (GVHD) is a condition that arises due to differences in the histocompatibility complex of the donor and recipient thereby resulting in immunological rejection of donated cell or organ, with subsequent infections and inflammation that follows.
Successful application of gene therapy has been developed to avert the effects of GVHD disease by transferring a suicide gene into the dower lymphocytes for the purposes of controlling allo-reactivity in the context of allogenic hematopoietic stem cell transplantation.
Mechanisms:- This basis concept is to insert a gene that renders the target susceptible to drug-induced cell death. This approach, pioneered by Claudio Bordignon in Milan and recently reviewed by his group (Bonin et al., 2007) represents the widest clinical application of T-cell targeted gene therapy to date.
This approach seeks to preserve the graft-versus infection and graft versus-leukaemia potential of donor lymphocytes while providing a safety value for abrogating graft-versus host disease (GVHD), if it occurs and proves clinically problematic.
The GVHD was abrogated by transducing Herpes sim plex virus carrying thymidine kinase gene which conveys sensitivity to Ganciclovir if GVHD occur during transplantation of the haematopoietic stem cell, administration of the pro-drugs results in ablation of allo-reactive lymphocytes and control of the diseases. In the absence of the transduced gene, the pro-drug (Ganciclovir) will not be converted to its active form and there will be a severe effect of GVHD.
Use of Gene therapy in treatment of Parkinson’s diseases
Parkinson’s disease is a degenerative disorder of the central nervous system that results from the death of dopamine generating cells in the substantial nigra region of the mid brain.
The cause of this cell death is unknown.
A university of California, Los Angeles research team in 2003, inserted genes into the brain using liposomes coated in a polymer called polyethylene glycol. The transfer of genes into the brain is a significant achievement because viral vectors are too big to get across the blood brain barrier. This method has potential for treating Parkinson’s disease.
- Use of gene therapy in treatment of Huntington’s disease
Huntington’s disease is a hereditary disease caused by a defect in a single gene that is inherited as an autosomal dominant characterized by unsteady gait and jerky in voluntary movement accompanied later by behavioural changes and progressive dementia .RNA interference or gene silencing may be a new way to treat Huntington’s disease.
In this approach, short pieces of double-stranded RNAs (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copies from a faculty gene, then the abnormal protein product of that gene will not be produced .
- Use of gene therapy in metastic melanoma
Scientists at the National Institutes of Health (Bethesda, Maryland) have successfully treated metastic melanoma in two patients using killer T-cells genetically retargeted to attack the cancer cells. This study constitutes one of the first demonstrations that gene therapy can be effective in treating cancer (Morgan et al., 2006).
- Treatment of Leber’s congenital amaurosis
This is an inherited blinding disease caused by mutations in the RPE65 gene. Studies carried out by a group of researchers at Moorefields Eye Hospital and University college London’s Institute of Ophthalmology announced the worlds first gene therapy trial for inherited retinal disease.
They researched the safety of the subretinal delivery of recombinant adeno-associated virus (AAV) carrying RPE65 gene, and found it yielded positive results, with patients having modest increase in vision effects (Maguire et al., 2008). The first operation was carried out on a 23 years-old British male, Robert Johnson in early 2007 as stated by BBC news on May 1 2007 (en.Wikipedia.com).
- Cure of Beta-Thalassaemia
Beta thalassaemia can be cured via gene therapy by using a lentiviral vector to transduce the human β-globin gene into purified blood and marrow cells obtained from the patient. This was first carried out by a team of researchers headed by Dr. Phillipe Lebouiche on a patient in France. Between 21 and 33 months after the transplant, the percentage of vector bearing cells in his blood gradually increased, and today, the 18 years old patient is transfusion independent (ever since June 2008) (Jacquelyn, 2010). His hemoglobin levels are presently stable at 9-10g/dl and about a third of the hemoglobin contains the form introduced by the viral vector. The clinical trial is, therefore, being heralded as a success around the world.
Use of Gene therapy trials have also proved successful on thalassaemia major patients, lipoprotein lipase deficiency etc.
In conclusion, gene therapy in near future is believe to put an end to most of the genetic and acquired disorder that threatens human race.