Gene Therapy
In the absence of an appropriate donor, the addition of a correct copy of a gene into autologous HSC is an appealing strategy. The hematopoietic system displays optimal characteristics for ex vivo gene therapy purposes. Its accessibility, ability to survive in ex vivo cell culture and transplantability are extremely favorable parameters for their use in gene therapy. Over twenty years of research on ex vivo manipulations of this stem cell compartment in association with several years of intense research in virology has enabled rapid advances in this field.
The most common gene therapy approach is to use a functional gene to replace a dysfunctional gene that could be the cause of the disease. The gene is inserted into a target cell via a vector. Currently, ‘domesticated’ or genetically modified viruses are the most common type of vector. Viral vectors infect the target tissue and insert the designated genes into the host cells. If the therapeutic gene is expressed, the cell is able to produce the protein or proteins that it had been missing the genetic disorder. The vector used on SCID gene therapy trails is a retroviral vector, a type of virus that has an RNA genome and reverse-transcribes double stranded DNA that can be integrated into the host genome.
Transduction
The transfer of genetic material into a cell mediated by a viral vector.
ADA-SCID Gene Therapy
Retroviral-based vector system was utilized in one of the first gene therapy clinical trials in United States realized between 1989 and 1990 for the treatment of adenosine deaminase (ADA). A retroviral vector, carrying the functional copy of adenosine deaminase was used for ex vivo gene transduction of autologous bone marrow-derived HSC, which were reinfused back into the patient. Moreover, a long-term clinical benefit was reported in the first patients who participated.
The functions of their immune system were resorted. The expression of the recombinant ADA gene was observed in 20% of lymphocytes of one patient ten years after the treatment. The requirement for a long-term transgene expression is the integration of the shuttle vector within the chromosomal DNA of the target cell. However, integrative gene transfer models have a potentially dangerous downside and they are associated with the risk of insertional mutagenesis.
SCID-X1 Gene Therapy
Spontaneous reversion of the mutation in the γc-encoding IL2RG gen led to significant correction of the immune deficiency. IL2RG is expressed by all hematopoietic cells and is not tightly regulated, this reduce the risk of toxicity related to aberrant expression.
Several clinical trails were performed following in vitro and in vivo preclinical tests in γc-deficient mice, the vectors were based on the use of retroviral (RV) constructs in which the common γc cytokine receptor subunit was placed under the transcriptional control of the long terminal repeat (LTR), with the use of either an amphotropic envelope or the gibbon ape leukemia virus evelope.
Treatment
