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Gene Therapy I


Many human diseases are caused by defective genes.

A few common examples:
DiseaseGenetic defect
hemophilia Aabsence of clotting factor VIII
cystic fibrosisdefective chloride channel protein
muscular dystrophydefective muscle protein (dystrophin)
sickle-cell diseasedefective beta globin
hemophilia Babsence of clotting factor IX
severe combined immunodeficiency (SCID)any one of several genes fail to make a protein essential for T and B cell function

All of these diseases are caused by a defect at a single gene locus. (The inheritance is recessive so both the maternal and paternal copies of the gene must be defective.) Is there any hope of introducing functioning genes into these patients to correct their disorder? Probably.

Other diseases, also have a genetic basis, but it appears that several genes must act in concert to produce the disease phenotype. The prospects of gene therapy in these cases seems far more remote.

Case study: severe combined immunodeficiency (SCID)

SCID is a disease in which the patient has neither

It is a disease of young children because, until recently, the absence of an immune system left them prey to infections that ultimately killed them.

About 25% of the cases of SCID are the result of the child being homozygous for defective genes encoding the enzyme adenosine deaminase (ADA). The normal catabolism of purines is deficient, and this is particularly toxic for T cells and B cells.

Treatment Options:

Gene Therapy: requirements

All these requirements seem to have been met for SCID therapy using a retrovirus as the gene vector. Retroviruses have several advantages for introducing genes into human cells. Packaging cells are treated so they express: Treated with these two genomes, the packaging cell produces a crop of retroviruses with:

Once the virus has infected the target cells, this RNA is reverse transcribed into DNA and inserted into the chromosomal DNA of the host.

External Link
View an animation showing the steps used in retroviral gene therapy at this Molecular Medicine in Action site. Navigate to Other → Viruses as Vectors on the main menu. (You need Flash 6.)
Please let me know by e-mail if you find a broken link in my pages.)

What to use for target cells?

T cells

The first attempts at gene therapy for SCID children (in 1990), used their own T cells (produced following ADA-PEG therapy) as the target cells.

The T cells were: The children developed improved immune function but:

Stem cells

In 1993, ADA gene therapy was attempted with blood ("hematopoietic") stem cells drained from the umbilical cords of three newborn babies who were known to be homozygous for ADA deficiency.

Blood stem cells:
Discussion of blood stem cells

At last report, some of the circulating T cells in these children carried the ADA gene. But because the children continue to receive ADA-PEG, it is unclear how much gene therapy has contributed to their good health.

However, in June of 2002, a team of Italian and Israeli doctors reported on two young SCID patients that were treated with their own blood stem cells that had been transformed in vitro with the ADA gene. After a year, both children had fully-functioning immune systems (T, B, and NK cells) and were able to live normal lives without any need for treatment with ADA-PEG or immune globulin (IG). The doctors attribute their success to first destroying some of the bone marrow cells of their patients to "make room" for the transformed cells.

Gene Therapy for X-linked SCID

Gene therapy has also succeeded for 15 French baby boys who suffered from another form of severe combined immunodeficiency, called X-linked SCID, because it is caused by a mutated X-linked gene encoding a subunit — called γc (gamma-c) — of the receptor for several interleukins, including interleukin-7 (IL-7).

IL-7 is essential for converting blood stem cells into the progenitors of T cells. [View]. Boys with X-linked SCID can make normal B cells, but because B cells need T-helper cells to function, these boys could make neither cell-mediated nor antibody-mediated immune responses and had to live in a sterile bubble before their treatment.

The French doctors The results: Now after as long as four years, 14 of these boys
* Three of the little boys have developed cancer (one has died):
Link to discussions of other approaches to gene therapy that are being tried.
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20 September 2005