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Gene Therapy for Leukemia
Gene therapy is a new technique being developed with the potential to treat a variety of diseases, from genetic disorders, to infections, to cancer. Gene therapy involves inserting a new gene into a cell, either to replace a defective gene or to change a specific function of a cell. Genes are most often inserted using a virus as a vector that can deliver DNA into the cell. While gene therapy offers exciting potential treatments, it has so far not been shown to be effective or safe. Many trials of gene therapy have shown the therapy to be only marginally effective, or to actually be dangerous to the patient. For example, some children that received gene therapy to treat severe compromised immunodeficiency syndrome (SCIDS), developed leukemia as a result of the therapy.

The viral vectors used to insert genes into the cells are one major cause of the problems associated with gene therapy. Firstly, a virus, being a foreign invader, is seen by the immune system as something that needs to be attacked. This can either over-stimulate the immune system, which can inadvertently damage host cells. Secondly, the gene may not be properly inserted into the cells 100% of the time. This could cause mutations, which could subsequently cause a normal cell to develop into a cancerous cell.

Acute B cell lymphoblastic leukemia is a cancer that is typically found in children, but can also be seen in adults as an aggressive, difficult to treat cancer. Even if the cancer is successfully treated and the adult patient enters remission, acute B cell lymphoblastic leukemia has a high rate of relapse. When this occurs, the relapsed cancer is normally resistant to the chemotherapeutic drugs used previously, making the cancer more difficult to treat, and the prognosis is very bad. Recently, researchers treated 5 patients with relapsed, chemotherapy-resistant acute B cell lymphoblastic leukemia with gene therapy. In this therapy, genes were inserted into the patients’ T cells, a type of white blood cell that fights infection and cancer. The inserted genes helped the T cells more efficiently target and kill the cancerous cells. The T cells were engineered to target and attack a protein called CD19, which is found on the surface of the cancerous B cells. In addition, the T cells also received costimulatory molecules to allow them to be more easily activated in the host. The T cells were then injected back into the patients.

The gene therapy was mostly well tolerated in the patients. High levels of cytokines, proteins produced by T cells to fight infections that can be dangerous to the host in very high quantities, were found in the patients. However, this effect was short lived and easily treated with steroids, and did not stop the therapy. Researchers noted rapid decreases in tumor volume, and by the end of the treatment, the patients had no detectable cancer. After receiving the gene therapy and removing most of the cancer cells, the patients were eligible for bone marrow transplants to help completely cure the cancer. All of the patients had remission of the cancer after receiving the gene therapy. Four of the 5 patients received follow up bone marrow transplants, and three have been free of cancer for up to 24 months.

The fifth patient had a relapse of acute B cell lymphoblastic leukemia, which the researchers attributed to a lack of CD19-specific T cells. This result suggested multiple treatments with the engineered T cells could be more beneficial than single treatments. This is not an uncommon occurrence with gene therapy. Techniques to insert genes permanently into cells have not been well developed yet. In addition, cells that receive the gene may not propagate well in the host, which would require multiple treatments to maintain therapeutic efficacy. Unfortunately, repeated rounds of gene therapy are not always effective. Because the new gene is introduced using a virus, an immune response may be developed against the virus. This means that when the virus is introduced into the host again, it may be rapidly attacked and destroyed by the immune system.

While the concept of gene therapy offers hope for many, and clinical studies have given promising results, it is clear that science still has a long way to go until safe, effective gene therapy is readily available. However, data obtained from the trial described above prove that we are heading in the right direction.

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Gene therapy and leukemia

As the previous articles explains, part of the problem with generally applying gene therapy in leukemia and other cancers lies with the viral vectors used in gene delivery. Therefore, a lot of research focuses on alternative gene delivery systems which may be more efficient and safer. A lot of attention has recently been paid to the potential of nanoparticles in gene therapy. Leukemia is one of the diseases for which these particles are under consideration.
Just as with viral delivery systems, use of nanoparticles is not without its problems in leukemic cells.

Genetically engineered monocytes loaded with magnetic nanoparticles can be delivered to tumour sites using magnetic fields, however the spherical shape of the nanoparticles reduces their efficacy as delivery systems. It has been shown, however, by use of the reporter dye fluorescein isothiocyanate (FITC), that magnetic carbon nanotubes are efficiently taken up by the human monocytic leukemia cell line THP-1 with no ill effect on cell viability.

Plasmonic nanobubbles (PNBs) are another innovation with potential for transgene delivery and transfection of leukemia cells. PNBs are are formed as a vapour nanobubble around a transiently heated gold nanoparticle upon exposure to a laser pulse. They have allowed mechanical injection of extracellular cDNA plasmids into the cytoplasm of target living cells, including cultured leukemia cells, detectable by the expression of a green fluorescent protein (GFP). PNB generation and lifetime correlated with the green fluorescent protein expression. Optical scattering facilitated cDNA injection at a single cell level. The PNBs have been shown to be selective, efficient and safe and have great potential as gene delivery systems.

Another nanocarrier, carbonate apatite, can lead to highly efficient delivery and release of DNA and transgene expression in some cells but has poor efficiency in human lymphocytes. However, manipulation of the carbonate apatite by electrostatic association of crystals with fibronectin and/or E-cadherin-Fc enhanced transgene delivery to a human T leukemia cell line. Disruption of actin filaments by cell adhesive protein-embedded particles enhanced transgene expression efficiency even further.


GUL-ULUDAG, H. et al., 2012. Efficient and rapid uptake of magnetic carbon nanotubes into human monocytic cells: implications for cell-based cancer gene therapy. Biotechnology Letters, 34(5), pp. 989-993

KUTSUZAWA, K. et al., 2009. Disrupting actin filaments promotes efficient transfection of a leukemia cell line using cell adhesive protein-embedded carbonate apatite particles. Analytical Biochemistry, 388(1), pp. 164-166

LUKIANOVA-HLEB, E. et al., 2011. Selective gene transfection of individual cells in vitro with plasmonic nanobubbles. Journal Of Controlled Release: Official Journal Of The Controlled Release Society, 152(2), pp. 286-293
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Many patients are successfully treated with chemotherapy or bone marrow or stem cell transplants, but transplants are risky and donors can’t always be found. So far, gene therapy has been tried on people who were in danger of dying because other treatments failed.
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