3. Gene Therapy

Gene Therapy

This PatientPlus article is written for healthcare professionals so the language may be more technical than the condition leaflets. You may find the abbreviations list helpful.

In the 1990s there was great hope that this novel approach may provide an answer to many hitherto incurable diseases. The basic idea is to correct defective genes responsible for disease development. This can be achieved in a number of ways:

  • Homologous recombination can be used to swap a defective gene for a normal, functioning one.
  • By altering the regulation of the gene, to effect its function.
  • By using selective reverse mutation to repair a defective gene.
  • However, the most common method is to insert a normal gene into a nonspecific location to replace a defective gene.

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When a normal gene is inserted into the genome, a carrier molecule (a vector) is used. This will deliver the new gene to the target cells. The most commonly used vectors are viruses. The most commonly used viruses are:

  • Retroviruses
  • Adenoviruses
  • Adeno-associated viruses
  • Herpes simplex viruses

These viruses are altered to carry normal human DNA. The patient's target cells are infected with the vector, which deposits its genetic load including the gene to be replaced . The target cell is then able to produce a functioning protein. More recently, success has been seen by combining a tumour-specific adenovirus vector and several single therapy genes. Targeting gene-virotherapy has killed tumour cells with minimal damage to normal cells in mice.[1][2] There are also nonviral insertion options. The simplest method is direct introduction of new DNA into the target tissues. This is limited by the type of tissue and the amount of DNA required. An artificial lipid sphere with an aqueous core is created - a liposome - which can both carry the therapeutic DNA and pass it through the target cells membrane. The therapeutic DNA can also bind chemically to molecules that will attach to target cell receptor sites. These are then taken into the cell's interior. This tends to be less effective than the other methods.

Human gene therapy is still largely in the experimental phase. There have been few big breakthroughs since the first trial started in 1990. There has also been at least one death attributed to therapy and two cases of leukaemia developing post-therapy. There are also technical problems involved:

  • Problems with viral vectors, such as toxicity, inflammatory and immune responses.
  • Disorders resulting from multiple gene defects, such as heart disease, Alzheimer's disease and diabetes are not good candidates for gene therapy. Single gene defects are the most responsive to therapy.
  • Gene therapy tends to be of short duration. The functioning DNA that is introduced must remain functioning and stable to effect a cure. Many cells divide quite rapidly, so multiple treatments are required.
  • The immune response to any foreign material may reduce the effectiveness of the treatment. It also makes multiple treatments unfeasible.
  • A team from Moorfields Eye Hospital and University College in London have conducted the first human gene therapy trials to treat Leber's congenital amaurosis, which is caused by a single abnormal gene (the procedure has already been successful at restoring vision for dogs). This is the first trial to use gene therapy in an operation to treat blindness in humans.[3]
  • A combination of two tumour-suppressing genes delivered in lipid-based nanoparticles has reduced the number and size of human lung cancer tumours in mice during trials conducted by researchers from The University of Texas.[4]
  • The National Cancer Institute (NCI), has successfully re-engineered lymphocytes, to target and attack cancer cells in patients with advanced metastatic melanoma.[5] This is the first time that gene therapy has been used successfully to treat cancer in humans.

In a bid to alleviate disease at the earliest possible stage, in utero fetal gene therapy has also been tried.[6] Prenatal screening for severe genetic disease such as Crigler-Najjar syndrome, Pompe's disease and haemophilia B has been tested in mouse models. There have been issues with the development of liver tumours, insufficient target cells are reached and the therapy is not toxic enough to target cells. There are attempts underway to manufacture antitumour vaccines.In this technique Epstein-Barr virus vectors mediate gene transfer into human B lymphocytes.[7] Other areas of research include:

A recent trial, approved by the American Food and Drug Administration, is for the treatment of Parkinson's disease. This is a phase 1 clinical trial with 11 patients already enrolled. They are aiming to produce the neuroprotective and restorative subthalamic glutamic decarboxylase. There have been no adverse events reported to date.[13]

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Further reading & references

  1. Liu XY, Gu JF, Shi WF; Targeting gene-virotherapy for cancer. Acta Biochim Biophys Sin (Shanghai). 2005 Sep;37(9):581-7.
  2. Liu XY, Gu JF; Targeting gene-virotherapy of cancer. Cell Res. 2006 Jan;16(1):25-30.
  3. Reuters. News article; May 2007
  4. University of Texas M. D. Anderson Cancer Center. Dual Gene Therapy Suppresses Lung Cancer in Preclinical Test
  5. National Cancer Institute. New Method of Gene Therapy Alters Immune Cells for Treatment of Advanced Melanoma; Technique May Also Apply to Other Common Cancers; August 2006
  6. Coutelle C, Themis M, Waddington SN, et al; Gene therapy progress and prospects: fetal gene therapy--first proofs of concept--some adverse effects.; Gene Ther. 2005 Nov;12(22):1601-7.
  7. Hellebrand E, Mautner J, Reisbach G, et al; Epstein-Barr virus vector-mediated gene transfer into human B cells: potential for antitumor vaccination. Gene Ther. 2006 Jan;13(2):150-62.
  8. Tarner IH, Neumann E, Gay S, et al; Developing the concept of adoptive cellular gene therapy of rheumatoid arthritis. Autoimmun Rev. 2006 Feb;5(2):148-52. Epub 2005 Oct 3.
  9. Cucchiarini M, Madry H; Gene therapy for cartilage defects. J Gene Med. 2005 Dec;7(12):1495-509.
  10. Kabay B, Aytekin FO, Aydin C, et al; Interleukin-10 gene therapy attenuates pulmonary tissue injury caused by mesenteric ischemia-reperfusion in a mouse model. Tohoku J Exp Med. 2005 Oct;207(2):133-42.
  11. Jeong JH, Lee M, Kim WJ, et al; Anti-GAD antibody targeted non-viral gene delivery to islet beta cells. J Control Release. 2005 Oct 20;107(3):562-70.
  12. Shen F, Wen L, Yang X, et al; The potential application of gene therapy in the treatment of traumatic brain injury. Neurosurg Rev. 2007 Aug 9;.
  13. Wu SS, Frucht SJ; Treatment of Parkinson's disease : what's on the horizon? CNS Drugs. 2005;19(9):723-43.
Original Author: Dr Hayley Willacy Current Version:
Last Checked: 22/03/2010 Document ID: 2185  Version: 21 © EMIS

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

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