Gene Therapy Prospects Improve With More Efficient Gene Targeting

Main Category: Genetics
Article Date: 20 Mar 2008 - 1:00 PDT

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The Nobel prize-winning MRC scientist Sir Aaron Klug and a team from an American company, Sangamo BioSciences, have announced a new way to target genes that may revolutionise medical research and pave the way for new treatments. Their findings are published in PNAS.

The scientists have developed a more efficient way to target genes using synthetic proteins. Many biological processes are determined by switching genes on or off. Genes give instructions for making the proteins involved in these processes. This regulation of gene expression is controlled by regulatory proteins called transcription factors.

Sir Aaron Klug, of the Medical Research Council's Laboratory of Molecular Biology in Cambridge, devised these synthetic transcription factors called zinc-finger nucleases based on a naturally occuring design. These zinc-fingered nucleases have the capacity to recognise specific sequences of DNA which makes them extremely good at targeting particular genes without affecting others.

Sir Aaron explains: "The beauty of zinc-finger nucleases lies in their simplicity. Where other methods are long, arduous and often messy, it is relatively easy to switch off genes using this method. The zinc-finger design allows us to target a single gene, while the nuclease disrupts the gene. The single step process is extremely quick and reliable and opens up exciting possibilities for research and gene therapy."

These findings confirm that this method of gene targeting will present an efficient option for scientists to create "knock-out" animals for research. Animal trials are already under way to use the technique to knock out the receptor of HIV in T-cells of AIDS patients, so leading to a supply of non-infectable T-cells, which will combat HIV and the other infections which occur in AIDS patients. Clinical trials are also in progress for stimulating the growth of new arteries in patients suffering from obstruction of the blood vessels in the limbs.

This is a powerful technology for intervening in gene expression in health or disease and therapeutic applications are planned for other diseases by Sangamo BioSciences.

1. Klug, A & Collingwood, TN (2008) Targeted gene knockout in mammalian cells using engineered zinc-finger nucleases. PNAS. March 17-21.

2. Zinc fingers are small DNA binding peptide motifs discovered by Sir Aaron Klug at the MRC Laboratory of Molecular Biology. A spin-off company, Gendaq, which was formed by the MRC in 1999, was acquired in 2005 by a US Company, Sangamo Biosciences Inc, together with licences to the MRC patents. They have begun clincial trials for various human conditions or diseases, including peripheral obstructive arterial disease, diabetic neuropathy; and gene correction in monogenic disease has now been developed.

3. Sangamo BioSciences, Inc. is focused on the research and development of novel DNA-binding proteins for therapeutic gene regulation and modification. The most advanced ZFP Therapeutic(TM) development program is currently in Phase 2 clinical trials for evaluation of safety and clinical effect in patients with diabetic neuropathy. Phase 1 clinical trials are ongoing to evaluate a ZFP Therapeutic for peripheral artery disease. Other therapeutic development programs are focused on stem cell mobilization, ALS, cancer, HIV/AIDS, neuropathic pain, nerve regeneration, Parkinson's disease and monogenic diseases. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TF(TM)) that can control gene expression and, consequently, cell function. For more information about Sangamo, visit the company's web site at http://www.sangamo.com.

Medical Research Council http://www.mrc.ac.uk