BLOCKING of genes should take place in all cells to avoid unintended effects on the behaviour of normal cells; a finding that should be considered when developing gene therapies. This is according to researchers from Uppsala University, Uppsala, Sweden, who studied the effects of removing the Vegfr3 gene on lymphatic vessel development in mice.
To understand the role of Vegfr3 in lymphatic vessels, the team deleted this gene, which encodes the receptor for a lymphatic growth factor, in cells lining lymphatic vessels in genetically modified mice. When removed early on in development, the vessel tip cells did not function normally, and the lymphatic vessels did not develop properly. This proved that Vegfr3 plays an essential role in the development of lymphatic vessels at this early stage.
Abnormal Cell Behaviour
The team then observed what happened when the gene was removed at later stages of development. Surprisingly, this caused the lymphatic vessels to grow excessively; this was because Vegfr3 was only deleted in some cells, which then caused neighbouring cells that did have the gene to act abnormally.
Effect on Gene Therapy
The study demonstrated that unanticipated mechanisms can occur if a signalling pathway is blocked in some but not all cells, with gene-deleted cells able to alter the behaviour of normal cells. The researchers believe this finding should be used to help inform the development of gene therapy.
“In gene therapy the aim is to block or replace a disease-causing gene by transferring a new gene. A major problem with such therapeutic approaches is an incomplete delivery of the new gene to the target cells, resulting in a mix of cells that have or lack the new gene. We have shown that in such situations it is important to understand if the cells influence each other in an unwanted way. This will be an important consideration for future studies,” commented Dr Taija Mäkinen, Uppsala University.
The study could therefore aid the development of gene therapy, a technique that is hoped will be used for the treatment of a number of diseases in the future.
James Coker, Reporter
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