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"I’ve been working with iTL over the past 5 years in the production of 3 different genetically altered mice. Not only did iTL help in the design of the mice, […]” - Raghu Mirmira, MD, PhD University of Chicago.
Our understanding of human health and disease has been advanced immeasurably by research using knockout mouse models. In the thirty years since targeted gene knockouts were first demonstrated, thousands of these models have been created. For many human genetic diseases a specific gene is found to be associated with the disease but its role isn’t well understood until mouse models are available to study. This has been the case for researchers studying different forms of muscular dystrophy, a large family of conditions characterized by muscle degeneration. Depending on the specific mutation affecting a patient the progress of this condition can be dramatically different, for example the muscles of the heart may or may not be affected.
By making a knockout mouse model for a specific gene researchers can work to understand how it fits into the network of genes that are required for maintaining healthy muscles. The knockout mouse is often the first tool for studying a new gene, and can later be used in conjunction with other kinds of mouse models that affect the same gene. All such studies are conducted with the hope that understanding a condition will lead to treatments or cures for affected patients. Naturally occurring knockout mice have also been valuable for research, particularly in the years before targeted knockout became widely available. Occasionally the normal low level of genetic mutations that occurs in all organisms will result in a mouse with a visible phenotype. In 1976 an affected mouse was observed at the Jackson Laboratory to have a specific pattern of muscle loss and twitching. Within a few years it was confirmed that these mice had a mutation in the GALC gene which encodes an enzyme called galactosylceramide β-galactosidase. It was already known that reduced levels of this enzyme caused Krabbe disease, which was identified as a heritable condition in 1916. Although a great deal of work had been done identifying the affected gene in human patients it was tremendously difficult to pursue research into possible treatments. A knockout mouse model opened up possible avenues of research that could be applied to Krabbe disease as well as other inherited conditions.
Knockout mouse models are used across all areas of human genetic disease research. In addition to genetic conditions such as muscular dystrophy or Krabbe disease, knockout mice can be models for diseases such as cancer, heart disease, or infectious disease. For studying these conditions a mouse with a specific gene knockout may be a better model than a wild-type mouse. The knockout mouse can be used to gain understanding of the disease and serve as a test case for potential treatments that may one day be used on human patients.
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