"Correction of Albinism Mutations By Targeted Genomic Rearrangements"
Exciting Update! Read more:
Dr._Brilliant_Research_Update_Jan_2009.pdf (31 KB)
Dr. Brilliant Research Update February 2007
Principal Investigator: Murray H. Brilliant, Ph.D.
Lindholm Professor of Mammalian Genetics Department of Pediatrics, College of Medicine Department of Molecular and Cellular Biology University of Arizona.
Abstract:
Background: Albinism is a genetically heterogeneous disorder associated with several distinct genes. All forms of albinism are defined by hypopigmentation of the retina leading to nystagmus, strabismus, foveal hypoplasia, abnormal crossing of the optic fibers, photophobia and reduced visual acuity. It may be possible to alleviate some of the visual problems associated with albinism by restoring the ability to make pigment in the eye through gene therapy. This has been accomplished in animal models of albinism by the introduction of a functional gene into retinal cells. However, sometimes the newly introduced gene inserts into the chromosomes in such a way that other genes are disrupted leading to other problems, including tumors (insertional mutagenesis).
Aim: To develop a strategy that avoids this complication. Our strategy is to get the cells to "correct" the mutations that lead to albinism. Most genetic disorders (including all but one form of albinism) are recessive. This means that affected individuals inherit a mutation in the same gene from both their mothers and fathers. Typically these mutations are in different parts of the same gene. Our strategy is to get the cells to "switch" DNA strands between the two mutations, resulting in one strand with both mutations and one with no mutations. The resulting cell is then as functional as a cell from a carrier individual (e.g., the parents of the affected child).
Method: (1)To engineer novel enzymes capable of cutting DNA at a very specific places (i.e., between the two mutation sites). (2) Introduce this endonuclease into retinal cells of albino mice to test the efficacy of treatment by looking for pigment production.
Expected Results: In this process the DNA strands often switch, potentially restoring normal gene function of one of the gene copies in the recipient cell leading to an ability to produce pigment. This trait would be present for its entire lifetime and in all of its descendants. Thus, we avoid the problems of insertional mutagenesis and gene expression variation that is seen in other gene therapy approaches.