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Correcting The Huntington’s Disease Mutation

June 29, 2012

(Ivanhoe Newswire) — Using a human induced pluripotent stem cell (iPSC) from a patient suffering from Huntington´s disease, researchers at the Buck Institute for Research on Aging have corrected the genetic mutation that is responsible for the disease.

To accomplish this process, researchers took the diseased iPSCs, made the genetic correction, generated neural stem cells, and then transplanted the mutation-free cells into a mouse model of Huntington´s disease where they are generating normal neurons in the area of the brain affected by the disease.

iPSCs are reverse-engineered from human cells (like skin) back to a state where they can be coaxed into becoming any kind of cell. They can model numerous human diseases and may serve as sources of transplantable cells that can be used in novel cell therapies (where the patient provides a sample of his or her own skin to the laboratory). “We believe the ability to make patient-specific, genetically corrected iPSCs from HD patients is a critical step for the eventual use of these cells in cell replacement therapy,” Buck faculty Lisa Ellerby, PhD, lead author of the study, was quoted as saying. “The genetic correction reversed the signs of disease in these cells — the neural stem cells were no longer susceptible to cell death and the function of their mitochondria was normal.” The corrected cells could populate the area of the mouse brain affected in Huntington´s disease, therefore, the next state of research involves transplantation of the corrected cells to see if the disease-afflicted mice show improved function. These studies are important because we can now deliver patient-specific cells for cell therapy that no longer have the disease-causing mutation.

Huntington’s disease is a neurodegenerative genetic disorder which affects muscle coordination and leads to cognitive decline and psychiatric problems. It is usually noticeable around mid-adult life, with symptoms beginning between 35 and 44 years of age. The life expectancy following onset of visual symptoms is about 20 years. The worldwide prevalence of the disease is 5-10 cases per 100,000 persons. More than a quarter of a million Americans have or are “at risk” of inheriting Huntington´s disease from an affected parent. The formation of specific protein aggregates (mostly abnormal clumps) inside some neurons is essential to the disease process.

Every human has two copies of the Huntingtin gene (HTT), which codes for the protein Huntingtin (Htt). Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change between generations. When the length of this repeated section reaches a certain threshold, it creates an altered form of the protein, called mutant Huntingtin protein (mHtt). The researchers corrected the mutation by replacing the expanded trinucleotide repeat with a normal repeat using homologous recombination (a type of genetic recombination where two molecules of DNA are exchanged). In this case, the diseased DNA sequence is exchanged for the normal DNA sequence.

Source: Cell Stem Cell, June 2012




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