Researchers Correct Huntington's Disease Mutation in Induced Pluripotent Stem Cells

Researchers have corrected the genetic mutation responsible for Huntington’s disease using human induced pluripotent stem (iPS) cells produced from a patient suffering from the neurodegenerative disorder. The diseased iPS cells were genetically corrected and used to generate neural stem cells. These mutation-free cells were then transplanted into a mouse model of Huntington's where they are generating normal neurons in the area of the brain affected by the disease.

“We believe the ability to make patient-specific, genetically corrected iPSCs from Huntington's patients is a critical step for the eventual use of these cells in cell replacement therapy,” said Buck Institute faculty member Lisa Ellerby, PhD. Here, “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.”

Induced Pluripotent Stem Cells are reverse-engineered from human cells such as skin, back to a state where they can be coaxed into becoming any type of cell.  They can be used to model numerous human diseases and may also serve as sources of transplantable cells that can be used in novel cell therapies. In the latter case, the patient provides a sample of his or her own skin to the laboratory.

Ellerby said the corrected cells could populate the area of the mouse brain affected in Huntington's. The next stage of research involves transplantation of corrected cells to see if the Huntington's afflicted mice show improved function.

Huntington's disease is a devastating, neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. It typically becomes noticeable in mid-adult life, with symptoms beginning between 35 and 44 years of age. Life expectancy following onset of visual symptoms is about 20 years. The worldwide prevalence of HD is 5-10 cases per 100,000 persons. More than a quarter of a million Americans have HD or are "at risk" of inheriting the disease from an affected parent. Key to the disease process is the formation of specific protein aggregates (essentially abnormal clumps) inside some neurons.

All humans have 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 produces an altered form of the protein, called mutant Huntingtin protein (mHtt). Scientists in the Ellerby lab corrected the mutation by replacing the expanded trinucleotide repeat with a normal repeat using homologous recombination. Homologous recombination is 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.

Adapted from the Buck Institute announcement.