Huntington’s Disease Mutation Corrected in Induced Pluripotent Stem Cells

Induced pluripotent stem cells (iPSCs)are made from adult cells by means of genetic engineering techniques that introduce transcription factors into the cells that drive the cell into an embryonic state that divides readily and can differentiate into a wide variety of cell adult cell types.

iPSCs are terrific tools for studying human genetic diseases, since iPSCs that bear the genetic mutations that cause the disease can be easily made from patients, those diseases can be studied in great detail. In a recent paper, scientists from the Ellerby lab at the Buck Institute of Aging (San Francisco, CA) used iPSCs made from a patient with Huntington’s disease to correct the genetic mutation that causes Huntington’s disease.

Lisa Ellerby, in whose lab this work was done, commented on her research in this way: “We believe that 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. 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 were potentially able to populate the regions of the brains of mice afflicted with Huntington’s disease, but there are no clear signs to date that transplantation of such cells would improve the function of the mouse. Therefore, the next step in this research is to transplant the corrected cells into the brains of HD-afflicted mice to determine if the mice show functional improvements.

Ellerby’s lab used a technique called homologous recombination to correct the mutation in the iPSCs derived from the skin of a patient with Huntington’s disease. Because Huntington’s disease consists of expansions of a triplet sequence (CAG), recombination replaces the expanded regions of the Htt gene that have excessive numbers of CAG repeats with those that have normal numbers of CAG repeats.

Ellerby’s groups will transplant neural stem cells made from the corrected iPSCs into the brains of mice that have Huntington’s Disease. The results should be rather telling.