A team at the Whitehead Institute has taken a step towards finding a cure for Parkinson’s disease (PD) following an approach similar to but falling short of the approach outlined in my blog post Treating genetic diseases with corrected induced pluripotent stem cells. The report’s headline is Breakthrough produces Parkinson’s patient-specific stem cells free of harmful reprogramming genes. “Deploying a method that removes potentially cancer-causing genes, Whitehead Institute researchers have “reprogrammed” human skin cells from Parkinson’s disease patients into an embryonic-stem-cell-like state. Whitehead scientists then used these so-called induced pluripotent stem (iPS) cells to create dopamine-producing neurons, the cell type that degenerates in Parkinson’s disease patients.”
The main innovation in this work was removal of the genes used for induction of reprogramming from the DNA of the produced iPSCs. The researchers used an approach employed “since August 2006 for reprogramming adult cells into iPS cells by using viruses to transfer four genes (Oct4, Sox2, c-Myc and Klf4) into the cells’ DNA. Although necessary for reprogramming cells, these genes, the known oncogene c-Myc in particular, also have the potential to cause cancer. In addition, the four genes interact with approximately 3000 other genes in the cell, which may change how the cell functions. Therefore, leaving the genes behind in successfully reprogrammed cells may cause unintended alterations that limit the cells’ applicability for therapeutic use, for drug screens or to study disease in cell culture.” In recent months, incidentally, several other approaches to creating iPSCs have been reported that do not require use of these genes, including approaches that do not require insertion of genes at all(ref).
The approach the Whitehead researchers used is a good example of gene editing. “In the current method, Whitehead researchers used viruses to transfer the four reprogramming genes and a gene coding for the enzyme Cre into skin cells from Parkinson’s disease patients. The reprogramming genes were bracketed by short DNA sequences, called loxP, which are recognized by the enzyme Cre. After the skin cells were reprogrammed to iPS cells, the researchers introduced the Cre enzyme into the cells, which removed the DNA between the two loxP sites, thereby deleting the reprogramming genes from the cells. The result is a collection of iPS cells with genomes virtually identical to those of the Parkinson’s disease patients from whom original skin cells came.” Clever!
“After removing the reprogramming genes, the — researchers differentiated the cells from the Parkinson’s disease patients into dopamine-producing nerve cells. In Parkinson’s disease patients, these cells in the brain die or become impaired, causing such classic Parkinson’s symptoms as tremors, slowed movement, and balance problems.”
Those cells might be very useful for testing out various treatments for PD in-vitro but of course retain any genetic defects that may have led to PD in the first place. These cells are therefore questionably suitable for stem-cell replacement therapy. The next step in developing a stem cell therapy for PD would be to strip out faulty genes that lead to PD susceptibility and replace them with healthy ones, as suggested in my post. There has been some progress in identifying genes related to PD susceptibility(ref)(ref), with several genes having been identified that, when mutated, have to do with forms of PD, genes like alpha-synuclein, parkin, DJ1, PINK1, and LRRK2. However, my impression is that not enough is known about these genes yet to allow such gene correction.
This work exemplifies hundreds of studies demonstrating modest steps of progress but aimed ultimately at stem-cell cures for diseases. An earlier blog post Gene therapy for fruit flies with Parkinson’s Disease discusses a different possible therapeutic approach, re-introducing a gene that has been lost on the process of evolution. For an approach that might be more immediately useful for prevention of PD, check out my blog entry Mitochondria and Parkinson’s Disease