Using stem cells to treat Parkinson's

We all start out as the ultimate stem cell; a fertilised egg generated you with all 200 different cell types that make up the human body. This is the definition of what a stem cell is; it has the potential to develop (or differentiate) into different types of cell. The body normally uses stem cells as a special reserve of cells to replenish any differentiated cells that are naturally lost (e.g. replacing blood cells).

Stem cells are directed towards a specific cell type by chemical messengers that give the go ahead for the stem cell to transform its blank canvas into, for example, a nerve cell.

To do this, a stem cell first of all switches off genes that make it a stem cell and activates other sets of genes within itself (e.g. nerve cell genes). Since genes produce proteins, this changes the proteins in the cell (i.e. stem cell proteins are replaced by nerve cell proteins). These new proteins set to work changing the structure and function of the cell so it becomes a specific cell type (e.g. nerve cell).

As the nerve cell is emerging one of the genes that is switched on may contain a Parkinson's related mutation and will therefore produce a faulty protein. This faulty protein will lower the efficiency of the cell either by over activating or inhibiting a specific function. Cells are dynamic entities so will try to compensate and adapt to this inefficiency; they are remarkably successful at this since it typically takes 60 years for Parkinson's to emerge. However, as cells age they accumulate additional wear and tear; this natural slowing down within the context of the Parkinson's mutation will be too much and will trigger the cell to die. As more cells die, less dopamine will be produced and more Parkinson's symptoms will emerge.

This is when science strides into the picture and tries to find ways to restore dopamine levels; there are at least three ways we can do this; stop cells from dying, replace the cells that are lost or replace the dopamine. Science has been moderately successful in replacing dopamine by giving it in tablet form. However, this does nothing to address the underlying cause of Parkinson’s; the loss of nerve cells. Current research is looking towards replacing the A9 substantia nigra nerve cells lost in Parkinson's with equivalent cells grown in the lab from stem cells.

In the future the procedure will probably be something like this: skin cells will be taken from sufferers and these cells will be transformed back into stem cells (called induced pluripotent stem cells) and then driven towards a specific nerve cell type. A9 nerve cells will be selected and the Parkinson's mutations will be corrected by replacing the mutant DNA with normal DNA.

These corrected, induced A9 nerve cells will be transplanted into the substantia nigra of sufferers, where they will connect to other nerve cells in the brain and generate dopamine to restore movement.

A recent paper by Sundberg et al (2013; http://onlinelibrary.wiley.com/doi/10.1002/stem.1415/full) has shown in principle all steps (except replacing mutant DNA) are successful in treating Parkinson's in the rat and transplanted cells survive in primates for at least a year.

The ability to precisely replace DNA is an emerging technology (http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2443.2012.01599.x/full). A specific part of DNA, which contains a Parkinson's mutation, is targeted by zinc finger nucleases (ZHF); these are proteins which grab onto specific sequences of DNA and essentially carry a pair of scissors to cut the DNA at this point. Normally the cell glues this cut together again. If two ZHF's are used and they bind a certain distance apart then the intervening bit of DNA (containing the mutation) will be cut out. A new bit of DNA can be introduced into the cell and it can slot into the gap created by the ZHF's and glued in by the cell. Therefore, the normal DNA sequence of a gene is restored. This technology has huge potential in the treatment of all disease.

Exciting prospects are slowly coming into focus!