Stem Cell Derived Neurons for Research Relevant to Alzheimer's and Niemann-Pick Type C Diseases

Science Daily, December 9, 2009

One of the major hurdles to curing diseases is finding ways in which to test potential cures (or treatments) without having to use people, or even animals. One way of trying to cure a disease is to associate it with a gene or series of genes that are either mutated or abnormally acting. When the cause of the disease is known, then scientists use computers to generate molecules that theoretically would inhibit the disease. These are then tested in the test-tube, and subsequently in animals having the disease. If it works on animals and is relatively non-toxic, then Phase I human trials are conducted to assess safety and what dosage can be tolerated.

Subsequently Phase II trials are performed to assess whether there is an effect of the drug on the disease. Finally Phase III trials are conducted, which assess the efficacy of the drug but in a manner that is double blind and placebo controlled. If the drug is successful, then the FDA or EMEA (in Europe) grants approval. The other way to approach diseases is to randomly screen compounds. The issue with random screening is that one needs to have a replica of the disease in a test tube that can be rapidly assessed whether there is or is not an effect.

The contributive role of stem cells in human medicine has to some extent been underestimated. For example, while it is well-known that embryonic stem cells have not been used in humans to date, embryonic stem cells have contributed tremendously to human medicine. Mouse embryonic stem cells are the key to development of genetically engineered animals in which a gene of interest to humans is either made to be artificially highly expressed in the animal (called transgenic animals), or in which the animal is selectively depleted of the gene of interest (called knockout animals). The development of genetically engineered animals for human testing was the basis of identifying numerous "Achilles Heal's" of diseases. For example, using knockout mice it was demonstrated that the molecule TNF-alpha is essential for animals to get rheumatoid arthritis. The development of antibodies to TNF-alpha has heralded a revolution in the therapeutic of not only rheumatoid arthritis but also several other inflammatory diseases such as Crohn's Disease and Psoriasis.

Today the group of Lawrence B. Goldstein, Ph.D., of the University of California, San Diego, School of Medicine and Howard Hughes Medical Institute (HHMI) presented data at the American Society for Cell Biology (ASCB) 49th Annual Meeting, in San Diego describing a new "model" of disease that they developed. The scientists wanted to develop means of testing drugs against the neurological disorders Alzheimer's disease (AD) and the rarer but always fatal disease, Niemann-Pick Type C (NPC).

In order to do this, the investigators needed to obtain the cells that develop the disease, specific types of neurons, from individuals with the disease. The problem with this approach is that it is in general very difficult to extract neurons, and it is even more difficult to grow them from patients with AD or NPC. To overcome this, stem cells were created from the skin of patients with these diseases and then the stem cells were made into disease-specific neurons by treatment with growth factors. Previous to this, researchers had to perform experiments in neurons from fruitflies which obviously have many differences as compared to humans.

According to Dr. Goldstein, who is a professor in the Department of Cellular & Molecular Medicine, an HHMI investigator and director of UC San Diego's Stem Cell Program "Such research may yield an understanding of what components of sporadic disease are defined by genetic characteristics"

Studies are currently being performed using these "in vitro" models of disease to assess random chemical compounds, a process called "screening" in order to identify potential drugs that may be useful in these conditions.