Developing an Effective Stem Cell Gene Therapy to Treat Human Disease

Funding Type: 
SEED Grant
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

The human body functions because there are specific proteins (enzymes) that perform all the work (chemical reactions) necessary to allow mechanical movement, eating, reproducing and eliminating wastes. Enzymes are produced by specific genes. Each person can have slightly different enzymes produced by slightly different genes. Sometimes these changes provide advantages, sometimes these changes cause dis-advantages. Essentially all diseases can be linked to the interference of one or more enzymes in regard to performing its chemical reaction. Human medicine has been based on drugs, which are chemicals that affect the activity of enzymes. By increasing or decreasing the activity of enzymes, drugs can reduce and (sometimes) eliminate the deleterious effects of diseases. A potential problem with many drugs is that they commonly are associated with unwanted side-effects and their potency can be reduced by acclimation of the body’s response to that particular drug.

With the advances in understanding the human body, it is now possible to cure diseases by altering the expression of genes to affect the activity of specific enzymes. The advantages of “gene therapy” are specificity to the established target, long-term duration of treatment and reduced chances of side-effects. While gene therapy has been proposed as a method to treat many human diseases having devastating effects, there are limited examples of successful outcomes. We are now at a cross-roads in our knowledge of being able to learn how to develop successful gene therapies for treating human disease. One of the major obstacles is having the appropriate vehicle to deliver the gene therapy to the patient.

We have developed a simple method to deliver therapeutic genes to mice using stem cells that will repopulate the liver in the form of liver macrophages (i.e. Kupffer cells). Kupffer cells are immunologic cells that normally have a long lifetime, reside on the surface of liver cells and protect the body from bacteria that enter the body via the intestine. A safe drug, used to visualize arteries when irradiated with x-rays, is eaten by Kupffer cells causing them to be rapidly eliminated and replaced by new Kupffer cells which are derived from stem cells. By switching the stem cells used for replacing Kupffer cells with stem cells carrying a specific therapeutic gene, we have shown we can reduce heart disease in mice in manner that is safe, without any toxic side effects and long-term (up to a year).

The goal of this research is to further develop the Kupffer cell gene transfer technique for treating human disease. By developing an efficient means to use embryonic stem cells as the vehicle, we will be able to provide a safe, versatile, reversible and effective means to provide gene therapies for many different type of human diseases including: diabetes, infectious disease, heart disease, liver failure and metabolic deficiency diseases.

Statement of Benefit to California: 

During the past 20 years, scientists (many residing in California) have discovered how to identify genes, how to identify the functional role of the proteins made from these genes and how to identify if individuals have mutations in genes that affect function. In addition to providing patients with an understanding why they may have a particular disease, these advances have provided new clues that may be useful in designing a new way to treat diseases called gene therapy. Gene therapy has the potential to cure many diseases for which drugs have not been developed or have been shown to have bad side-effects.

Because of its many potential benefits, scientists have spent ~20 years designing methods to administer gene therapies that are safe and effective. So far, successful amelioration of human disease via gene therapy has been a rare occurrence.

We have developed a new method to administer gene therapy to mice. This method is safe and effective (treating mice with this gene therapy reduced heart disease in mice by 50%). We wish now to further develop this method so it can be used to treat humans. The goal of this research to develop this method and show that it is safe and effective in mice. Achieving this goal will justify it being further developed for use in humans in treating many diseases including: diabetes, heart disease, liver disease, several metabolic deficiency diseases, several forms of malignant diseases involving plasma cells, infection diseases and diseases associated with impaired immunity.

This investment by CIRM in supporting this research has the potential to provide new, safe and effective gene therapies to the citizens of California.