Dr. Stanley Nelson, a scientist with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, has been awarded a $6 million grant from California's stem cell agency to develop a combination therapy for Duchenne muscular dystrophy, a potentially fatal disease that currently has no effective treatment.
Two other scientists with the Broad Center, Dr. Owen Witte and Kathrin Plath, were each awarded grants of $1.38 million from the state agency to investigate basic mechanisms underlying stem cell biology and differentiation.
Nelson's Early Translational award and the two Basic Biology IV grants — together totaling more than $8.7 million — are part of the continuing efforts of the California Institute for Regenerative Medicine (CIRM) to build support for research designed to take stem cell science from the laboratory bench into the clinic. The studies supported by these awards will form the foundation for translational and clinical advances and will demonstrate the potential of human stem cells for therapies and as tools for biomedical innovation.
To date, UCLA and its stem cell scientists have received 57 grants from CIRM totaling more than $182.7 million.
"It is very rewarding to see the breadth and quality of the basic science translation to clinical applications at UCLA's stem cell center recognized with the awarding of these grants," said Witte, who directs the Broad Center and is a professor of microbiology, immunology and molecular genetics in the UCLA Life Sciences Division and a Howard Hughes Medical Institute Investigator. "The science supported by them will propel future translational and clinical research, such as that being done by the Nelson team, and hopefully result in more new and effective therapies for a host of diseases."
Stanley Nelson's research
Nelson, a professor and vice chair of human genetics and psychiatry, will develop a combination therapy for Duchenne muscular dystrophy (DMD), an inherited disease that affects about one in 3,600 boys and results in muscle degeneration and eventual death. The research is supported strongly by parents of children with the disease, who made an eloquent appeal for research funding at the last CIRM meeting.
Nelson will team up on this project with his wife, Carrie Miceli, a professor of microbiology, immunology and molecular genetics in the UCLA Life Sciences Division and a member of the Broad Center.
In DMD, a genetic mutation occurs that results in a completely non-functional dystrophin protein, leading to the disease's severe symptoms. An exon or exons are deleted in the mutated DMD gene, interfering with its function.
One way to address this is a technique known as exon-skipping, which encourages the cellular machinery to "skip over" an exon. Small pieces of DNA called antisense oligonucleotides (AOs), or molecular patches, are used to mask the exon that requires skipping.
A drug has been identified through the use of muscle stem cells that can enhance the effectiveness of this exon-skipping using AOs in order to restore dystrophin expression and at least partially correct the defect responsible for the loss of muscle function. Nelson and Miceli propose to test the effectiveness of a combination therapy that uses an AO with an FDA-approved drug that boosts its activity, a therapy discovered at UCLA.
The study will use patient-derived stem cells as a novel therapeutic strategy. DMD generally leads to death in the teens or early 20s, making it one of the most severe disorders in humans and one of the more common genetic disorders.
Owne Witte's research
Witte has contributed to recent scientific advances that identified normal prostate-tissue stem cells and the biological mechanisms that regulate their growth. These mechanisms, called regulatory signaling pathways, work like telephone lines between cells, telling them how and when to grow.
Human cancer cells use these same pathways to grow into tumors. Witte recently discovered a molecule called Trop2 that plays a key role in making the pathways work. Trop2 was discovered in cells from advanced-stage prostate cancer and found to have the ability to make tumors grow back. Trop2 can also appear in other cancer cells, and its presence can predict poor outcomes in many types of cancer, including ovarian, pancreas, breast, stomach, colon and rectal cancers.
Witte intends to develop a combination of treatments that will block Trop2 and other pathways to prevent cancer progression and recurrence. This novel combination could significantly extend life and reduce the suffering of men with advanced prostate cancer, and it may benefit patients with other types of cancer as well.
Kathrin Plath's research
Because human embryonic stem cells can ultimately become any cell in the human body, stem-cell based therapies have the potential to revolutionize modern medicine. Male stem cells possess an X chromosome and a Y chromosome — chromosomes being the parts of DNA that carry hereditary information — while female cells have two X chromosomes. Female cells use a mechanism called X-chromosome inactivation to shut down one X chromosome so that there is a balance with the male cells, which have only one X chromosome. When exactly this shutdown happens is not clear.
When embryonic stem cells are grown in the laboratory, some display X-chromosome inactivation, while others have two active X chromosomes. Why this happens is unknown, but it makes the cells unstable for use in therapies. For scientists to use stem cells in therapies, they need to be able to grow high-quality, stable cells that have the same X-chromosome state.
Plath, an associate professor of biological chemistry, will focus her research on the X chromosome to determine why this cell instability occurs and to find biological markers that can be used as benchmarks to assess the quality and X-chromosome stability of stem cells, which will allow scientists to grow high-quality stem cells for future treatments.
The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA's stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA's Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.