UCSF stem cell studies to focus on muscular dystrophy, heart disease, cancer

Three UCSF scientists have received grants from the California Institute for Regenerative Medicine to advance their investigations of treatment strategies for degenerative muscle diseases, such as muscular dystrophy, and heart disease, and to determine why human embryonic stem cells are susceptible to forming tumors.

The grants, totaling nearly $4.2 million, were awarded to Harold Bernstein, MD, PhD, UCSF professor of pediatrics and a member of the UCSF Cardiovascular Research Institute; John Murnane, PhD, a professor of radiation oncology and a member of the Helen Diller Family Comprehensive Cancer Center; and Deepak Srivastava, MD, professor of pediatrics and biochemistry and biophysics and director of the UCSF-affiliated Gladstone Institute of Cardiovascular Disease.

The grants are among 27 Basic Biology III Awards worth $37.7 million awarded on May 4 by the CIRM governing board for studies in stem cell biology and disease origins.

The grants were awarded against the backdrop of CIRM's decision to help fund the first Food and Drug Administration-approved clinical trial based on cells derived from human embryonic stem cells. The grant, to Geron Corp of Menlo Park, will support the biopharmaceutical company's on-going early phase trial for people with spinal cord injury.

A review of the grants to UCSF faculty follows:

Harold S. Bernstein, MD, PhD, ($1,381,296 grant) - Bernstein's team will examine human embryonic stem cells as they become muscle stem cells and mature into muscle in the culture dish, with the goal of defining the stages of normal muscle development. They will then transplant these stem cells at various stages of development into the leg muscles of mice with muscular dystrophy, and study how these cells become new muscle tissue, how this impacts the animals' ability to exercise and the strength of the treated muscles.

"Muscular dystrophies affect more than 1 in 3,500 males at birth," said Bernstein. "This research will identify human embryonic stem cells that are able to repair damaged muscle, and provide a promising new approach to therapy for patients with muscle disease."

CIRM grant: http://www.cirm.ca.gov/grant/phenotypic-analysis-human-es-cell-derived-muscle-stem-cells

John Murnane, PhD ($1,074,355 grant) - Murnane will investigate whether the loss of telomeres - the DNA caps at the ends of chromosomes - in human embryonic stem cells grown in cell culture makes the cells particularly susceptible to out-of-control replicating to form tumors. If the loss of telomeres is a factor, scientists could develop steps to avoid this effect during human embryonic stem cell therapy.

Normal cells become cancerous when their DNA undergoes changes that cause the cell to replicate uncontrollably. Because multiple changes must occur to cause this unchecked growth, the likelihood of cancer is low. However, some cellular changes - including telomere loss - can increase the rate at which subsequent changes occur.

"Understanding how culture conditions can influence genetic changes in human embryonic stem cells will allow scientists to avoid these changes and limit the likelihood of complications resulting from hESC therapy," said Murnane.

CIRM grant: http://www.cirm.ca.gov/grant/genomic-instability-duringculturing-human-embryonic-stem-cells

Deepak Srivastava, MD ($1,708,560 grant) - Building on his lab's previous finding, Srivastava's team will examine the mechanism by which connective tissue cells, known as fibroblasts, in the heart can be reprogrammed into heart muscle cells, which are damaged in heart disease.

In earlier work the team was able to reprogram fibroblast cells into heart muscle cells in mice by adding just three genes. The cells were directly converted to new muscle without ever becoming a stem cell. In the current study, the lab will investigate the mechanism of the reprogramming process and how it progresses over time.

"Five million Americans suffer from heart failure," said Srivastava. "Our goal is to develop a strategy for producing new heart muscle cells to regenerate damaged tissue in adults and in infants with congenital heart malformations."

CIRM grant: http://www.cirm.ca.gov/grant/mechanisms-direct-cardiac-reprogramming