Recapitulating development of the musculoskeletal axis in vitro with pluripotent cells
Grant Award Details
Grant Type:
Grant Number:
LA1-06920
Investigator(s):
Award Value:
$0
Status:
Closed
Grant Application Details
Application Title:
Recapitulating development of the musculoskeletal axis in vitro with pluripotent cells
Public Abstract:
Muscle dystrophies are a family of degenerative diseases in which groups of muscles progressively degenerate with age. Duchenne Muscular Dystrophy is the most common muscular dystrophy (affecting 1 in 3,500 boys) and one of the most common human genetic diseases. The number of patients is estimated at 26,500 in US and Europe with an average life expectancy of 20-30 years. Duchenne muscular dystrophy is caused by mutations in the dystrophin gene, the largest gene of the human genome, located on the X chromosome. These mutations prevent the production of a functional protein and lead to muscle weakness and wasting. In the early stages of the disease, degeneration stimulates the regeneration of new fibers, a physiological response that counterbalances fiber loss and maintains normal muscle function. As the disease progresses, regeneration capacity slows down leading to the first clinical symptoms. There are currently no cures for human dystrophies and the only effective drugs target the symptoms of disease without slowing its fatal course. Restoring muscle populations by cell therapy is a promising approach to cure the disease. Such an approach involves grafting healthy muscle precursors to reconstitute functional muscle. While muscles possess adult stem cells called satellite cells that in principle could be used for grafting, these are far too limited in number for any therapeutic application. We propose to use an alternative strategy. First, patient cells will be reprogramming to a pluripotent state. Cells will then be genetically corrected and differentiated into muscle precursors prior to being grafted in patients to regenerate the lost muscles. This method should allow the production of large amounts of healthy immuno-compatible muscle progenitor cells.
A first important bottleneck in the development of such therapies is the development of protocols to differentiate stem cells cells into muscle precursors. While the in vitro differentiation of cardiac cells or neurons from stem cells can be easily achieved today, there is currently no protocol for the efficient differentiation of muscle cells. Thus a major aim of this project will be to develop protocols to differentiate stem cells into muscle precursors. My laboratory has been studying the early stages of muscle and vertebrae differentiation for many years and we will use our knowledge of these processes to recapitulate the early development of these lineages in stem cells to produce the muscle precursors. This will constitute an essential step in the development of cell therapies for muscular dystrophy. In addition, since muscles and vertebrae share a common origin in the embryo, the protocols that we develop for the production of muscle precursors could also be used for the production of vertebral precursors. We also propose to generate vertebral precursors from healthy and diseased patients to study diseases of the human spine such as congenital scoliosis.
A first important bottleneck in the development of such therapies is the development of protocols to differentiate stem cells cells into muscle precursors. While the in vitro differentiation of cardiac cells or neurons from stem cells can be easily achieved today, there is currently no protocol for the efficient differentiation of muscle cells. Thus a major aim of this project will be to develop protocols to differentiate stem cells into muscle precursors. My laboratory has been studying the early stages of muscle and vertebrae differentiation for many years and we will use our knowledge of these processes to recapitulate the early development of these lineages in stem cells to produce the muscle precursors. This will constitute an essential step in the development of cell therapies for muscular dystrophy. In addition, since muscles and vertebrae share a common origin in the embryo, the protocols that we develop for the production of muscle precursors could also be used for the production of vertebral precursors. We also propose to generate vertebral precursors from healthy and diseased patients to study diseases of the human spine such as congenital scoliosis.
Statement of Benefit to California:
Muscle dystrophies are a family of degenerative diseases in which groups of muscles progressively degenerate with age. Duchenne Muscular Dystrophy (DMD) is the most common muscular dystrophy (affecting 1 in 3,500 boys) and one of the most common human genetic diseases. The number of DMD patients is estimated at 26,500 in US and Europe. The pathology is very severe, with an average life expectancy of 20-30 years. In early stages, muscle degeneration stimulates the regeneration of new fibers, a physiological response that counterbalances fiber loss and maintains normal muscle function. As the disease progresses the regeneration capacity slows, leading to the first clinical symptoms.
For this CIRM award, I propose to begin to develop new approaches for cell therapy for Duchenne muscular dystrophy. Such protocols once established should allow the production of healthy muscle precursor cells that could be safely grafted to restore muscle function. A first roadblock for the development of such therapies lies in the efficient production of human muscle cells in vitro from pluripotent precursors, which has not been reported yet. We intend to use our expertise of muscle embryonic development to recapitulate these processes in culture to produce large amounts of muscle precursors for grafting in patients. The strategies developed will also permit studies of the early stages of musculoskeletal axis development in humans, of which virtually nothing is known today. This will allow understanding of the pathology of diseases of the spine such as congenital scoliosis.
There is no cure for DMD (as well for other dystrophies in general) and current treatments are limited to palliative care, mainly consisting of supportive care to control the onset of symptoms, slow disease progression, and prevent the cardiac, respiratory, and orthopedic complications caused by the disease. Muscular dystrophies represent a heavy social burden due to the very significant medical costs necessary to care for the affected children. The successful development of stem-cell based therapies will place the state of California in a leading position for treatment of muscle dystrophies and diseases of the musculoskeletal axis in general. These advances could improve the treatment of diseases that affect the people of California, potentially reducing morbidity, mortality, and health care costs. Advances in our understanding of muscular dystrophies could also lead to the founding of new biotechnology companies that create high-paying jobs and economic development for California. Finally, the point of CIRM Leadership Awards is to recruit highly successful stem cell laboratories to California. Our laboratory would bring millions of dollars in grant funding from the federal government and from private foundations to California. This would directly create jobs and economic development in California, independent of any discoveries that arise from our future research.