Lead author Josef Kaplan, PhD, postdoctoral fellow; and senior authors Eileen M. Shore, PhD, and Frederick S. Kaplan, MD, both from the Department of Orthopaedic Surgery, published this new proof-of-principle approach for treating the disease, called FOP, in the online edition of Gene Therapy.
FOP, fibrodysplasia ossificans progressiva, is a rare genetic disorder of progressive extra bone formation for which there is presently no cure. It is caused by a mutation in the gene for ACVR1/ALK2, a bone morphogenetic protein (BMP) receptor that occurs in all classically affected individuals. Individuals who have FOP harbor one normal copy and one damaged copy of the ACVR1/ALK2 gene in each cell. The mutation increases the amount of BMP in cells to greater than normal levels, which initiates the transformation of muscles and cartilage into a disabling second skeleton of bone.
Using a special type of RNA molecule engineered to specifically silence the damaged copy of the gene rather than the normal copy — a process known as RNA interference, or RNAi — the scientists restored the cellular function caused by the FOP mutation by ridding cells of the mutant ACVR1/ALK2 mRNA. Cells were essentially left with only normal copies of ACVR1/ALK2 mRNA, thus adjusting the protein’s activity to normal, similar to that of cells without the FOP mutation.
The human cells used in the experiments were adult stem cells obtained directly from discarded baby teeth donated by FOP patients. These contained the exact combination of damaged and normal ACVR1/ALK2 receptor proteins found in all classically affected FOP patients worldwide. The discarded teeth were obtained from FOP pediatric patients and normal controls, usually non-affected siblings, in the ongoing “FOP Good Tooth Fairy Program.”
The authors caution that the utility of the RNAi approach must be confirmed in mouse models of classic FOP prior to its consideration for human use. Additionally, other hurdles stand in the way of human application at the present time, most notably safe delivery of the small RNA molecules to cells in the human body.
The authors acknowledge that they have a long way to go, but have taken a big first step. “Improvements in RNAi design are advancing at a rapid rate and will enhance the stability, potency, and specificity of inhibitory RNAs, allowing for long-term experiments both in vitro and in vivo,” says Shore.
This work was supported in part by the International Fibrodysplasia Ossificans Progressiva Association, the Center for Research in FOP and Related Disorders, the Ian Cali Endowment for FOP Research, the Whitney Weldon Endowment for FOP Research, the Isaac & Rose Nassau Professorship of Orthopaedic Molecular Medicine (Fred Kaplan) and by grants from the Rita Allan Foundation, and the National Institute of Arthritis and Musculoskeletal Diseases.
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4 billion enterprise.
Penn’s Perelman School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools and among the top 10 schools for primary care. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year.
The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital – the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2010, Penn Medicine provided $788 million to benefit our community.