Proof-of-Principle for RNAi Treatment of Genetic Bone Disease

Scientists at Penn’s Perelman School of Medicine Center for Research in FOP and Related Disorders have developed a new genetic approach to specifically block the damaged copy of the gene for a rare bone disease, while leaving the normal copy untouched. Lead author Dr. Josef Kaplan, postdoctoral fellow; and senior authors Dr. Eileen M. Shore and Dr. Frederick S. Kaplan, both from the Department of Orthopaedic Surgery, published this new proof-of-principle approach for treating the disease, called FOP, online on October 20, 2011 in Gene Therapy. FOP (fibrodysplasia ossificans progressive) 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.