Lay summary of October 19, 2022 article in Nature Communications, "Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery"
About 320 million people worldwide live with a rare genetic disease; 900-1,000 known individuals have fibrodysplasia ossificans progressive (FOP). In FOP, part of the ACVR1 receptor protein on the surface of repair cells is defective. Cells without this mutation repair noticeable and unnoticeable microtears in muscles, tendons, and ligaments. However, cells with specific gene mutations in the ACVR1 gene are misdirected to become bone cells.
Researchers and clinician scientists have worked for decades on ways to modify, replace and silence mutant genes responsible for genetic diseases like FOP. The first gene therapy clinical trial was conducted in 1990. Over 1,000 clinical trials followed before 2012 when the first gene therapy in a living person was approved for lipoprotein lipase deficiency in Europe, and in 2017 and when the first gene therapy for RPE-mutation-associated eye disease was approved in the United States. In 2019, Jae-Hyuck Shim, a leader in gene therapy from the University of Massachusetts Chan Medical School (UMass Chan), attended the International Fibrodysplasia Ossificans Progressiva Association (IFOPA) FOP Drug Development Forum.
In 2020, the same year the US FDA issued its first guidance on the development of gene therapy to treat disease, the IFOPA funded Dr. Shim's plan to investigate the potential of gene therapy to treat FOP. In October 2022, the results of this work were published in Nature Communications, ranked in the top 1% of 28,000 science and technology journals. The publication was also selected as "Editors’ Highlights" in the field of translational and clinical research. This accomplishment is a testament to the exciting results, their comprehensive nature, and the sheer quality of the work of Drs. Shim, Gao, and their colleagues at UMass Chan and the bioinformatics expert, Dr. Chun, at Korea Advanced Institute of Science and Technology. This work was further enhanced by input from FOP experts Dr. Edward Hsiao at the University of California-San Francisco and Drs. Eileen Shore and Fred Kaplan at the University of Pennsylvania.
These results demonstrate that gene therapy using recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver healthy ACVR1 genes and artificial microRNA silencing substantially reduced the accumulation of unwanted and misplaced bone in a humanized mouse model for FOP that expresses the human mutant ACVR1 gene. Researchers showed that gene therapy stopped undesirable Activin A signaling of the mutant ACVR1 receptor. In vitro studies using human FOP patient-derived induced pluripotent cells (iPSCs) show that human early and late-stage bone-making cells could be treated. Treatment of mice at birth and early adulthood via injection into the bloodstream or local transdermal injection in areas at risk for developing HO resulted in the substantial reduction of HO and prevention of disability.
The results of Dr. Shim and his colleagues are just the beginning. Next up, researchers at UMass Chan, Korea Advanced Institute of Science and Technology, University of California-San Francisco, University of Pennsylvania, AAVAA Therapeutics and others at the University of Amsterdam, University of Connecticut, University of Washington, University of Texas Southwestern Medical Center and Harvard Medical School will optimize the timing, concentration and delivery of healthy ACVR1 DNA together with silencing microRNA. Ensuring that the therapy does not target the liver and heart, shown to occur in other gene therapies, will be a priority together with understanding why inflammation, shown to instigate HO remains high in treated mice and what that could mean for those with FOP undergoing gene therapy. In the line with this, developing multi-functional rAAV vectors or small interference RNAs (siRNAs) that can simultaneously inhibit the ACVR1 mutation, Activin A, and inflammation in flareup lesions is in progress. Eventually, correction of the ACVR1 mutation in FOP-causing cells via CRISPR/Cas-mediated gene editing would an attractive approach to cure FOP. This work will continue to be assisted by the IFOPA FOP Gene Therapy Working Group of Drs. Jeffrey Chamberlain, Guangping Gao, David Goldhamer, Edward Hsiao, Frederick Kaplan, Jung-Min Kim, Benjamin Levi, Jae-Hyuck Shim, Eileen Shore, Jun Xie, Yeon-Suk Yang and Paul Yu.
Thank you to those who have donated to the IFOPA's In Pursuit of a Cure campaign! Your generous contributions have made this gene therapy research possible.