Chemical Control of Heterotopic Ossification: ALK2(R206H)-Targeted PROTACs to treat FOP

Abstract

Fibrodysplasia Ossificans Progressiva (FOP) is a rare and severely disabling genetic disorder in which muscles, tendons, and ligaments are gradually replaced by bone. This progressive ossification stems from a mutation in the ACVR1 gene, also known as activin-like kinase 2 (ALK2). ACVR1 encodes ALK2, a type I BMP receptor that normally guides bone growth and tissue repair. In FOP, the common R206H mutation makes ALK2 abnormally active, triggering BMP signaling without proper cues. This drives connective tissue—including endothelial cells—to become bone-forming cells, slowly creating an unwanted secondary skeleton.The mutated receptor activates pathways that are normally reserved for bone development. Because of this, bone forms in soft tissues after even minor trauma or inflammation. One drug currently being studied for FOP is palovarotene. It aims to reduce abnormal bone growth. However, it has shown limited effectiveness and can cause side effects, especially in younger patients. These challenges highlight the need for more precise and reliable therapies. One promising strategy involves PROTACs (Proteolysis-Targeting Chimeras). These are specialized molecules that guide harmful proteins—such as mutant ALK2—to the cell’s natural disposal system, the ubiquitin–proteasome pathway. Unlike traditional treatments, PROTACs remove the protein entirely. This could lead to more specific and longer-lasting effects. This project explores the potential of using PROTACs to treat FOP. The focus is on the selective degradation of mutant ALK2. The study will examine how PROTACs might distinguish the mutant version from the normal one. It will also explore ways to improve delivery to bone and connective tissues. The goal is to provide well-supported suggestions on how PROTACs could become a new, targeted treatment option for FOP.