Gene therapy strategy for classical Osteogenesis Imperfecta due to mutations in COL1A2 gene

Osteogenesis Imperfecta (OI), better known as brittle bone disease, is a rare genetic skeletal disorder that occurs in about 1 in 15’000-20’000 live births1. The major clinical manifestations of OI are liability to fractures throughout life, bone deformities, and growth retardation, and the disease severity can span from subclinical osteoporosis to intrauterine lethality. Classical forms of OI are caused by dominant mutations in collagen type I genes COL1A1 and COL1A2, coding for collagen α1 and α2 chains respectively, mainly leading to Glycine substitutions. This type of mutation leads to the synthesis of abnormal collagen molecules, resulting in qualitative defects often associated to severe outcomes, OI type II, III and IV. Nowadays no definitive cure is available for OI patients and mainly palliative treatments aiming to ameliorate the patients quality of life are available2,3. Since OI is a genetic disorder, only a gene therapy approach aimed to correct or suppress the expression of the mutant allele could be effective to cure patients. The main aim of this study was to develop a novel gene therapy approach for the treatment of classical OI with mutations in the COL1A2 gene. In humans null mutations in both COL1A2 alleles lead to a mild form of Ehler-Danlos Syndrome (EDS), a vascular disease without bone phenotype4. This finding suggested that a bone specific COL1A2 suppression will not be associated with a bone phenotype. To this purpose, we developed a siRNA gene therapy approach to suppress only in bone both Col1a2 alleles in the Amish/+ murine model of OI, carrying a G610C mutation in the Col1a2 gene, in order to convert a severe phenotype characterized by collagen structural defects to a mild OI due to collagen insufficiency. The second aim of this study was the characterization of the bone healing process in the Amish/+ mouse model of OI since OI bones are susceptible to fractures and the management of multiple fractures is one of the main problem affecting OI patients and very limited information are available on this process.