New frontiers for dominant osteogenesis imperfecta treatment: gene/cellular therapy approaches

Abstract

Osteogenesis imperfecta (OI) is a rare heritable disease characterized by skeletal fragility, bone deformity, and growth retardation. In its classical and more common forms, it is caused by dominant mutations in collagen type I genes, COL1A1 and COL1A2. A wide range of clinical severity is described in OI, ranging from very mild to moderately severe, progressively deforming, and perinatal lethal. Mutations causing null allele and consequent synthesis of half of the amount of normal collagen are responsible for milder OI phenotypes, whereas point mutations altering amino acid sequence, thus affecting protein structure, lead to severe OI outcomes. Because no resolutive cures are so far available for OI patients and given the new advances in gene-targeting technology, genetic and cellular therapy represent an appealing option for OI treatment. In this review, we briefly summarized what has been done so far for classical OI in terms of novel regenerative approaches. The different strategies adopted to silence the mutant allele with the aim of converting severe qualitative defects to milder quantitative ones, and for transplanting normal multipotent cells to generate a mosaic condition, which in OI is associated to lack of clinical symptoms, are presented. The key issues that still need to be addressed for the effective clinical application of these strategies are critically discussed.