Gene therapy approaches for osteogenesis imperfecta

Abstract

Osteogenesis imperfecta (OI) is a heterogeneous group of genetic disorders that affect connective tissue integrity. The hallmark of OI is bone fragility, although other manifestations, which include osteoporosis, dentigenesis imperfecta, blue sclera, easy bruising, joint laxity and scoliosis, are also common among OI patients. The severity of OI ranges from prenatal death to mild osteopenia without limb deformity. Most forms of OI result from mutations in the genes that encode either the proa1or proa2 polypeptide chains that comprise type I collagen molecules, the major structural protein of bone. Treatment depends mainly on the severity of the disease with the primary goal to minimize fractures and maximize function. Current treatments include surgical intervention with intramedullarly stabilization and the use of prostheses. Pharmacological agents have also been attempted with limited success with the exception of recent use of bisphosphonates, which have been to shown to have some effect. Since OI is a genetic disease, these agents are not expected to alter the course of the collagen mutations. Cell and gene therapies as potential treatments for OI are therefore currently being actively investigated. The design of gene therapies for OI is however complicated by the genetic heterogeneity of the disease and by the factor that most of the OI mutations are dominant negative where the mutant allele product interferes with the function of the normal allele. The present review will discuss the molecular changes seen in OI, the current treatment options and the gene therapy approaches being investigated as potential future treatments for OI.

Nonviral genetic modification mediates effective transgene expression and functional RNA interference in human mesenchymal stem cells

“…Continuing this strategy, it seems feasible that expression of one gene of interest and knock-down of another gene via RNA interference can be performed at the same time. This would be of fundamental clinical interest in reference to dominantnegative disorders, where a successful genetic treatment would require both the elimination of the transcripts encoding the dominant-negative protein and the transfer of the intact allele [22,48].…”

Treatment of children with osteogenesis imperfecta

“…Thus, it is not sufficient to replace a missing protein, as is the case in many recessive enzyme disorders. Rather, it is necessary to first inactivate the mutant allele and then substitute for its product [38,39].…”

Differential effect of flavonoids on glycosaminoglycan content and distribution in skin fibroblasts of patients with type I osteogenesis imperfecta

“…flowers and the Erigeron acris L. herb (14-16) on collagen biosynthesis in the skin fibroblasts of patients with OI to identify bioactive compounds with the potential for use in the pharmacological therapy of disease (10). Because of structural mutations in patients with OI types II, III and Iv, which affect connective tissue through a dominant-negative mechanism, the goal of gene therapy is the selective suppression of mutant allele expression (24,25). By contrast, in OI type I, bone formation is defective due to a deficiency of type I collagen caused by one null allele of the COL1A1 gene (1,2,4,5), and agents that augment collagen production may have a beneficial effect.…”