title: A mutation-independent therapeutic strategem for osteogenesis imperfecta.
abstract: Given the genetically heterogeneous nature of many dominantly inherited disorders, it will be imperative to design mutation-independent therapeutic strategies to circumvent such heterogeneity. Intragenic polymorphism represents a genomic resource that may be harnessed in the development of allele-specific mutation-independent therapeutics. A hammerhead ribozyme, Rzpol1a1, selectively cleaves a common single-nucleotide polymorphism (SNP) of the human COL1A1 transcript (heterozygosity frequency of 2 pq = 0.4032, from Hardy-Weinberg equilibrium). One SNP variant contains a hammerhead ribozyme cleavage site, and the other does not. Kinetic evaluation shows Rzpol1a1 to be both specific and extremely efficient in vitro. Thus, a single efficient ribozyme has been characterized that should be valuable in the development of a gene therapy suitable for up to 1 in 5 dominant-negative osteogenesis imperfecta (OI) patients, where over 150 different mutations have been identified to date. Given the increasing characterization of intragenic SNP, it is predicted that such a mutation-independent strategy, based on selective silencing of mutant alleles at SNP, may become increasingly important in future genomics-driven drug development for many heterogeneous dominant disorders and complex traits.
authors.affiliation: Genetics Department, Trinity College Dublin, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Millington-Ward
authors.forename: B
authors.initials: B
authors.lastname: O'Neill
authors.forename: A S
authors.initials: AS
authors.lastname: Kiang
authors.forename: P
authors.initials: P
authors.lastname: Humphries
authors.forename: P F
authors.initials: PF
authors.lastname: Kenna
authors.forename: G J
authors.initials: GJ
authors.lastname: Farrar
mesh_terms: D000483:Alleles; D001483:Base Sequence; D003094:Collagen / Q000235:genetics; D005799:Genes, Dominant; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D020641:Polymorphism, Single Nucleotide; D016337:RNA, Catalytic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D016337:RNA, Catalytic; D003094:Collagen