Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-09-21
2004-03-30
Wang, Andrew (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S006120, C435S091310, C435S091100, C435S325000, C435S375000, C435S320100, C536S023100, C536S024500, C536S024310, C536S023200
Reexamination Certificate
active
06713457
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a strategy and medicaments for suppressing a gene. In particular the invention relates to the suppression of mutated genes which give rise to a dominant or deleterious effect either monogenically or polygenically. The invention relates to a strategy for suppressing a gene or disease allele such that (if required) a replacement gene, gene product or alternative gene therapy can be introduced.
The invention also relates to a medicament or medicaments for use in suppressing a gene or disease allele which is present in a genome of one or more individuals or animals. The said medicament(s) may also introduce the replacement gene sequence, product or alternative therapy.
Generally the strategy of the present invention will be useful where the gene, which is naturally present in the genome of a patient, contributes to a disease state. Generally, the gene in question will be mutated, that is, will possess alterations in its nucleotide sequence that affect the function or level of the gene product. For example, the alteration may result in an altered protein product from the wild type gene or altered control of transcription and processing. Inheritance or the somatic acquisition of such a mutation can give rise to a disease phenotype or can predispose an individual to a disease phenotype. However the gene of interest could also be of wild type phenotype, but contribute to a disease state in another way such that the suppression of the gene would alleviate or improve the disease state.
BACKGROUND OF THE INVENTION
Studies of degenerative hereditary ocular conditions, including Retinitis Pigmentosa (RP) and various macular dystrophies have resulted in a substantial elucidation of the molecular basis of these debilitating human eye disorders. In a collaborative study, applying the approach of genetic linkage, two x-linked RP genes were localised to the short arm of the X chromosome (Ott et al. 1990). In autosomal dominant forms of RP (adRP) three genes have been localised. The first adRP gene mapped on 3q close to the gene encoding the photoreceptor specific protein rhodopsin (McWilliam et al. 1989; Dryja et al. 1990). Similarly, an adRP gene was placed on 6p close to the gene encoding the photoreceptor specific protein peripherin/RDS (Farrar et al. 1991a,b; Kajiwara et al. 1991). A third adRP gene mapped to 7q (Jordan et al. 1993); no known candidate genes for RP reside in this region of 7q. In addition, the disease gene segregating in ha Best's macular dystrophy family was placed on llq close to the region previously shown to be involved in some forms of this dystrophy (Mansergh et al. 1995). Recently, an autosomal recessive RP gene was placed on 1q (Van Soest et al. 1994). Genetic linkage, in combination with techniques for rapid mutational screening of candidate genes, enabled subsequent identification of causative mutations in the genes encoding rhodopsin and peripherin/RDS proteins. Globally about 100 rhodopsin mutations have now been found in patients with RP or congenital stationary night blindness. Similarly about 40 mutations have been characterised in the peripherin/RDS gene in patients with RP or with various macular dystrophies.
Knowledge of the molecular aetiology of some forms of human inherited retinopathies has stimulated the establishment of methodologies to generate animal models for these diseases and to explore methods of therapeutic intervention; the goal being the development of treatments for human retinal diseases (Farrar et al. 1995). Surgical procedures enabling the injection of sub-microlitre volumes of fluid intravitinally or sub-retinally into mouse eyes have been developed by Dr. Paul Kenna. In conjunction with the generation of animal models, optimal systems for delivery of gene therapies to retinal tissues using viral (inter alia Adenovirus, Adeno Associated Virus, Herpes Simplex Type 1 Virus) and non-viral (inter alia liposomes, dendrimers) vectors alone or in association with derivatives to aid gene transfer are being investigated.
Generally, gene therapies utilising both viral and non-viral delivery systems have been applied in the treatment of a number of inherited disorders; of cancers and of some infectious disorders. The majority of this work has been undertaken on animal models, although, some human gene therapies have been approved. Many studies have focused on recessively inherited disorders, the rationale being, that the introduction and efficient expression of the wild type gene may be sufficient to result in a prevention/amelioration of disease phenotype. In contrast gene therapy for dominant disorders will require the suppression of the dominant disease allele. Notably the majority of characterised mutations that cause inherited retinal degenerations such as RP are inherited in an autosomal dominant fashion. Indeed there are over 1,000 autosomal dominantly inherited disorders in man. In addition there are many polygenic disorders due to the co-inheritance of a number of genetic components which together give rise to a disease phenotype. Effective gene therapy in dominant or polygenic disease will require suppression of the disease allele while in many cases still maintaining the function of the normal allele.
Strategies to differentiate between normal and disease alleles and to selectively switch off the disease allele using suppression effectors inter alia antisense DNA/RNA, ribozymes or triple helix DNA, targeted towards the disease mutation may be difficult in many cases and impossible in others—frequently the disease and normal alleles may differ by only a single nucleotide. For example, the disease mutation may not occur at a ribozyme cleavage site. Similarly the disease allele may be difficult to target specifically by antisense DNA/RNA or triple helix DNA if there are only small sequence differences between the disease and normal alleles. A further difficulty inhibiting the development of gene therapies is the heterogeneous nature of some dominant disorders—many different mutations in the same gene give rise to a similar disease phenotype. The development of specific gene therapies for each of these would be extremely costly. To circumvent the dual difficulties associated with specifically targeting the disease mutation and the genetic heterogeneity present in some inherited disorders, the present invention aims to provide a novel strategy for gene suppression and replacement exploiting the noncoding and control regions of a gene.
Suppression effectors have been used previously to achieve specific suppression of gene expression. Antisense DNA and RNA has been used to inhibit gene expression in many instances. Many modifications, such as phosphorothioates, have been made to antisense oligonucleotides to increase resistance to nuclease degradation, binding affinity and uptake (Cazenave et al. 1989; Sun et al. 1989; McKay et al. 1996; Wei et al. 1996). In some instances, using antisense and ribozyme suppression stategies has led to the reversal of the tumor phenotype by greatly reducing the expression of a gene product or by cleaving a mutant transcript at the site of the mutation (Carter and Lemoine 1993; Lange et al. 1993; Valera et al. 1994; Dosaka-Akita et al. 1995; Feng et al. 1995; Quattrone et al. 1995; Ohta et al. 1996). For example, neoplastic reversion was obtained using a ribozyme targeted to the codon 12 H-ras mutation in bladder carcinoma cells (Feng et al. 1995). Ribozymes have also been proposed as a means of both inhibiting gene expression of a mutant gene and of correcting the mutant by targeting trans-splicing (Sullenger and Cech 1994; Jones et al. 1996). Ribozymes can be designed to elict autocatalytic cleavage of RNA targets. However the inhibitory effect of some ribozymes may be due in part to an antisense effect of the variable antisense sequences flanking the catalytic core which specify the target site (Ellis and Rodgers 1993; Jankowsky and Schwenzer 1996). Ribozyme activity may be augmented by the use of non-specific nucleic acid binding protiens or faci
Farrar Gwenyth Jane
Humphries Peter
Kenna Paul Francis
Schultz James Douglas
Testa Hurwitz & Thibeault LLP
Wang Andrew
LandOfFree
Strategy for suppressing the expression of an endogeneous... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Strategy for suppressing the expression of an endogeneous..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Strategy for suppressing the expression of an endogeneous... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3253155