Therapeutic stratagems for dominant genetic disorders

Abstract

Autosomal dominant genetic diseases exhibit a phenotype when one gene allele is mutated whereas recessive diseases require both alleles to be mutated for disease pathology to arise. Disease alleles inherited in a dominant manner may give rise to disease pathology via a com bination of one or more of the follow ing mechanisms: 1) a reduction in the level of wild-type (wt) protein (haploinsufficiency), 2) interference with the activity of the wt protein or 3) the gaining of new functions. For diseases where pathology arises from haploinsufficiency, delivery of the wt gene may be sufficient to provide therapeutic benefit. However, for mutations that have a dom inant effect, delivery of the wt gene alone may not be sufficient and hence, suppression of the mutant gene may be necessary. Examples of diseases that arise as a result of dominant mutations include autosomal dominant retinitis pigmentosa (adRP) and osteogenesis imperfecta (01) (Millington-Ward et al., 1997). In addition, mutations that act in a dominant manner may contribute to the pathology of multi-factorial diseases such as p53-related cancer and Alzheimer's disease (Farrar el al., 2002).