A Review of the Type-1 Fibrillinopathies: Pathophysiology, Diagnosis and Novel Therapeutic Strategies

Type-1 ifibrillinopathies iare ia ifamily iof iconnective itissue idisorders iwith imajor iclinical imanifestations iin ithe iskeletal, iocular iand icardiovascular isystems. iThe itype-1 ifibrillinopathies iare icaused iby imutations iin ithe ifibrillin-1 igene i(FBN1), iwhich iencodes ifibrillin-1, ia ilarge iglycoprotein iand ia imajor icomponent iof ithe iextracellular imatrix imicrofibrils, iproviding iboth istructural iand iregulatoryisupportitoiconnectiveitissues.i The itype-1 ifibrillinopathies ihave ibeen iassociated iwith iover i1800 iunique imutations iwithin ithe iFBN1 iand idemonstrate ia iwide irange iof iphenotypic ivariability. iThis, iin iconjunction iwith ia inumber iof iother ifactors ihas iimpacted ion ithe iidentification iof igenotypephenotype icorrelations, ipathogenesis iand idiagnostic itests ifor ithis ifamily iof idiseases, ileaving imany iopenended itheories. iCurrent istandard iof icare irelies iheavily ion isurgical iintervention iand ilifelong iuse iof iβ-blockers ito islow idisease iprogression, iwith iresearch ifocused iheavily ion iantagonism iof itransforming igrowth ifactor iβ, iwhich iis iknown ito ibe idysregulated iin ipatientsiwithiFBN1imutations.i Antisense ioligonucleotides ipresent ia inovel itherapeutic istrategy ifor ithe itype-1 ifibrillinopathies, iby imediating ithe ialteration iof iexon iarrangement iof iboth ithe inormal iand idisease-causing imRNA itranscripts, ito ireestablish ithe iperiodicity iof ifibrillin-1. iThe iinduced iproteins, iwhile iinternally itruncated, ishould ibe ihomologous iand ithus ibe iable ito iform imultimer iunits. iThis itreatment ialone ior iin iassociation iwith iisoform iswitching, iTGF-β iantagonism ior ienhanced/inhibited iprotein idegradation icould ifacilitate ithe iassembly iof ifibrillin-1 imonomers iinto imultimers iand iconsequently ia idecrease iin iphenotypic iseverity

Author(s): Steve D Wilton

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