Intravitreal injection of fibrillin 2 (Fbn2) recombinant protein for therapy of retinopathy in a retina-specific Fbn2 knock-down mouse model.

Mutations in the extracellular matrix gene Fibrillin-2 (FBN2) are related to genetic macular degenerative disorders including age-related macular degeneration (AMD) and early-onset macular degeneration (EOMD). It was reported that the retinal protein expression of FBN2 was reduced in patients with AMD and EOMD. The effect of exogenously supplied fbn2 recombinant protein on fbn2-deficiency-related retinopathy was not known. Here we investigated the efficacy and molecular mechanism of intravitreally applied fibrin-2 recombinant protein in mice with fbn2-deficient retinopathy. The experimental study included groups (all n = 9) of adult C57BL/6J male mice which underwent no intervention, intravitreal injection of adeno-associated virus (AAV) empty vector or intravitreal injection of AAV-sh-fbn2 (adeno-associated virus for expressing short hairpin RNA for fibrillin-2) followed by three intravitreal injections of fbn2 recombinant protein, given in intervals of 8 days in doses of 0.30 µg, 0.75 µg, 1.50 µg, and 3.00 µg, respectively. Eyes with intravitreally applied AAV-sh-fbn2 as compared to eyes with injection of AAV-empty vector or developed an exudative retinopathy with involvement of the deep retinal layers, reduction in axial length and reduction in ERG amplitudes. After additional and repeated application of fbn2 recombinant protein, the retinopathy improved with an increase in retinal thickness and ERG amplitude, the mRNA and protein expression of transforming growth factor-beta (TGF-ß1) and TGF-ß binding protein (LTBP-1) increased, and axial length elongated, with the difference most marked for the dose of 0.75 µg of fbn2 recombinant protein. The observations suggest that intravitreally applied fbn2 recombinant protein reversed the retinopathy caused by an fbn2 knockdown.

[Fibrillin-2 gene mutations associated with hereditary connective tissue diseases].

Fibrillin-2 (FBN2) is an important component of microfibers which are involved in the formation of elastic fibers in connective tissue throughout the human body. Hereditary connective tissue diseases may result from genetic mutations of FBN2 causing heterogeneity of fibrin. Genetic mutations of FBN2 are associated with a variety of hereditary connective tissue diseases including Congenital Contractural Arachnodactyl (CCA), Macular Degeneration (MD), and myopathy. Studies have shown that the FBN2 gene is recognized as the only pathogenic gene related to CCA and that CCA patients have different clinical presentations depending on the identified genetic mutations at different FBN2 sites. In this review, we summarize the roles of FBN2, its mutations and impact on the physiological and pathological processes of many hereditary connective tissue diseases. We include brief descriptions of clinical manifestations of these diseases providing a basis for further exploration of the specific molecular mechanism of FBN2 gene mutation pathogenesis which provides a theoretical basis for the therapy and medications for refractory diseases caused by FBN2 gene mutation.