Gene therapy for treatment of craniofacial dysplasia

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DESCRIPTION (provided by applicant): The purpose of this study is the development of a novel gene therapy regime for the perinatal treatment of craniofacial dysplasia, a cardinal characteristic of many genetic disorders, including Apert, Crouzon, Treacher Collins, Hurler and Hunter syndromes, just to name a few. Clinically, they present with abnormal size and shape of the jaws, frontal bossing and midface hypoplasia, as well as skeletal anomalies in other areas of the body (Hurler & Hunter). Recent advances in molecular biology have allowed scientists to investigate the etiologic factors for many of these disorders, in which distinct genetic mutations cause abnormal bone growth and skeletal development, giving rise to abnormal craniofacial phenotype. Cells of mesenchymal origin are primarily involved in skeletal growth and development, including chondrocytes, osteocytes, endothelial cells and fibroblasts, whereby normal cellular function appears central to physiologic bone growth and development. Therefore we hypothesize that genetic factors deleterious to cells involved in bone formation and growth can adversely affect skeletal development, ultimately resulting in craniofacial dysplasia. Depending on the particular genetic anomaly, the correlate phenotype may be diagnosed prenatally, at birth (neonatally) or soon after (perinatally), using clinical as well as molecular approaches. The purpose of this study is to determine whether timely restoration of a mutation by gene therapy can attenuate or even prevent craniofacial dysplasia. For this purpose, we will employ an animal model with craniofacial dysplasia, growth retardation and facial dysmorphism secondary to abnormal bone growth due to cellular dysfunction resulting from beta-hexosaminidase deficiency (hexA-/-/hexB-/- double knockout mice). Interestingly, these mice display only mild phenotypic changes at birth, but quickly develop their aberrant features by 4-5 weeks of age. Furthermore, they have progressive decline in motor function, and limited life span (1-4 months). Utilizing a pseudotyped feline immunodeficiency viral vector developed in our laboratory for beta-hexosaminidase gene therapy, FIV(Hex), we will test whether restoration of the underlying genetic deficiency in hexA-/-/hexB-/- mice will result in restitution of beta-hexosaminidase activity and normalization of skeletal development. Based on our Preliminary Results, we anticipate successful transfer and expression of our therapeutic gene in vivo, leading to normalization of cellular function and attenuation of the hexA-/-/hexB-/- phenotype. Completion of this study will aid in the development of novel therapies for the management of genetic disorders.