User:Camella Mangum/sandbox

The discoveries for the advancement of gene therapy for Osteogenesis Imperfecta is considered rather complicated essentially due to the genetic heterogeneity of the disease. Osteogenesis Imperfecta mutations are dominant negative, in which the mutant allele interferes with the function of the normal allele; therefore, supplementation to the the normal gene without silencing the abnormal gene will not be affective. Gene therapy for Osteogenesis Imperfecta requires numerous clinical application approaches to tackle this disease, in order to provide the most efficient therapy. Since Osteogenesis Imperfecta is an incurable genetic disease, potential treatments are still being investigated for gene therapy. Scientists have tested null mutations in which an allele is not expressed or alternatively silencing the mutant allele to make the normal allele prone. Moreover, overexpression of the normal collagen gene could potentially lead to production of a sufficient amount of normal molecules to normalize the cells.

According to the gene therapy strategy of mutant gene silencing of Osteogenesis Imperfecta, treatment will be performed ex vivo, which is experimentation done in or on the tissue of an organism in an external environment. Mesenchymal cells collected from the same Osteogenesis Imperfecta patient can be genetically modified in vitro, and then returned to the patient. Mesenchymal cells were used because they separate into many different tissues after infusion in vivo. Chamberlain et al. created a strategy to silence the mutated alleles on the cells of bone marrow mesenchymal cells. In the experiment Chamberlain and his colleagues designed a gene construct that targeted exon 1 of the gene for collagen type 1 alpha 1. They concluded that upon insertion of the bone marrow mesenchymal cells, the construct would inactivate COL1A1. The consequence of the allele gene silencing for Osteogenesis Imperfecta would be the result of COL1A1 haploinsufficiency, this will convert an unusual phenotype to some what normal phenotype similar to type I. This allows only one copy of the wild-type allele to be express therefore it is not sufficient to produce the wild-type phenotype. The heterozygous COL1A2 null alleles will have no apparent phenotype displayed.

Scientists are currently experimenting with a mouse model of human Osteogenesis Imperfecta, by using none marrow cells to deliver normal collagen to the bone, with the possibility of developing gene therapy. Within the study they evaluated the concepts of the mutations in Type I collagen genes which led to different Osteogenesis Imperfecta phenotypes. Scientists explored this by collecting the stem cells of patients with the disease from the bone marrow and used the targeted gene therapy to disrupt the mutations. The collagen protein from the stem cells produced, improved its overall stability and function necessary for bone strength; essentially this allowed the cells opportunity to form new bone when implanted later in mice.

Effective gene therapy for Osteogenesis Imperfecta will involve the suppression of mutant collagen alleles without disrupting the normal alleles. With the high heterogeneous nature of Osteogenesis Imperfecta dominant mutations, development of mutation-independent strategies would be necessary to cover a wide spectrum of mutations. A combination of gene overexpression and gene silencing approaches in stem cells will be necessary to develop treatment for Osteogenesis Imperfecta patients with dominant-negative mutations. The continual evolution of methods to suppress genes or silence genes will aid in the expansion of gene therapy approaches.