Genetic Therapy Using the 'STUB' Gene Demonstrates Potential in Rodent Studies
In a significant breakthrough, a team of scientists at the Morsani College of Medicine at the University of South Florida have developed a novel gene therapy for Angelman syndrome. The study, titled "Improving Gene Therapy for Angelman Syndrome with Secreted Human UBE3A", was published in Neurotherapeutics.
Angelman syndrome, a genetic disorder caused by mutations in the UBE3A gene, affects the production of the UBE3A protein. The new therapy, developed by the research team, codes for a version of the UBE3A protein that can be secreted by cells. This novel version, named "STUB" (short for "secreted TAT UBE3A"), aims to overcome the limitation of traditional AAV-based therapies where each viral vector delivers a copy of the gene to one single cell.
The STUB construct increases the effectiveness of treatment by supplying the replacement of UBE3A to cells that were not transduced with the viral administration. In a rat model of Angelman syndrome, the gene therapy delivering the STUB version of the UBE3A protein had a more potent effect compared to the gene therapy encoding the unmodified UBE3A protein.
The study, led by Marta Figueiredo, PhD, demonstrated that both STUB and unmodified UBE3A gene therapies normalized scores on fear conditioning testing. However, while both therapies normalized electrical activities in the rats' brains, STUB-coding gene therapy led to a marked normalization on both the rotarod test and hind limb clasping test, though scores were still different from those of rats without Angelman syndrome.
The scientists concluded that the secretion of hUBE3A adds an additional enhancement to the vector design above native hUBE3A. The secreted version of the UBE3A protein can be taken up by other cells, potentially increasing the number of cells receiving the gene.
The research team at Encoded Therapeutics has been working on an AAV-based gene therapy encoding a version of the UBE3A protein that can be secreted by cells to treat Angelman syndrome. This development is part of their pipeline targeting UBE3A restoration in Angelman syndrome patients.
Despite the promising results, it's important to note that no information about the specific method used to administer the gene therapies via injections into the rats' brains or the details of the comprehensive gene testing required to spot rare UBE3A mutations were provided in the study. Further research is needed to fully understand the potential of this novel gene therapy for treating Angelman syndrome in humans.
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