Development of siRNA-based compounds to potently silence MECP2 towards the treatment of MECP2 Duplication Syndrome 

Anastasia Khvorova, PhD

$435,515 AWARDED

MECP2 Duplication Syndrome (MDS) is caused by a genetic error resulting in a duplicated section of the X chromosome that includes the MECP2 gene. A promising approach to treating MDS is to reduce levels of the MECP2 protein by silencing gene expression. Gene silencing can be compared to turning down the volume on your phone, radio, or TV. Some silencers are weak and reduce gene expression only a small degree, like turning the volume down a little, while others are quite potent and result in no detectable gene expression like turning the volume all the way down.

One way to silence genes is through small interfering RNA oligonucleotides (siRNAs). siRNA interferes with the translation of targeted proteins by binding to and promoting the degradation of their RNA. In Dr. Khvorova’s project an MECP2 siRNA will guide molecular scissors to the MECP2 RNA for destruction, thereby reducing the level of MECP2 RNA in the cell.

Dr. Khvorova has developed a new RNA interference scaffold that in animal models shows robust siRNA distribution throughout the brain and spinal cord. Her approach suggests that the siRNA treatment would need to be dosed every 9 to 12 months in humans and may have a better safety profile than other forms of gene silencing.

Dr. Khvorova is a pioneer in the field of oligonucleotides and is part of the RNA Therapeutics Institute at UMASS that brings together a critical mass of scientists with RNA expertise, including Nobel laureate Craig Mello. The Institute has a strong emphasis on developing therapeutics for neurological disease.

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