NAF Ataxia Research Studies Currently Underway

Gumei Liu, PhD

University of Iowa
Disease-regulated RNA interference for Spinal Ataxia Type 1 therapy

Summary: Spinal cerebellar ataxia remains a fatal, dominant neurogenetic disease. While supportive therapies exist, the development of an effective treatment is warranted. We previously showed that attacking the fundamental problem of mutant gene expression could be one approach to therapy. To accomplish this, we used a method called ANA interference, or RNAi. RNAi refers to a process whereby target genes are inhibited from being expressed. We showed, using a mouse model of SCA 1 that reducing disease gene expression improved the motor incoordination and improved the pathology in the cerebellum, the major site of disease in this model.

In our prior work, we accomplished RNAi using a system that would have it 'on' at all times. We do not know if such a system is needed or safe for a disease that can span decades. For this reason, I propose to develop an RNAi system that turns on when the cells are sick, and off when the cells recover. We know the cells can recover to some extent because of other mouse work done by Dr. Harry Orr, U of Minn. How to accomplish this? I propose that this can be done using inhibitory RNA which are naturally expressed in brain cells. While we don't know what these naturally occurring RNAi are doing, we do know that some of them are expressed at higher levels in SCA 1 mice brains. We will use the elements that make them be expressed upon disease onset, and off in healthier brains, to drive RNAi specific for mutant ataxin-1. This system would take advantage of the cells natural ability to turn things on and off as needed, and represents a very novel approach to SCA1 therapy.