My lab aims to develop RNAi therapy for diseases of the central nervous system (CNS), including neurodegenerative disease. Due to the growth of the aging population in the US and around the world, neurodegenerative diseases are becoming an increasingly prominent health problem. The major neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS) are devastating and fatal. Currently there is no means to arrest or reverse the progression of these diseases. RNAi, a cellular gene-silencing mechanism discovered by Fire and Mello, holds great potential as a therapeutic tool for treating these diseases. In the last several years, we have been developing an RNAi therapy for ALS. This disease causes motor neuron degeneration, muscle weakness and paralysis. Half of patients live just three years after diagnosis. At five years, only ten percent of patients are alive. One cause for this disease is mutations in an enzyme called SOD1. Research has shown that the mutations imbue SOD1 with a toxic activity that kills motor neurons. Therefore, silencing mutant enzyme expression may be an effective therapeutic strategy.
We have been testing RNAi in a mouse that has been engineered to produce the toxic, mutant human SOD1. These mice mimic the human disease and have a predictable disease course. To determine whether the RNAi strategy might ultimately be of benefit in people, we used the mice to test three different RNAi strategies, including directly infusing a small, double-stranded RNA molecule called siRNA into the cerebral spinal fluid; using an siRNA-producing transgene that is permanently part of the mouse DNA; or by delivering an siRNA-producing transgene to cells in the CNS cells using a specially engineered virus. RNAi delivered by all of these means can reduce the production of mutant SOD1 in the CNS, slowing progression of the disease in mice and extend their survival. We are thus optimistic that RNAi may one day be used to treat fatal CNS diseases.
At present a safe and effective delivery method for RNAi therapy remains a major challenge. Our ongoing effort focuses on developing specially engineered viruses called adeno-associated virus (AAV) as a delivery vehicle. AAV was tolerated in human clinical trials for CNS diseases such as Leber congenital amaurosis (LCA) and Parkinson's disease. However, because ALS causes neurodegeneration in broad areas of the CNS, including the motor cortex, brain stem, and spinal cord, we do not yet know if a single type of virus, delivered in a single injection can be used for ALS therapy. To solve this problem, my lab is collaborating with Dr. Guangping Gao's lab in the Gene Therapy Center to find new types of AAV viruses that can deliver the therapeutic gene to many different types of cells in the brain and central nervous system. Our recent efforts have identified some viral types that can deliver to broad areas of the CNS after a single injection. These are promising delivery vehicles for RNAi to treat CNS diseases, including ALS, Alzheimer's disease and frontal temporal dementia. Currently we are optimizing these vectors and testing their therapeutic efficacy in delivering RNAi therapy in the mouse model of ALS.
Dr. Zuoshang Xu
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