Reprogramming Reactive Astrocytes Directly into Functional Motor Neurons in the Spinal Cord of ALS Model

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is mainly caused by severe motor neuron loss followed by skeletal muscle weakness and eventually death. My lab has recently developed an innovative technology for brain repair by directly converting reactive glial cells into functional neurons inside mouse brain with traumatic brain injury or Alzheimer's disease. In this proposal, we will apply this novel in vivo reprogramming technology in the ALS mouse model and convert reactive glial cells into functional motor neurons in the spinal cord. Our approach will regenerate functional motor neurons from endogenous reactive glial cells, and simultaneously reduce glial cell-mediated neuroinflammation, making a supportive environment for both native and newly converted motor neurons to survive and repair motor function. Since motor neuron loss and neuroinflammation are the common features of both familial and sporadic ALS, our novel approach to regenerate functional motor neurons in the spinal cord will benefit both types of ALS patients. We are using an ALS mouse model with human SOD1 mutant in this proposal and have developed gene delivery system using Food and Drug Administration (FDA)-approved adeno-associated viral vectors (AAV) for neuroregeneration. Therefore, this preclinical study is highly oriented toward the development of future clinical therapies.

The unique clinical aspect of our direct reprogramming technology is that we are making use of native glial cells to regenerate motor neurons, without any cell transplantation involved. This will completely eliminate the serious side effects associated with conventional stem cell therapy. Our work has been highlighted by Nature and Cell Stem Cell and widely reported in the news media. More recently, our work has been selected as one of the Best of 2014 articles by Cell Stem Cell, the top stem cell journal in the world. I have organized and chaired the first symposium in history on in vivo reprogramming for brain repair at the 2014 annual meeting of Society for Neuroscience in Washington, DC, and more than 800 people attended our symposium. As a leader in this emerging new field of in vivo reprogramming, I want to open a new research field and develop clinically effective therapy to treat ALS.

This 2-year Therapeutic Idea Award will allow us to finish the fundamental studies on in vivo reprogramming reactive astrocytes into functional motor neurons in ALS mouse models. If successful, we will apply for fast-track clinical trials to bring our cutting-edge technology from our lab bench to the bedside. In fact, many patients have already made phone calls or sent me emails to inquire when we can start clinical trials. We project that it may take 3-5 years to bring our new technology to clinical trial. However, if this ALS mouse model shows significant improvement after in vivo reprogramming, we may apply for earlier clinical trial from the FDA because currently there is no effective therapy that can substantially prolong the lifespan of ALS patients.