ALS is a progressive neurodegenerative disease that primarily affects motor neurons (MNs). It results in paralysis and loss of control of vital functions, such as breathing, leading to premature death. Life expectancy of ALS patients averages 2–5 years from diagnosis. About 5,600 people in the U.S. are diagnosed with ALS each year, and about 30,000 Americans have the disease. There is a clear unmet need for novel ALS therapeutics because no drug blocks the progression of ALS. This may be due to the fact that multiple proteins work together to cause the disease and therapies targeting individual toxic proteins will not prevent neurodegeneration due to other factors involved in the ALS disease process. We propose to develop a novel ALS therapy involving small molecule drugs that stimulate a natural defense system in MNs, autophagy, which will remove all of the disease-causing proteins in MNs to reduce neurodegeneration. We previously reported on a class of neuronal autophagy inducers (NAIs) and in this grant will prioritize those drugs for blocking neurodegeneration of human iPSC derived MNs from patients with familial and sporadic ALS to identify leads that will then be tested for efficacy in vivo in animal models of ALS to select a clinical candidate. Since all of our NAIs are FDA approved for treating indications other than ALS, our clinical candidate could be rapidly transitioned to testing for efficacy and safety in treating ALS patients near the end of this grant.
Neurodegenerative diseases such as ALS as well as Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s Disease (HD) are devastating to the patient and family and create a major financial burden to California (CA). These diseases are due to the buildup of toxic misfolded proteins in key neuronal populations that leads to neurodegeneration. This suggests that common mechanisms may be operating in these diseases. The drugs we are developing to treat ALS target this common mechanism, which we believe is an impairment of autophagy that prevents clearance of disease-causing proteins. Effective autophagy inducers we identify to treat ALS may turn out to be effective in treating other neurodegenerative diseases. This could have a major impact on the health care in CA. Most important in our studies is the translational impact of the use of patient iPSC-derived neurons and astrocytes to identify a new class of therapeutics to block neurodegeneration that can be quickly transitioned to testing in clinical trials for treating ALS and other CNS diseases. Future benefits to CA citizens include: 1) development of new treatments for ALS with application to other diseases such as AD, HD and PD that affect thousands of individuals in CA; 2) transfer of new technologies to the public realm with resulting IP revenues coming into the state with possible creation of new biotechnology spin-off companies and resulting job creation; and 3) reductions in extensive care-giving and medical costs.
ALS is a progressive neurodegenerative disease that primarily affects motor neurons (MNs). It results in paralysis and loss of control of vital functions, such as breathing, leading to premature death. Much scientific evidence indicates that ALS is due to the buildup of toxic misfolded proteins in key neuronal populations that leads to neurodegeneration. In this CIRM-funded project, we are developing drugs that can improve a cellular process called “autophagy” by which cells, including neurons, clear out built-up toxic misfolded proteins and increase their longevity. We had discovered that a series of FDA-approved drugs already on the market for other indications happen to induce autophagy in a manner that is independent of their original purpose. Our goal is to show that these FDA-approved drugs can induce autophagy and slow neurodegeneration in ALS patient-derived neurons, and to repurpose these drugs for ALS. In the last year, we have made significant progress towards testing these drugs on neurons that we derived from induced pluripotent stem cells engineered from skin cells taken from ALS patients. We have built robotic microscopes that can rapidly image ALS patient neurons that are treated with drugs in the lab and determine whether any of these “autophagy-inducing” FDA-approved drugs slowdown the rate of neurodegeneration. We have optimized large-scale methods to grow patient neurons, treat them with drugs, image them over many days, and analyze the images to measure neurodegeneration. In August 2014, we published a paper in the journal Nature Chemical Biology that showed two FDA-approved drugs can in fact induce autophagy and increase the clearing of an ALS-related protein called TDP43 in neurons. The drugs were also able to slow neurodegeneration in neurons and astrocytes derived from a familial ALS patient with an altered version of the TDP43 gene. We have now obtained stem cells from broader types of familial ALS as well as sporadic ALS patients, have made neurons from their stem cells, and have treated their stem cell-derived neurons with more than 10 autophagy-inducing drugs at varying concentrations to determine whether autophagy-inducers can slow neurodegeneration in neurons from broader forms of ALS. These neurons are currently being imaged using our robotic microscope. In addition, we have started to make astrocytes from patient stem cells and plan to test the drugs on astrocytes in the coming months.