Novel CDNF Variants and Optimizing Delivery in SOD1 Mouse Model: Toward Successful Clinical Trials
Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal, motor neuron (MN) disease characterized by progressive degeneration of MNs. About 5%-10% of ALS is familial, while the remaining 90%-95% of people diagnosed with ALS are classified as having an apparently sporadic form of the disease. There is no treatment for ALS that could halt the progression or cure the disease; thus, there is a crucial medical need to find drug therapies that would slow disease progression, treat the disease, and extend survival of the patients. The clinical hallmark of ALS is the combination of upper and lower MN signs and symptoms, causing muscle weakness with a wide range of disabilities. Most patients with ALS die from respiratory failure, usually within 1 to 3 years from the onset of symptoms Neurotrophic factors (NTFs) are small secretory proteins that regulate the survival of neurons, neurite growth and branching, and neuronal phenotype. Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) enhance embryonic MN survival in vitro and also decrease MN death in vivo, but clinical trials with NTFs on the ALS patients have been unsuccessful. In 2007, we discovered a novel NTF called Cerebral Dopamine Neurotrophic Factor (CDNF). CDNF has unique structure and mode of action unlike other NTFs. CDNF protects and restores dopaminergic neurons in rat and mouse model of Parkinson s disease. CDNF and the related mesencephalic astrocyte-derived neurotrophic factor (MANF) are stable proteins, which diffuse better than any other trophic factor in brain tissue. We recently found that a single injection of CDNF increases survival and improves motor coordination in SOD1-G93A mouse model of ALS. CDNF also preserves innervation at neuromuscular junctions (gastrocnemius muscle) at the end stage of disease and protects MNs in spinal cord and also reduces endoplasmic reticulum (ER) stress in SOD1-G93A mouse model of ALS. No other NTF or drug has been that effective. CDNF and the related MANF are stable proteins, which diffuse better than any other trophic factor in brain tissue. CDNF and MANF have a unique three-dimensional structure consisting of two structurally independent domains: N-terminal domain and C-terminal domain. Based on our new unpublished results, CDNF variant is more effective than full CDNF in an experimental Parkinson s disease model in rats and in addition, our recent unpublished data from distribution studies in suggest that C-CDNF can pass the blood-brain barrier. This proposal has three goals: (1) Test the therapeutic effect of the CDNF variants in genetic models of ALS; (2) optimize and compare the therapeutic effect of constitutive and regulated expression of CDNF and CDNF variants using adeno-associated viral (AAV) vectors in SOD1 mice; and (3) examine the effects of CDNF on ER stress and oxidative stress caused by ALS. This is an ambitious but feasible project that, with the expertise of the various Co-Principal Investigators, we will conduct experiments that test and optimize delivery of CDNF and its fragments in SOD1 mouse and rat models of ALS to move CDNF towards successful clinical trials in 2018-2019. We hypothesize that CDNF treatment will be of significant benefit to ALS patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710074
Entities
People
- Mart Saarma
Organizations
- United States Army
- University of Helsinki