Development of a PIKFYVE Antisense Oligonucleotide Treatment for ALS
Abstract
While there are a number of gene therapy approaches in development for amyotrophic lateral sclerosis (ALS), these only target known genetic causes of the disease such as mutations in the SOD1 or C9ORF72 genes. Unfortunately, the vast majority of ALS patients (> 80%), referred to as sporadic ALS patients, do not have a known genetic cause for their disease, despite the fact that ALS is a highly heritable disease and their form of ALS likely derives from genetic causes. Therefore, since many of the larger biopharma companies are focused on treating known genetic causes of ALS, AcuraStem has made a major push to identify therapeutic approaches that will work broadly across different types and for the majority of ALS patients. AcuraStem’s platform utilizes cellular reprogramming technology to create living motor neurons from ALS patients with both sporadic and known genetic causes of disease. We used this platform to scan in an unbiased fashion for therapeutic approaches that could help the diseased patient neurons function more like healthier motor neurons from healthy donors. We have tested in over 20 ALS patients with different forms of ALS; there are many differences between patients in what works. We found that reducing the functionality of a protein called PIKFYVE is the most effective way to help motor neurons from most ALS patients. One of the most common features of neurodegenerative diseases is that the neurons in the brain have trouble clearing aggregated and misfolded proteins, and this ultimately results in the death of the neurons (neurodegeneration). It turns out that reducing the function of PIKFYVE triggers the cells to engage an alternative method to clear these clogged proteins. This alternative method, called secretory autophagy, is highly innovative and has yet to be tested in the clinic for neurodegenerative diseases. A small molecule that reduces the function of PIKFYVE has been tested safely in the clinic for autoimmune disorders, but it is not a good drug for ALS because it does not do a good job getting past the blood brain barrier and into the central nervous system (CNS) where it needs to do its job. Antisense oligonucleotides (ASOs) are a type of gene-targeted therapy that can be used to reduce the function of PIKFYVE by suppressing the PIKFYVE gene. While they are not as convenient to take as a small molecule, ASOs are injected into the spine (and CNS) similar to an epidural block given during childbirth and therefore they do not need to be engineered to cross the blood brain barrier, they are relatively restricted to the CNS, which may cause less toxicity than a small molecule that distributes throughout the body, and they are much faster to manufacture and get into the clinic. For all of these reasons, AcuraStem is developing an ASO therapeutic to suppress PIKFYVE. Our research has shown that ASO-mediated suppression of PIKFYVE helps prevent degeneration of patient motor neurons in a dish, and strongly prevents loss of motor function in an ALS mouse model. The approach has been tested in multiple animal models of ALS with positive results. Importantly, it has not caused toxicity in the human motor neurons nor in animal models. The objective of this project is to further validate the efficacy and safety of our development candidate ASO called AS-202. We will further test the ASO in motor neurons from a larger number of ALS patients and in a larger cohort of mice to assess its efficacy and safety. In addition, it is important that we develop a way to assess that the ASO is doing its job in the body when we start clinical trials, so a big part of this project is to develop such a mechanistic biomarker for use in animal toxicity testing and in future clinical trials. The final part of this project is the manufacture of the AS-202 drug product for use in comprehensive toxicity studies in rats and nonhuman primates under good laboratory practice standard. These studies will ena
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110355
Entities
People
- Wen-hsuan Chang
Organizations
- United States Army