Development of an UNC13A Antisense Oligonucleotide Treatment for ALS and FTD
Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a complex disease with diverse genetic causes. While a few genes are known to cause ALS (i.e., SOD1, C9ORF72, etc), these only account for around 15% of patients. We know that most of the other 85% of ALS patients also have genetic causes, because twin studies have shown that ALS is highly heritable, but those causes are unknown (these patients are referred to as sporadic ALS). A major focus of AcuraStem is to develop therapeutic treatments that will work for most ALS patients, both sporadic and genetically defined. Recent research has identified an event that appears to be early in ALS disease progression and central to ALS pathology. In >95% of ALS cases a protein TDP-43 is inexplicably lost from the nucleus of neurons and forms into toxic cytoplasmic aggregates. While most treatments in development focus on pathology resulting from the aggregates, the new research focuses on pathology resulting from the loss of TDP-43 in the nucleus. TDP-43 is involved in RNA processing -- the act of turning DNA into messenger RNA and thus into proteins. The researchers identified that, when TDP-43 is absent from the nucleus, a piece of intronic DNA (i.e., the non-coding region) from the UNC13A gene, is mistakenly included into the mRNA and less UNC13A protein is made. This mistaken piece of mRNA is referred to as a cryptic exon. This UNC13A cryptic exon has now been identified in post-mortem brain samples from many ALS and FTD patients that have the TDP-43 pathology. This is exciting because a genetic mutation in UNC13A has been known for many years as a major risk factor for ALS. Now we know why. The mutation is in the same region where the cryptic exon gets included into the mRNA and it makes it worse. If you have the mutation on both alleles you get more cryptic exon than if you have the mutation on one allele, which provides more cryptic exon than if you are an ALS patient but don’t have the mutation. Similarly, patients who have the mutation have a dose-dependent reduction in survival as compared to other patients that don’t have the mutation. This strongly suggests that the disruption to the UNC13A protein is central to disease pathology, and that fixing this could have substantial therapeutic benefit. Furthermore the treatment would be relevant to all patients who have TDP-43 pathology (not just the UNC13A mutation carriers), since they all have the cryptic exon which is caused by the loss of TDP-43 from the nucleus. Project Objectives: AcuraStem has a proven platform comprising cellular models of ALS derived from ALS patients. We were able to recapitulate the cryptic exon event on our platform and design drugs that suppress the cryptic exon and restore normal UNC13A protein levels. In this project we will develop functional experiments that will help us understand exactly how the cryptic exon disrupts UNC13A and its impact on neurotransmission. This will give greater confidence that targeting the cryptic exon will make a big impact for patients. In parallel, we will make a mouse model of the human cryptic exon event to ensure our drugs suppress the cryptic exon in a living animal. Lastly we will identify potential target engagement biomarkers -- proteins or mRNA that we can measure in patient biofluids to estimate the potency of a given dose level in the clinic. At the end of this project we will have the assays established that we can use to optimize our drug candidates and identify a bona fide development candidate for advancement into toxicity studies -- a major milestone. Clinical Application and Timelines: The genetic studies show a 3- to 4-year survival benefit for patients without the UNC13A mutation versus mutation carriers, and provides an estimate of potential clinical benefit. No other drugs in the ALS pipeline have such compelling genetic data. No animal model correctly recapitulates the cryptic exon pathology and it will take years t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310469
Entities
People
- Zhihua Feng
Organizations
- United States Army