SBIR-STTR Award

Development of a SYF2 antisense oligonucleotide treatment for ALS and FTD Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are complex diseases that result from many diverse genetic etiologies. Although therapeutic strategies that target specific causal mutations (e.g. C9ORF72 antisense oligonucleotides (ASOs)) may prove effective against individual forms of ALS or FTD, these approaches cannot address the vast majority of cases that have unknown genetic etiology. Moreover, given the large number of different genes that likely contribute to ALS and FTD and the fact that each genetic form is relatively rare, this strategy may be difficult to implement for all cases. Thus, there is a pressing need for new therapeutic strategies that rescue multiple forms of ALS and FTD, particularly those with unknown genetic etiologies. A hallmark pathological feature of ALS and FTD is the depletion of TAR DNA-binding protein 43 (TDP-43) from the nucleus of neurons in the brain and spinal cord to the cytoplasm where it aggregates into insoluble inclusion bodies in >95% of ALS cases and ~45% of FTD cases post mortem. While studies suggest that these neuronal TDP-43 aggregates drive neurodegeneration58, reduction in TDP-43 from the nucleus also alters the splicing or expression levels of more than 1,500 RNAs9, including disease hallmarks such as STMN2. Thus, both the loss of TDP-43 from the nucleus and its aggregation in the cytoplasm contribute to neurodegeneration, and it is critical to develop treatments that address both aspects of this challenging pathology. We found that suppressing the gene encoding the spliceosome-associated factor SYF2 alleviates TDP-43 aggregation and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and sporadic ALS survival. Moreover, Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Mice with one loss-of-function copy of Syf2 are healthy and humans carrying a loss-of-function SYF2 allele are not affected by pediatric diseases or known to be affected by disease in adulthood. Thus, suppression of spliceosome-associated factors such as SYF2 is a promising and broadly-effective genetic target for ALS and FTD. Antisense oligonucleotides (ASOs) are an attractive approach for genetic targets in the central nervous system (CNS) like SYF2 because they can be injected directly into the spinal cord, achieve sustained target engagement throughout the CNS, and are less likely to cause peripheral toxicity. Leveraging our proprietary ASO design software, we assessed all possible SYF2 ASO sequences in silico and prioritized several hundred leads predicted to have enhanced stability and manufacturability, and reduced immunogenicity and off-target effects. The objective of this Direct to Phase 2 project is to identify a bona fide development candidate SYF2 ASO from among these leads for advancement in investigational new drug (IND)-enabling toxicity studies. The broad aims of the project are to establish the therapeutic index of Syf2 suppression in TDP-43 mice, assess SYF2 leads for potency, efficacy and tolerability in a large panel of ALS patient-derived neurons and a bacterial artificial chromosome human SYF2 transgenic mouse, and lastly to assess the leads in an exploratory toxicity study in rodents.

Public Health Relevance Statement:
Development of a SYF2 antisense oligonucleotide treatment for ALS and FTD Project Narrative Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are complex diseases that result from many diverse causes. While there are currently no drugs that slow the progression of ALS or FTD, most of the new promising therapeutic strategies are focused narrowly on modifying the specific genetic mutations known to cause disease, however these treatments won't work for the vast majority (>80% in ALS) of patients for whom the genetic cause of their disease is not known. Therefore, AcuraStem's focus has been to develop treatments that can work for all ALS and FTD patients, including those for whom the genetic factors driving their disease have yet to be discovered - a large population with urgent unmet need.

Project Terms:
ALS therapy; ALS treatment; amyotrophic lateral sclerosis treatment; amyotrophic lateral sclerosis therapy; 21+ years old; Adult Human; adulthood; Adult; Affect; Allelomorphs; Alleles; Amyotrophic Lateral Sclerosis Motor Neuron Disease; Gehrig's Disease; Lou Gehrig Disease; Amyotrophic Lateral Sclerosis; Automobile Driving; driving; Autopsy; necropsy; postmortem; Brain; Brain Nervous System; Encephalon; Cell Nucleus; Nucleus; Inclusion Bodies; Cellular Inclusions; Cytoplasm; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Exons; Genes; Government; Human; Modern Man; Investments; Transgenic Mice; Mus; Mice; Mice Mammals; Murine; Persons; Nerve Degeneration; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; Neuromuscular Junction; Myoneural Junction; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Pathology; Patients; Phenotype; Probability; RNA; Non-Polyadenylated RNA; RNA Gene Products; Ribonucleic Acid; RNA Splicing; Splicing; Rodent; Rodentia; Rodents Mammals; Software Design; Designing computer software; Spinal Cord; Medulla Spinalis; Tissues; Body Tissues; Work; stathmin; Lap18 protein; leukemia-associated phosphoprotein p18; metablastin; oncoprotein 18; phosphoprotein p18; phosphoprotein p19; prosolin; Generations; Antisense Oligonucleotides; Anti-Sense Oligonucleotides; Antisense Agent; anti-sense agent; anti-sense oligo; antisense oligo; Data Set; Spliceosomes; improved; Peripheral; Phase; Chemicals; Evaluation; motor disease; motor dysfunction; motor disorder; pediatric; Childhood; Individual; TAR DNA-binding protein 43; TDP-43; TDP43; protein TDP43; protein TDP-43; Therapeutic; Genetic; Genetic Predisposition to Disease; Genetic Predisposition; Genetic Susceptibility; Genetic propensity; Inherited Predisposition; Inherited Susceptibility; genetic etiology; genetic mechanism of disease; genetic vulnerability; genetically predisposed; Frontotemporal Dementia; Frontal Temporal Dementia; front temporal dementia; frontal lobe dementia; frontotemporal lobar dementia; frontotemporal lobe degeneration associated with dementia; Complex; success; cohort; Toxic effect; Toxicities; Therapeutic Index; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; Bacterial Artificial Chromosomes; BAC clone; BACs; Artificial Human Chromosomes; Central Nervous System; CNS Nervous System; Neuraxis; Bio-Informatics; Bioinformatics; C9ORF72; chromosome 9 open reading frame 72; Address; Dose; DNA Sequence Alteration; DNA Alteration; DNA mutation; Genetic mutation; Sequence Alteration; genomic alteration; Pre-Clinical Model; Preclinical Models; Pathologic; Development; developmental; immunogenicity; designing; design; Outcome; Population; Amyotrophic lateral sclerosis and frontotemporal degeneration; Amyotrophic lateral sclerosis and frontotemporal dementia; FTD/ALS; FTLD/ALS; Frontotemporal Lobar Degeneration/Amyotrophic lateral sclerosis; amyotrophic lateral sclerosis with frontotemporal dementia; amyotrophic lateral sclerosis/FTLD; amyotrophic lateral sclerosis/frontotemporal dementia; amyotrophic lateral sclerosis/ftd; frontotemporal dementia-amyotrophic lateral sclerosis; frontotemporal lobar dementia amyotrophic lateral sclerosis; murine model; mouse model; loss of function; commercialization; new drug target; new druggable target; new pharmacotherapy target; new therapy target; novel drug target; novel druggable target; novel pharmacotherapy target; novel therapeutic target; novel therapy target; new therapeutic target; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; new treatment approach; new treatment strategy; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; novel therapeutic intervention; bio-markers; biologic marker; biomarker; Biological Markers; screenings; screening; genetic strategy; genetic approach; glial cell activation; glial activation; Amyotrophic Lateral Sclerosis patients; ALS patients; lead candidate; manufacturability; causal allele; causal gene; causal mutation; causative mutation; causative variant; causal variant; in silico; TDP-43 aggregate; TDP43 aggregate; TDP43 aggregation; TDP-43 aggregation; sALS; sporadic ALS; sporadic amyotrophic lateral sclerosis