ALS is a devastating neurodegenerative disease with two FDA-approved therapies that can prolong a patientÂ’s lifespan by only a few months. Thus, an effective therapeutic to treat ALS is needed. ALS can arise sporadically or through inherited mutations in one or a combination of several genes. The heterogeneity of ALS makes it difficult to create a therapeutic that can effectively treat a broad ALS patient population. However, many cases share a common pathological hallmark: the presence of the protein TDP-43 within neuronal inclusions. Recent research has shown that loss of normal TDP-43 function leads to the incorrect splicing of stathmin-2 (STMN2), a protein essential for neurite extension and maintenance of the neuromuscular junction. Indeed, in vitro evidence demonstrates that restoring STMN2 levels rescues motor neuron growth, and STMN2 protein levels are low in ALS patients. Since TDP-43 mislocalization and low STMN2 levels are common among sporadic and inherited ALS cases, STMN2 is a novel gene target to treat ALS. QurAlis has demonstrated that antisense oligonucleotides (ASO) can restore STMN2 RNA expression in a dose-dependent manner and can restore STMN2 protein levels in motor neurons derived from induced pluripotent stem cells lacking TDP-43. Since TDP- 43 regulation of STMN2 splicing only occurs in humans, no animal efficacy testing can be performed on our four Lead ASO candidates. Thus, with this proposal, QurAlis will develop a method for ASO detection after intrathecal ASO delivery and perform a dose-range finding study in rats (Phase I) and then with our Clinical Candidate ASO, validate the ASO detection assay and perform IND-enabling toxicology studies (Phase II). These studies will then allow QurAlis to file an IND with the FDA and begin a clinical trial testing the ASO efficacy in ALS patients.
Public Health Relevance Statement: PROJECT NARRATIVE ALS is a devastating neurodegenerative disease in part characterized by TDP-43 dysfunction, which has been recently implicated in the loss of Stathmin-2 (STMN2), a protein critical for neuronal process outgrowth and maintenance of the neuromuscular junction. TDP-43 dysfunction occurs in greater than 90% of all ALS patients, suggesting that therapies targeting restoration of STMN2 could benefit most patients. Thus, QurAlis is developing therapeutic antisense oligonucleotides (ASO) that will correct the misregulation of STMN2 to rescue neurons from axonal degeneration.
Project Terms: ALS patients; Amyotrophic Lateral Sclerosis; animal efficacy; Antisense Oligonucleotides; Axon; axonal degeneration; base; Biodistribution; Biological Assay; Chemistry; clinical candidate; Clinical Trials; Collection; Data; design; Detection; Development; Diagnosis; disease-causing mutation; Distant; Dose; Drug Kinetics; efficacy testing; Enzyme-Linked Immunosorbent Assay; Evaluation; exon skipping; Exons; familial amyotrophic lateral sclerosis; FDA approved; Functional disorder; functional loss; Gene Targeting; Genes; Genetic; Genetic Transcription; Growth; Hereditary Disease; Heterogeneity; Human; In Vitro; in vivo; induced pluripotent stem cell; Inherited; Intrathecal Injections; Lead; lead series; Length; Link; Longevity; loss of function; Maintenance; Medical; Messenger RNA; method development; Methods; Modeling; Motor Cortex; Motor Neurons; Mutation; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; No-Observed-Adverse-Effect Level; novel; Pathologic; Pathology; patient population; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Polyadenylation; preclinical development; premature; Prevalence; Process; protein TDP-43; Proteins; Rattus; Regulation; repaired; Research; restoration; Rivers; RNA; RNA metabolism; RNA Sequences; RNA Splicing; Safety; Sensitivity and Specificity; Series; Signal Transduction; Spinal Cord; Spinal Muscular Atrophy; stathmin; targeted treatment; Testing; Therapeutic; Tissues; Toxicology; Treatment Efficacy; Validation
