UNC13A

UNC13A is an essential regulator of neurotransmitter release at synapses; mis-splicing is a critical RNA alteration occurring in up to 63 percent of all ALS patients and up to one-third of all FTD cases Preclinical data to be featured in a poster presentation at AD/PD™ 2024 CAMBRIDGE, Mass., March 4, 2024 /PRNewswire/ -- QurAlis Corporation, a clinical-stage biotechnology company driving scientific breakthroughs into powerful precision medicines that will alter the trajectory of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative diseases, today announced preclinical data that showed the company's UNC13A splice-switching antisense oligonucleotides (ASOs) modulate UNC13A splicing and restore normal synaptic activities in ALS and FTD. QurAlis' ASOs prevented cryptic exon inclusion in UNC13A transcripts, increased UNC13A protein levels, and normalized localization of UNC13A protein at the synapse. Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by the loss of neurons in the spinal cord, brainstem, and brain. A defining feature of both sporadic and familial disease is the cytoplasmic mis-localization of TAR DNA Binding Protein-43 (TDP-43). TDP-43 pathology is implicated in 95 percent of ALS cases and 50 percent of FTD cases. UNC13A is an essential regulator of neurotransmitter release at synapses and is one of a number of pre-mRNAs that becomes mis-spliced due to loss of nuclear TDP-43 in disease. Up to 63 percent of ALS patients and up to one-third of FTD patients carry a single nucleotide polymorphism in the UNC13A gene or show TDP-43 pathology which greatly exacerbates UNC13A mis-splicing leading to loss of function of the UNC13A protein. "There are currently no cures for ALS or FTD and limited therapeutic options are available for ALS and FTD patients who are in desperate need for effective therapies," said Dan Elbaum, Ph.D., chief scientific officer of QurAlis. "QurAlis has identified ASOs that modulate UNC13A splicing and restore normal synaptic activities. We believe that correction of UNC13A splicing can provide therapeutic benefit in relevant patient populations." These data will be featured in a poster presentation at the AD/PD™ 2024 International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders being held March 5-9, 2024 in Lisbon, Portugal. Details of the presentation are as follows: Title: UNC13A Targeting Splice Switching ASOs Ameliorate TDP-43 Dependent Mis-splicing Phenotypes in FTD and ALS Date(s)/Time: Thursday, March 7, 2024, and Friday, March 8, 2024 at 1:50-3:50PM CET Poster and Abstract Number: P1214 / 2851 Poster Topic: FTD, ALS: TDP43, C9orf72, and TMEM106B 1 Session: D02 Therapeutic Targets, Mechanisms for Treatment Location: Auditorium VIII Presenter: Marisa Kamelgarn, Ph.D., senior scientist, QurAlis Splice-switching oligonucleotides targeting UNC13A were screened via quantitative polymerase chain reaction (qPCR) and a small subset demonstrated correction of splicing and rescue of protein. From those rescue experiments, ASOs were used for functional assay testing. Using in-house models of induced pluripotent stem cell (iPSC) motor and cortical neurons, QurAlis established a phenotype to demonstrate the cellular consequences of UNC13A mis-splicing due to TDP-43 loss of function. TDP-43 mediated UNC13A loss partially disabled SNARE complex assembly and evoked synaptic vesicle release in human motor neurons. QurAlis' ASOs restored all or some aspects of SNARE complex assembly and synaptic vesicle fusion and release. About QurAlis' FlexASO™ Splice Modulator Platform Incorporating its proprietary FlexASO™ Splice Modulator Platform, QurAlis' ASOs correct UNC13A mis-splicing, restore UNC13A protein production, and reduce cryptic exons that may contribute to disease progression. The QurAlis FlexASO Splice Modulator Platform was developed to generate splice-switching ASOs with improved potency and an increased therapeutic index. In addition to UNC13A, QurAlis is currently exploring this ASO technology for multiple other disease targets. About QurAlis Corporation At QurAlis, we are neuro pioneers on a quest to cure. We work with a relentless pursuit of knowledge, a precise attention to craft, and an optimistic mindset to discover and develop effective precision medicines that will alter the trajectory of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative diseases. Founded by an internationally recognized team of neurodegenerative biologists from Harvard Medical School and Harvard University, QurAlis is advancing a pipeline with therapeutic candidates that target specific components of ALS and FTD pathology and defined patient populations based on both disease-causing genetic mutation(s) and clinical biomarkers. For more information, please visit or follow us on Twitter @QurAlisCo. SOURCE QurAlis

AcuraStem Leverages iNeuroRx® Platform to Drive Innovative SYF2 and UNC13A Treatments Forward Toward Clinical Trials PASADENA, Calif., Jan. 30, 2024 /PRNewswire/ -- AcuraStem, a patient-based biotechnology company advancing treatments for amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative diseases, announced today that it has successfully raised nearly $7 million in grant funding for ALS / FTD research from the National Institutes of Health (NIH) and the Department of Defense (DOD). This latest achievement—building upon the recent licensing agreement with Takeda worth $580 million to develop and commercialize AcuraStem's PIKFYVE targeted therapeutics including AS-202—enables the company to advance multiple programs towards clinical trials. "We are thrilled to receive continued support from NIH and the DOD," said Sam Alworth, MS, MBA, AcuraStem co-founder and CEO. "Leaders from the scientific community selected AcuraStem for these awards through a rigorous peer-review process, which demonstrates the excellence of our research." AcuraStem has made a significant advancement in understanding the pathophysiology of ALS, focusing on the crucial role of UNC13A. An overwhelming majority of ALS cases, and roughly half of FTD cases, are characterized by TDP-43 pathology. TDP-43, a RNA-binding protein typically found in the nucleus, is mislocalized to the cytoplasm in affected neurons, leading to RNA processing errors. These errors result in the incorporation of a cryptic exon into the UNC13A messenger RNA, causing a loss of UNC13A protein. This loss is further exacerbated by a risk variant in the UNC13A gene, closely linked to the TDP-43 binding site and associated with reduced survival in ALS and FTD patients. AcuraStem's iNeuroRx® platform has successfully replicated UNC13A pathology in patient neurons, enabling the rapid development and testing of antisense oligonucleotides (ASOs). These ASOs effectively suppress the cryptic exon and restore normal UNC13A function, offering a promising therapeutic approach for TDP-43 proteinopathies and a deeper understanding of UNC13A's role in disease progression. Additionally, AcuraStem has made a pivotal discovery with its focus on SYF2, a novel target in TDP-43 pathology. In collaboration with co-founder Dr. Justin Ichida's lab at USC, AcuraStem's extensive research on patient neurons via the iNeuroRx® platform, coupled with a comprehensive bioinformatic analysis, identified SYF2 as a key therapeutic target. SYF2, a pre-mRNA splicing factor, plays a crucial role in the regulation of splicing affected by the depletion of nuclear TDP-43, a common feature in most ALS cases (Linares GR et al Cell Stem Cell 2023). AcuraStem's findings highlight that SYF2 can address both the toxic aggregation of TDP-43 in cytoplasm and also counter the widespread gene dysregulation, including critical genes like UNC13A and STMN2, caused by TDP-43's absence from the nucleus. Targeting SYF2 could offer a more direct and potentially effective therapeutic strategy compared to addressing each dysregulated gene individually. Funding from NIH and the DOD was awarded through rigorous peer-reviewed processes, suggesting the award matches the health-related missions established by each agency. For additional information, please visit AcuraStem at acurastem.com and follow on LinkedIn, Facebook and X. Disclaimer This project will be supported by an NIH grant (R44AG085411). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, or the U.S. Army Medical Research Acquisition Activity at the U.S. Army Medical Research and Development Command, in the amount of $839,898.40 through the ALSRP under Award No. HT9425-23-1-0469. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. About AcuraStem AcuraStem is a patient-based biotechnology company pioneering treatments for neurodegenerative diseases including sporadic ALS and FTD. AcuraStem's best-in-class disease modeling platform, iNeuroRx®, enables the discovery of innovative, effective, and broadly acting treatments. The team's strong expertise in ASO technology provides for the rapid advancement of treatments to the clinic. AcuraStem's research is funded in part by support from the Alzheimer's Drug Discovery Foundation, Harrington Discovery Institute, Alzheimer's Association, Rainwater Charitable Foundation, Muscular Dystrophy Association, Department of Defense and the National Institute of Neurological Disorders and Stroke. Contact: Kissy Black [email protected] 615.310.1894 SOURCE AcuraStem - Patient-Based Therapeutics

New location in Leiden, The Netherlands will serve as hub for European operations and production of QurAlis' products for clinical trials through commercialization CAMBRIDGE, Mass., Jan. 3, 2024 /PRNewswire/ -- QurAlis Corporation, a clinical-stage biotechnology company driving scientific breakthroughs into powerful precision medicines that will alter the trajectory of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative diseases, today announced the opening of its European Union (EU) headquarters in Leiden, The Netherlands. This new location will serve as the hub for the Company's European operations including the production of QurAlis' products for its clinical trials through commercialization. "The expansion of our operations into Europe represents a new chapter for QurAlis, building upon the tremendous momentum of our organization," said Kasper Roet, Ph.D., CEO and co-founder of QurAlis. "In a short period of time, QurAlis has made significant progress with regulatory approvals for our clinical programs in the EU, Canada, and the UK. The successful completion of the quality systems inspection by the Dutch regulatory agency will allow us to directly leverage our world-class ASO manufacturing expertise and control our end-to-end production supply chain. With our new European headquarters, and the skilled talent network in Leiden and the region, we will further strengthen our position as we bring breakthrough precision medicines to patients with ALS, FTD, and other neurodegenerative diseases." QurAlis is currently advancing a pipeline with therapeutic candidates that target specific components of ALS pathology and defined ALS patient populations based on both disease-causing genetic mutations and clinical biomarkers. The company is focused on patients who have a loss of Kv7.2/7.3, patients who have loss of STATHMIN-2, as well as patients with loss of UNC13A and impairment in synaptic signaling. The QurAlis team is leveraging insights, platforms, and successes in ALS to collaborate and expand its pipeline to other neurodegenerative diseases, such as FTD. There are currently no cures for ALS or FTD. Limited therapeutic options are available for ALS and FTD patients who are in desperate need for effective therapies. "QurAlis' new location in Leiden is designed to not just meet our current needs, but also to scale with our business as we continue to grow," said Hagen Cramer, Ph.D., chief technology officer of QurAlis. "Our new European headquarters will allow us to release ASOs and other products into the European market for our programs so that we can deliver innovative solutions and make a meaningful difference in patients' lives." In addition to the new Leiden office, QurAlis' global corporate headquarters are in Cambridge, Massachusetts. About QurAlis Corporation At QurAlis, we are neuro pioneers on a quest to cure. We work with a relentless pursuit of knowledge, a precise attention to craft, and an optimistic mindset to discover and develop effective precision medicines that will alter the trajectory of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative diseases. Founded by an internationally recognized team of neurodegenerative biologists from Harvard Medical School and Harvard University, QurAlis is advancing a pipeline with therapeutic candidates that target specific components of ALS and FTD pathology and defined patient populations based on both disease-causing genetic mutation(s) and clinical biomarkers. For more information, please visit or follow us on Twitter @QurAlisCo. SOURCE QurAlis