POLG

– First-in-class approach to targeting mitochondrial DNA polymerase (POLG) with disease modifying potential across mitochondrial DNA depletion syndromes (MDDS) and broader neurodegenerative diseases – – Regulating cellular bioenergetics to impede disease progression and severity across high unmet need indications – – Awarded grant from Parkinson’s UK to evaluate POLG activation mechanisms in Parkinson’s disease models – WALTHAM, MA, USA I April 03, 2025 I Pretzel Therapeutics, a leader in harnessing cellular energetics to develop novel treatments for a range of conditions spanning neurological, muscular atrophies, metabolic and rare disease, today announced that it has initiated recruitment in a Phase 1 clinical study of PX578, the lead therapeutic in its bioenergetics restoration franchise. The randomized, double-blind, placebo-controlled study is designed to evaluate the safety, tolerability and pharmacokinetics of single and multiple ascending doses of PX578 in healthy adult participants, with a potential clinical trial in MDDS patients planned for 2026. The initiation of our Phase 1 clinical trial of PX578 reflects the important progress we are making in turning our unique bioenergetics approach into a reality, with a deep, first-in-class pipeline. Share “The initiation of our Phase 1 clinical trial of PX578 reflects the important progress we are making in turning our unique bioenergetics approach into a reality, with a deep, first-in-class pipeline of energetics restoring and energetics modulating compounds to positively impact high unmet need indications,” said Jay Parrish, Ph.D., Chairman of the Board and Chief Executive Officer of Pretzel. “Our energetics restoration franchise, led by PX578, our small molecule POLG activator, has broad potential spanning from rare mitochondrial DNA depletion syndromes for which there are no disease-modifying treatments to larger neurodegenerative conditions, such as Parkinson’s and Alzheimer’s disease. We look forward to reporting further progress in the months to come.” The company also announced that it has been awarded grant funding from Parkinson’s UK to support evaluation of Pretzel’s POLG activation mechanism in Parkinson’s disease models in collaboration with Dr. Roberta Filograna’s lab at the Karolinska Institute, Stockholm, Sweden. “We’re excited to be funding Pretzel Therapeutics to take early but important steps in the development of a compound that has potential for the treatment of Parkinson’s. Targeting the mitochondria, specifically boosting levels of mitochondrial DNA, could lead to us finding a way to slow or stop Parkinson’s, something that no treatment can currently do,” said Professor David Dexter of Parkinson’s UK. About Pretzel Therapeutics Pretzel Therapeutics is dedicated to developing life-changing medicines with a broad pipeline of first-in-class treatments addressing novel targets within the mitochondria. By harnessing cellular energetics to modulate disease processes and improve survival, function and quality of life, we are ushering in a new treatment paradigm for a breadth of conditions spanning neurological, muscular atrophies, metabolic and rare disease. PX578, the lead therapeutic in Pretzel’s bioenergetics restoration franchise, represents a first-in-class approach to targeting mitochondrial DNA polymerase (POLG) across mitochondrial DNA depletion syndromes (MDDS). PX578 is in Phase 1 clinical development . POLRMT, the lead program in our energetics modulation franchise, targets mitochondrial RNA polymerase for the treatment of metabolic conditions including obesity. POLRMT is in late preclinical development. The company is headquartered in Waltham, MA and has research facilities in Mölndal, Sweden. For more information, visit www.pretzeltx.com . SOURCE: Pretzel Therapeutics

Scientists report that a progressive neurodegenerative disease can be triggered by a viral infection. The mechanism relates to mitochondrial roles in antiviral defense mechanisms. A multidisciplinary team of scientists led by University of Helsinki report that a progressive neurodegenerative disease can be triggered by a viral infection. The mechanism relates to mitochondrial roles in antiviral defense mechanisms. The scientists report that a specific gene variant affecting the mitochondria disturb cellular antiviral defense responses. The results implicate that viral infections can trigger and modify symptoms of neurological diseases in subjects carrying genetic sensitivity. The article is published in Nature. Viking-age gene mutation alters viral defense Why a disease manifests at a certain age, and what kind of triggers may be involved, are still open questions. Recent data indicate that mitochondria, the cellular centers of energy and nutrient metabolism, have new important roles in protecting cells from both internal and external stresses. Importantly, a novel role of mitochondria in strengthening the immune system has been recognized, but the relevance of these functions for human diseases has been unclear. The current study shows that deficient mitochondrial functions in immune defense is connected to manifestation of brain diseases and sometimes also liver dysfunction. A multidisciplinary team led by academy professor Anu Suomalainen discovered that a genetic variant affecting the function of mitochondrial POLG enzyme delays detection of viral infection, leading to delayed severe inflammatory reaction damaging the brain and liver. The POLG variant originates from a single individual dating back to Viking times and has spread to populations of European origin. Especially Northern European countries show high carrier frequencies: one in a hundred individuals in Finland and Norway. If a subject inherits the POLG-variant from both parents, a neurological disease, MIRAS (mitochondrial recessive ataxia syndrome), manifests. However, the ages of onset and manifestations of MIRAS are highly variable, raising the question whether the disease is triggered by additional factors. Using a variable set of model systems, the team shows that the POLG variant leads to a weakened initial immune activation in response to viral infection, followed by a delayed, overactivated inflammation damaging the brain and liver. The scientists suggest that this mechanism explains why some MIRAS patients manifest in teenage with severe epilepsy, while some other patients with the same genetic background show disease signs years or even decades later, as motor coordination defects or Parkinson's disease. "Our results indicate that external factors, such as viral infections, can modify manifestation and age-of-onset of neurological diseases," postdoctoral scientist Yilin Kang comments. "Identification of susceptibility factors and triggering mechanisms are valuable targets for new therapy developments. The current findings indicate the importance of new mitochondrial functions in maintaining brain health." The work has been made possible by Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Research Council of Finland , European Molecular Biology Organization and PolG foundation.

NEW YORK and PARIS, Nov. 15, 2023 /PRNewswire/ --The PolG Foundation is a nascent foundation established in 2022 by a PolG family, with the mission to support and accelerate research to find effective treatments and a cure for PolG mitochondrial disorders. To view the Multimedia News Release, please click: Continue Reading THE PoLG FOUNDATION ©Mei Fa Tan , Montreux Media Ventures With both a dedicated and experienced Board of Directors and Scientific Advisory Board, including some of the top mitochondrial scientists in the world, the Foundation is quickly becoming a leading funder of basic, translational, and clinical PolG research. Working with the global scientific community, we are investing in developing critical tools and continue to make our findings available to mitochondrial scientists, clinicians, and patients worldwide. In addition to the development of IPS Cell Lines, RNA Sequencing and two transgenic mouse models for the use of PolG researchers, the Foundation is also actively working on the creation of a PolG global registry and prospective natural history study. Frederik de Nassau, a POLG warrior and son of founding parents, designs a MITO clothing line to raise awareness and funds for The PolG Foundation. View Shop - A central pillar of the Foundation is to raise funding and provide grants to world-class investigators of basic science, clinical trial research and development of novel therapies for PolG mitochondrial disorders in both paediatric and adult PolG populations. Today, The PolG Foundation is pleased to announce four awardees granted to our first Call for Research Initiatives proposals. We are excited to see these grants being implemented by the four research groups who will pursue outstanding R&D work in the field of POLG biology: Prof Vamsi K. Mootha Broad Institute of MIT and Harvard, Boston (USA) Title: A variant-to-function map of POLG via deep mutational scanning Synopsis of the work: POLG-deficiency is associated with tremendous allelic heterogeneity, and at present it is very challenging to know which observed variants are benign versus pathogenic. The goal is to create a comprehensive dashboard for POLG that connects all possible variants to biological and biochemical functions. Next generation DNA synthesis to create a saturation mutagenesis library for POLG will be combined with functional genetic screens that quantitatively score POLG variants. It will be a durable toolbox that will be valuable for both basic research and clinical communities. Prof Anu Suomalainen Wartiovaara University of Helsinki, Research Programs Unit, Faculty of Medicine (Finland) Title: TargetPOLG: Mechanisms of POLG-disease and approaches to therapy Synopsis of the work: The Finnish POLG patient's cohort we support has the same homozygous mutation, however, manifest with a variability of symptoms, indicating that strong environmental and/or genetic factors affect the variable outcomes of POLG disease, from childhood to middle-age. Understanding and targeting such mechanisms have the potential to control the progression of POLG disease. Specifically, mechanisms will be explored and identified that might contribute and promote POLG-disease manifestations. Selected molecular targets will be tested and challenged to generate preclinical evidence for human trials. Dr Kristina Xiao Liang, Department of Clinical Medicine, University of Bergen (Norway) Title: Stem Cell-Based Study for Drug Discovery for POLG disease Synopsis of the work: The overarching goal of the project is to establish a human stem cell-based 2D neural system and 3D brain organoid platform for drug discovery and to identify mitochondria-targeting therapies that are repurposing-ready and can quickly trigger clinical trials in POLG patients. Dr Yi Shiau Ng, Wellcome Centre for Mitochondrial Research (WCMR), Newcastle University (UK) Title: Coalition for trial readiness in POLG (C4TR-POLG): Clinical trial readiness for POLG-related mitochondrial disease and ataxia: a prospective, longitudinal study identifying sensitive and ecologically valid biomarkers Synopsis of the work: Studying treatments for ultra-rare forms of mitochondrial disease is challenging. Participant pools are small and restricted by rigid inclusion and exclusion criteria. There is often incomplete understanding of genotype–phenotype relationships and natural history to inform trial endpoint development. Tackling these disparities is recognised as a long-standing, complex conundrum. Leveraging value in multi- stakeholder innovative networks is urgently needed. Fully aligned with the strategy of the Foundation, these research grants cover different building blocks that characterise the disease: from understanding how the disease develops and progresses, to monitoring phenotypes with outcome measures. Herewith, we are committed to discovering and developing potential new medicines and therapies. As a standard bearer for the global PolG community, we are deeply moved by all the interest and support received from individuals, foundations, scientific, biotech, pharma, patient advocacy and medical ecosystems. With your help and financial backing we can further our ambitious mission by discovering new therapies and a potential cure for PolG. Thank you! Donate: ©2023 | The POLG Foundation is a 501(c)(3) non-profit organization. EIN 87-1876876. Donations are tax-deductible in the USA as allowable by law. Donations may be sent to: THE POLG FOUNDATION, 99 Park Ave., 24th Floor, New York, NY 10016 Contact: Paula Casanova [email protected] Photo - Logo - SOURCE The PolG Foundation