TfR1 x α-glucosidase

WALTHAM, Mass., June 24, 2024 (GLOBE NEWSWIRE) -- Dyne Therapeutics, Inc. (Nasdaq: DYN), a clinical-stage muscle disease company focused on advancing innovative life-transforming therapeutics for people living with genetically driven diseases, today announced new preclinical data in a Pompe disease model demonstrating the potential of the FORCE™ platform to deliver enzyme replacement therapy to cardiac and skeletal muscle and the central nervous system (CNS). The data were presented at the New Directions in Biology and Disease of Skeletal Muscle Conference, being held June 23-26 in Fort Lauderdale, FL. “These preclinical data show for the first time the ability of FORCE to deliver enzymes to skeletal and cardiac muscle as well as the CNS, expanding the modularity of our platform beyond oligonucleotides. The data support the potential of FORCE to enable effective enzyme replacement therapy with the opportunity to substantially improve upon available treatments for Pompe disease,” Oxana Beskrovnaya, Ph.D., chief scientific officer of Dyne. “We look forward to continuing to explore this application of our platform as part of our mission to deliver life-transforming therapies for people with serious muscle diseases.” Pompe disease is a rare, severe neuromuscular disorder caused by deficiency of the lysosomal enzyme, acid alpha glucosidase (GAA). Lack of GAA leads to glycogen accumulation and increase in lysosomal size in muscle and subsequent weakness, cardiomyopathy and respiratory failure. Enzyme replacement therapy with GAA is the standard of care and increases survival but has inadequate efficacy in skeletal muscle. Pompe is also characterized by CNS manifestations, including behavioral and cognitive deficits due to glycogen accumulation in CNS cells, which are not addressed by the standard of care therapy. Dyne engineered FORCE-GAA by leveraging the FORCE platform and evaluated efficacy in vivo using hTfR1/6Neo mice, that were developed by crossing the well-established 6Neo mouse model of Pompe with mice expressing human transferrin receptor 1. Intravenous administration of FORCE-GAA cleared glycogen in muscle and the CNS and normalized lysosomal size in hTfR1/6Neo mice. FORCE-GAA reduced serum neurofilament light chain, a biomarker of axonal injury, providing evidence of benefit in the CNS. FORCE-GAA also displayed superior efficacy and dose potency compared to GAA alone. Additional data with FORCE-GAA showed the potential for monthly dosing which is less frequent than approved enzyme replacement therapies. The presentation entitled, “FORCE™ Platform for the Development of Targeted Therapeutics for Rare Muscle Diseases” is available in the Scientific Publications & Presentations section of Dyne’s website at . About Pompe Disease Pompe disease is a severe neuromuscular disorder caused by a deficiency of the lysosomal enzyme, acid alpha glucosidase (GAA). Lack of GAA causes glycogen accumulation in tissue leading to muscle weakness, cardiomyopathy, respiratory failure, and central nervous system (CNS) manifestations. Pompe disease belongs to a group of diseases known as the lysosomal storage disorders (LSDs). It can present as infantile-onset, the most severe form of the disease with early onset of symptoms in infancy that rapidly progress, or late-onset, which progressively damages muscles over time. An estimated 5,000 to 10,000 individuals worldwide are affected by Pompe. About the FORCE™ Platform The proprietary FORCE™ platform drives Dyne’s efforts to develop targeted, modern oligonucleotide therapeutics with the potential to be life-transforming for patients with serious muscle diseases. Dyne designed the FORCE platform using its deep knowledge of muscle biology and oligonucleotide therapeutics to overcome the current limitations in delivery to muscle tissue with the goal of stopping or reversing disease progression. The FORCE platform leverages the importance of transferrin receptor 1 (TfR1) in muscle biology as the foundation for its novel approach. TfR1, which is highly expressed on the surface of muscle cells, is required for iron transport into muscle cells. Dyne links therapeutic payloads to its TfR1-binding fragment antibody (Fab) to develop targeted therapeutics for muscle diseases. About Dyne Therapeutics Dyne Therapeutics is a clinical-stage muscle disease company focused on advancing innovative life-transforming therapeutics for people living with genetically driven diseases. With its proprietary FORCE™ platform, Dyne is developing modern oligonucleotide therapeutics that are designed to overcome limitations in delivery to muscle tissue. Dyne has a broad pipeline for serious muscle diseases, including clinical programs for myotonic dystrophy type 1 (DM1) and Duchenne muscular dystrophy (DMD) and a preclinical program for facioscapulohumeral muscular dystrophy (FSHD). For more information, please visit , and follow us on X, LinkedIn and Facebook. Forward-Looking Statements This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release, including statements regarding Dyne’s strategy, future operations, prospects and plans, objectives of management, the potential of the FORCE platform, the anticipated timelines for reporting additional data for FORCE-GAA, expectations regarding the initiation of additional preclinical studies or clinical trials of FORCE-GAA, and plans to provide future updates on pipeline programs, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “objective,” “ongoing,” “plan,” “predict,” “project,” “potential,” “should,” or “would,” or the negative of these terms, or other comparable terminology are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Dyne may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various important factors, including: uncertainties inherent in the identification and development of product candidates, including the initiation and completion of preclinical studies and clinical trials; uncertainties as to the availability and timing of results from preclinical studies and clinical trials; the timing of and Dyne’s ability to enroll patients in clinical trials; whether results from preclinical studies and initial data from early clinical trials will be predictive of the final results of the clinical trials or future trials; whether Dyne’s cash resources will be sufficient to fund its foreseeable and unforeseeable operating expenses and capital expenditure requirements; as well as the risks and uncertainties identified in Dyne’s filings with the Securities and Exchange Commission (SEC), including the Company’s most recent Form 10-Q and in subsequent filings Dyne may make with the SEC. In addition, the forward-looking statements included in this press release represent Dyne’s views as of the date of this press release. Dyne anticipates that subsequent events and developments will cause its views to change. However, while Dyne may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Dyne’s views as of any date subsequent to the date of this press release. Contacts: Investors Amy Reilly areilly@dyne-tx.com 857-341-1203 Media Stacy Nartker snartker@dyne-tx.com 781-317-1938

OXFORD, United Kingdom, May 26, 2022 (GLOBE NEWSWIRE) -- Evox Therapeutics Ltd (‘Evox’ or the ‘Company’), a leading exosome therapeutics company, announced advances in exosome engineering, manufacturing and tissue targeting at the International Society for Extracellular Vesicles (ISEV) Annual Meeting, on May 25 to 29, 2022, in Lyon, France. The nine presentations highlight the progress the Company has made in modulating exosome pharmacokinetics through extension of circulation half-life and improved tissue-targeting via display of ligands on the exosome surface. Other advances around exosome manufacture, in vivo production, and exosome biology were also presented. “Exosomes have significant potential as a new therapeutic modality to treat a number of diseases by enabling broader use of a variety of drug payloads including proteins and nucleic acids,” said Antonin de Fougerolles, Ph.D., Chief Executive Officer of Evox Therapeutics. “As demonstrated by our presentations, we are making good progress in engineering exosomes that possess desired drug-like attributes such as tissue targeting and extended circulation half-life. In parallel, we are also focused on advances in exosome manufacturing, including exploring new ways to produce exosome therapeutics. We believe our advances will allow exosome therapeutics access to cellular compartments and tissues that are currently out of reach using other approaches”. Engineering the surface expression on exosomes for improved pharmacokinetics and tissue-targeting While the rapid clearance of exosomes from circulation and uptake into tissues can be beneficial by enabling a localised site of action, for certain applications an extended circulating half-life is desirable. Albumin binding exosomes to extend circulation time (OF16.01): One approach to extending plasma half-life is to engineer ligands on the surface of exosomes that bind albumin and thereby impart albumin’s long circulation half-life to these engineered exosomes. In a presentation by Liang et al., it was found that this dramatically increased the circulation time of exosomes in mice regardless of route of administration. This could provide significant benefit for both creating feasible dosing regimens and to ensure sufficient plasma residence time for tissue-specific targeting. Engineered display of ligands on the surface of exosomes can be used to increase specific targeting of exosomes to desired tissues. In four presentations and posters, Evox scientists and collaborators, reported on improved targeting of exosomes to tumors, muscle cells, inflamed endothelium, and ability to engage with receptors involved in blood brain barrier (BBB) crossing. Targeted therapy by antibody displaying exosomes (OT09.05): A variety of ligands can be expressed on exosomes to help skew their uptake and distribution into specific tissues. Wiklander et al. presented on the development of an exosome engineered to express a protein capable of binding to the Fc region of antibodies (Ab). Using this as a rapid screening platform, they demonstrated the ability of Abs displayed on the exosome surface to dramatically improve by several orders of magnitude the in vitro uptake and delivery of drug cargo to the desired target cells. The studies were extended in vivo using a PD-L1 Ab-targeted exosome containing the chemotherapeutic agent, doxorubicin (dox). Following systemic administration in tumor-bearing mice, significantly increased uptake of exosomes and improved anti-tumor efficacy were seen with these drug-loaded targeted exosomes as compared to either non-targeted dox-loaded exosomes or PD-L1 Ab-targeted exosomes lacking dox. Exosome targeting and cell-based functional activity in the context of Pompe disease (PT12.16): Pompe disease is a rare inherited lysosomal storage disease in which lysosomal glycogen catabolism is reduced or depleted due to deficiency in acid-alpha-glucosidase (GAA). Current enzyme replacement therapy (ERT) is beneficial but poorly targets skeletal muscle. Lobo et al. designed exosomes to contain GAA and express a muscle targeting peptide on its surface. Non-targeted exosomes containing GAA were active and showed similar enzymatic activity in GAA-deficient myotubes as compared to ERT, while the muscle-targeted GAA-containing exosomes showed a significant increase in enzymatic activity and resulted in greater glycogen removal in comparison with the current ERT. In contrast to ERT, the mechanism of exosome uptake into cells was found to be independent of mannose 6-phosphate, suggesting an ability of GAA-containing exosomes to reach multiple cell types that ERT cannot. Exosome targeting to enhance anti-inflammatory efficacy (OS23.05): Endothelial cells at inflammatory sites upregulate E-selectin and other adhesion molecules to facilitate leukocyte infiltration via binding to the surface glycan sialyl Lewis-X (sLeX). Zheng et al. engineered exosomes to display sLeX on their surfaces and demonstrated improved uptake into activated endothelial cells and suggested a utility for site-specific targeting in inflammatory disease. In addition, display of sLeX also extended the circulation time of the exosome in several mouse models. Exosome targeting to the central nervous system (CNS) using transferrin receptor (PT12.10): Exosomes could be a useful modality to deliver complex therapeutics to the CNS. Antibodies (Abs) to the transferrin receptor have been shown to carry biologic drugs across the BBB. Hewlett et al. showed in cell-based studies that exosomes expressing transferrin receptor-targeting nanobodies showed significantly improved receptor engagement over control non-targeted exosomes. This study is an important step toward developing systemic-delivered exosomes engineered to cross the BBB and treat CNS diseases. Exosome manufacture and in vivo production Exosomes are released from all cells in the body. From a manufacturing perspective, it has not been clear whether their cell source confers manufacturing advantages and if there are optimal doses. In addition, storage conditions for exosomes are an important aspect of developing them as therapeutics and Evox has developed proprietary formulations in this regard. Comparison of the effect of exosome cell source on transcriptional response (PF04.04): Hagey et al. examined in a dose responsive manner the transcriptional response of cells exposed to exosomes produced from twelve different cell sources. They found that dose was a more important contributor to transcriptional response than cell source and it was only at lower exosome doses that cell source-specific responses were seen. These studies provide useful insights into the cell biology of exosome uptake and can inform the selection of exosome manufacturing cell source and optimal dosing regimens. Identification of storage conditions stabilizing exosome preparations (PT02.07): Görgens et al. identified storage conditions that stabilize exosomes for up to two years. Phosphate buffered saline (PBS) supplemented with albumin and trehalose improved short-term and long-term exosome preservation at temperatures ranging from 4oC to -80oC including through several freeze-thaw cycles. This is another important step in enabling exosomes to be a commercially viable therapeutic modality. Since exosomes are naturally released by cells in the body, it may be possible to engineer cells within the body to release therapeutically useful engineered exosomes in vivo rather than administer purified exosomes parentally. This approach uses Evox’s proprietary exosome engineering knowledge to enable an organ, such as the liver, to act as a factory to produce drug-loaded exosomes which are designed for extra-hepatic delivery. In vivo production of drug-loaded exosomes to enable potent biotherapeutics delivery in vivo (OS23.02): Gupta et al. utilised established nucleic acid delivery approaches to program cells in vivo to produce drug-loaded exosomes. Molecular constructs encoding the information enabling cells to produce drug-loaded exosomes were delivered in vivo to the liver and spleen. Using a bioluminescence signal, a body-wide distribution of exosomes was detected in multiple extra-hepatic and extra-splenic organs. This system also achieved a dramatic increase in pharmacokinetic pro to the prolonged in vivo production of these drug-loaded exosomes. Using liver as a bio factory, in vivo produced exosomes delivered an anti-inflammatory protein that alleviated intestinal inflammation in an animal disease model. This approach utilizes the power of established delivery approaches to enable exosome-based delivery to hard-to-reach organs. Exosome biology Exosomes have been implicated in modulating immune responses with tumor-produced exosomes generally promoting tumor immune escape. Given that melanoma cells have been reported to create an immunosuppressive environment, Evox collaborators explored the ability of melanoma-produced exosomes to impact the immune response to tumors. Melanoma-produced exosomes contribute to melanoma-induced immunosuppression (PS01.08): Mamand et al. reported that mice receiving melanoma-derived exosomes contributed to a melanoma-induced immunosuppression by promoting the generation of immunosuppressive erythroid progenitors. About Evox Therapeutics Evox Therapeutics is a privately held, Oxford-based biotechnology company that is a leader in harnessing and engineering the natural delivery capabilities of extracellular vesicles (EVs), known as exosomes, to develop an entirely new class of therapeutics for the treatment of severe rare diseases. Evox uses its proprietary DeliverEX™ technology to engineer exosomes to facilitate drug delivery to organs of interest, including the brain and the central nervous system. Exosome-based drugs have the potential to address some of the limitations of protein, RNA, and gene therapy-based therapies by enabling safe non-immunogenic repeated delivery to cells and tissues that are currently out of reach using other drug delivery technologies. Evox is backed by leading life sciences venture capital groups including Redmile and Orbimed, and is supported by a comprehensive intellectual property portfolio. For further information visit: For enquiries, please contact: U.S. Investors: Burns McClellan Investor.Relations@burnsmc.com U.S. Media: Burns McClellan Media.Relations@burnsmc.com Evox: Dr. Antonin de Fougerolles, CEO +44 (0) 1865 819140