β-galactosidase

HYOGO, Japan--( BUSINESS WIRE )-- JCR Pharmaceuticals Co., Ltd. (TSE: 4552) made significant contributions at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium 2024, held in Porto, Portugal from September 3-6, 2024. We highlighted our proprietary J-Brain Cargo ® technology through two key presentations focused on advanced therapies for lysosomal storage disorders, demonstrating our pioneering role in medical innovation. "In treating lysosomal storage disorders, it's critical to address the neurological symptoms that often accompany these conditions,” said Shin Ashida, Chairman and President of JCR. “Our focus is on developing therapies that meet these unmet medical needs. Clinical data for JR-171 show its potential to be an effective treatment for both the somatic and neurological symptoms associated with mucopolysaccharidosis I (MPS I). Additionally, the preclinical trials in our GM1 gangliosidosis AAV gene therapy development program have demonstrated the potential of combining our J-Brain Cargo ® technology with gene therapy. We will continue to update on the progress of these programs." JCR showcased the following two presentations: JR-171: Mucopolysaccharidosis Type I (MPS I) Poster The following poster presentation provides a case report for four individuals with MPS I who were treated with JR-171: Neurobehavioural and somatic improvements observed in MPS I patients treated with lepunafusp alfa (JR-171): report of four cases (PO-238) Presenter: Ana Maria Martins, M.D., Ph.D. (Federal University of São Paulo, São Paulo, Brazil) This study reports clinical data from four individuals with MPS I in Brazil who were treated intravenously with JR-171 (2 mg/kg weekly, n=2; 4 mg/kg weekly, n=2), focusing on neurobehavioral changes. These individuals with MPS I experienced marked neurobehavioral and somatic improvements, which resulted in tangible, positive changes in their quality of life. These cases illustrate the positive neuropsychiatric and behavioral changes observed during the Phase 1/2 study of JR-171, as well as the drug’s somatic efficacy, and they demonstrate its potential as an effective treatment for the somatic symptoms and neuronopathy found in individuals with MPS I. Further neurocognitive and developmental evaluation is required to consolidate and establish the efficacy of JR-171 for neuronopathic symptoms. GM1 Gangliosidosis Poster This poster presentation was selected as one of the highest-ranked posters. It highlights preclinical data from an adeno-associated virus (AAV) gene therapy in a mice model of GM1 gangliosidosis: Gene therapy for GM1 gangliosidosis mediated by AAV vector carrying BBB-penetrable enzyme (PO-211) Presenter: Saki Matsushima, Ph.D. (Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan) This study reports preclinical data that demonstrated efficacy of AAV that expresses anti-transferrin receptor-antibody (anti-TfR antibody) fused β-galactosidase (TβGal). AAV was administered intravenously to the GM1 gangliosidosis mouse models. TβGal expressed in the liver was secreted into the blood and efficiently penetrated the central nervous system (CNS) as well as peripheral organs. Substrates in the CNS decreased in a dose-dependent manner. The data also demonstrated efficacy of TβGal in survival, histology, and behavioral evaluations. This therapeutic approach, which is the combination of AAV and anti-TfR antibody fused biotherapeutics, is expected to be applied for the treatment of several hereditary neurological diseases with CNS involvement. Further evaluation is required. About the Society for the Study of Inborn Errors of Metabolism (SSIEM) Established in 1963, the aim of the society is to foster the study of inherited metabolic disorders and related topics. An international annual symposium is held to promote exchange of ideas between professional leaders in different disciplines who are interested in inborn errors of metabolism. Learn more about SSIEM: https://www.ssiem.org/ . About the J-Brain Cargo ® Platform Technology JCR Pharmaceuticals has developed a proprietary blood-brain barrier-penetrating technology J-Brain Cargo ® , to bring biotherapeutics into the central nervous system. The first drug developed based on this technology is IZCARGO ® (INN: pabinafusp alfa) and was approved in Japan for the treatment of a lysosomal storage disorder. About Mucopolysaccharidosis I (Hurler, Hurler-Scheie, Scheie Syndrome) Mucopolysaccharidosis I (MPS I) is an autosomal recessive lysosomal storage disorders (LSDs) caused by a deficiency of α-L-iduronidase, an enzyme that breaks down glycosaminoglycans (mucopolysaccharides) in the body. The current worldwide prevalence of MPS I is estimated to be approximately 3,000-4,000 (according to JCR internal research). MPS I gives rise to a wide range of somatic and neurological symptoms. A major limitation of current ERT is that it does not address central nervous system (CNS) symptoms because of the enzyme’s inability cross the blood-brain barrier (BBB). MPS I is the only LSD in which hematopoietic stem cell transplantation (HSCT) is part of the standard of case for the severe form of the disease. Significant unmet medical need persists in all forms of MPS I. About GM1 Gangliosidosis GM1 gangliosidosis is an autosomal recessive disease caused by pathogenic mutations in the GLB1 gene which results in dysfunction or lack of production of lysosomal enzyme, β-galactosidase, responsible for the breakdown of GM1 gangliosides and other glycolipids. Accumulation of GM1 gangliosides in multiple tissues including the brain leads to severe neurodegeneration and systemic disease manifestations resulting in premature mortality. GM1 gangliosidosis is classified into three forms (Type I to III) based on the age of onset of clinical symptoms. About JR-171 JR-171 is a recombinant fusion protein of an antibody against the human transferrin receptor and α-L-iduronidase, the enzyme that is missing or malfunctioning in patients with MPS I. By crossing the blood brain-barrier (BBB) through transferrin receptor mediated transcytosis it is expected to be effective against central nervous system (CNS) signs and symptoms of the disease thereby addressing a significant unmet need for the treatment of MPS I. JR-171 previously was granted Fast Track designation by the US Food and Drug Administration (FDA). About JCR Pharmaceuticals Co., Ltd. JCR Pharmaceuticals Co., Ltd. (TSE 4552) is a global specialty pharmaceuticals company that is expanding possibilities for people with rare and genetic diseases worldwide. We continue to build upon our 49-year legacy in Japan while expanding our global footprint into the US, Europe, and Latin America. We improve patients’ lives by applying our scientific expertise and unique technologies to research, develop, and deliver next-generation therapies. Our approved products in Japan include therapies for the treatment of growth disorder, MPS II (Hunter syndrome), Fabry disease, acute graft-versus host disease, and renal anemia. Our investigational products in development worldwide are aimed at treating rare diseases including MPS I (Hurler, Hurler-Scheie and Scheie syndrome), MPS II, MPS IIIA and B (Sanfilippo syndrome type A and B), and more. JCR strives to expand the possibilities for patients while accelerating medical advancement at a global level. Our core values – reliability, confidence, and persistence – benefit all our stakeholders, including employees, partners, and patients. For more information, please visit https://www.jcrpharm.co.jp/en/site/en/ . Cautionary Statement Regarding Forward-Looking Statements This document contains forward-looking statements that are subject to known and unknown risks and uncertainties, many of which are outside our control. Forward-looking statements often contain words such as “believe,” “estimate,” “anticipate,” “intend,” “plan,” “will,” “would,” “target” and similar references to future periods. All forward-looking statements regarding our plans, outlook, strategy and future business, financial performance and financial condition are based on judgments derived from the information available to us at this time. Factors or events that could cause our actual results to be materially different from those expressed in our forward-looking statements include, but are not limited to, a deterioration of economic conditions, a change in the legal or governmental system, a delay in launching a new product, impact on competitors’ pricing and product strategies, a decline in marketing capabilities relating to our products, manufacturing difficulties or delays, an infringement of our intellectual property rights, an adverse court decision in a significant lawsuit and regulatory actions. This document involves information on pharmaceutical products (including those under development). However, it is not intended for advertising or providing medical advice. Furthermore, it is intended to provide information on our company and businesses and not to solicit investment in securities we issue. Except as required by law, we assume no obligation to update these forward-looking statements publicly or to update the factors that could cause actual results to differ materially, even if new information becomes available in the future.

Compounds significantly restored β-Gal function and reduced intracellular toxic substrates in model of GM1 gangliosidosis Results published in PLOS ONE in collaboration with Institute for Research in Biomedicine Gain Therapeutics, Inc., (Nasdaq: GANX), a clinical-stage biotechnology company leading the discovery and development of the next generation of allosteric small molecule therapies, today announced the publication of preclinical data identifying a novel class of small molecule allosteric regulators that demonstrate therapeutic potential for galactosidase beta 1 (GLB1)-related lysosomal storage disorders (LSDs), including GM1 gangliosidosis. The study, “Validation of a highly sensitive HaloTag-based assay to evaluate the potency of a novel class of allosteric β-Galactosidase correctors,” was published in PLOS ONE. GM1-gangliosidosis is an inherited, progressive disorder characterized by the degeneration of brain and spinal cord cells, leading to muscle weakness, skeletal abnormalities, dystonia, and vision problems. Mutations in the GLB1 gene significantly reduce the activity and function of the lysosomal hydrolase enzyme β-galactosidase (β-Gal) due to protein misfolding. Depending on the age of onset, which can occur during infancy and up into adulthood, life expectancy of patients can be significantly shortened. Additionally, there are no available disease-modifying treatments for GM1 gangliosidosis, with available therapies only focused on reducing symptoms and improving quality of life. To enhance patient outcomes, there is a significant need to bring safe and effective treatments into the clinic that can alter progression of the disorder. “Lysosomal storage disorders are difficult to treat with traditional pharmacological interventions because most approaches cause an inhibitory effect on the lysosomal enzyme by acting on the active site. The small allosteric regulators that we are characterizing correct protein misfolding by binding the mutated proteins outside the active site, without interfering with enzymatic activity,” said Maurizio Molinari, PhD, Protein Folding and Quality Control Group Leader, Institute for Research in Biomedicine in Switzerland and senior author on the paper. “This impressive data demonstrates the potential of allosteric modulators as a therapeutic option for hard-to-treat, genetic diseases where there are no effective approaches for disease modification.” In the PLOS ONE study, scientists from Gain used Gain’s proprietary Site-directed Enzyme Enhancement Therapy (SEE-Tx) technology followed by molecular interaction and ligand binding studies to identify and characterize two structurally targeted allosteric regulators of β-Gal. A biochemical HaloTag cleavage assay was developed by the researchers from the Institute for Research in Biomedicine and utilized to measure lysosomal delivery capabilities of β-Gal. Results showed that the two compounds (GT-00513 and GT-00413) stabilized, enhanced and restored the key biological lysosomal transport functions of β-Gal and reduced the levels of the intracellular toxic substrate, GM1 ganglioside, in GM1 gangliosidosis patient-derived cells. “Restoring the function of misfolded proteins is a therapeutic approach that is accessible only through allosteric small molecule regulators that can be efficiently discovered with our pioneering computational drug discovery platform,” said Manolo Bellotto, Chief Strategy Officer and General Manager of Gain Therapeutics and co-author on the paper. “This approach has been validated with our clinical-stage lead drug candidate GT-02287, which restores the function of glucocerebrosidase for the treatment of Parkinson’s disease and repairs the disease cascade triggered by protein misfolding.” Gain Therapeutics, Inc. is a clinical-stage biotechnology company leading the discovery and development of next generation allosteric therapies. Gain’s lead drug candidate GT-02287, in development for the treatment of GBA1 Parkinson’s disease, is currently being evaluated in a Phase 1 clinical trial. Leveraging AI-supported structural biology, proprietary algorithms and supercomputer-powered physics-based models, the company’s SEE-Tx® discovery platform can identify novel allosteric binding sites on disease-implicated proteins, pinpointing pockets that cannot be found or drugged with current technologies. Gain’s unique approach enables the discovery of novel, allosteric small molecule modulators that can restore or disrupt protein function. Deploying its highly advanced platform, Gain is accelerating drug discovery and unlocking novel disease-modifying treatments for untreatable or difficult-to-treat disorders including neurodegenerative diseases, rare genetic disorders and oncology. For more information, please visit GainTherapeutics.com and follow us on LinkedIn. Founded in 2000 in Bellinzona, Switzerland, the Institute for Research in Biomedicine (IRB) hosts 13 research groups studying infectious, inflammatory, tumors and rare diseases in order to identify new therapeutic strategies. As a result of its activities, the IRB has gained considerable international recognition in the fields of immunology, cell and structural biology and DNA repair. Molinari’s laboratory investigates the molecular mechanisms regulating chaperone-assisted protein folding and the quality control processes determining whether a polypeptide should be transported at the intra- or extra-cellular site of activity, or if it should be selected for degradation. Emphasis is given on establishing causes of diseases resulting from misfolding of mutant gene products such as α1-antitrypsin deficiency and lysosomal storage disorders and to explore novel therapeutic approaches to alleviate disease phenotypes. IRB offers training opportunities for young researchers at all levels. This is made possible through collaborations with Swiss and foreign universities. Since its opening, IRB has trained more than 1210 PhD students who have gone on to careers in academia or industry both in Switzerland and abroad. In 2021, IRB and IOR (Institute of Oncology Research) formed the Bios+ (Bellinzona Institutes of Science) association, with the mission to create new synergies and to promote and coordinate the scientific research and teaching activities of the two institutes. The vision of Bios+ is to promote the growth of a biomedical research center in Italian-speaking Switzerland. For more information, please visit www.irb.usi.ch. The Protein Folding and Quality Control group lead by Prof. Molinari was established at the IRB in 2000. The group is dissecting the mechanisms that regulate the chaperone-assisted production of correctly folded proteins in the Endoplasmic Reticulum (ER), and the quality control events that select misfolded proteins for proteasome-driven ER-Associated Degradation (ERAD), or for lysosome-driven ER-to-Lysosome-Associated Degradation (ERLAD). Studies are ongoing to characterize the unfolded protein responses (UPR) and the ER-phagy pathways that operate in mammalian cells to ensure the adaptation of ER size and activity to the cellular needs. A thorough knowledge of the processes that maintain ER function is instrumental to identify drug targets and to design and assess therapies for human diseases elicited by pathogens or linked to aberrant ER homeostasis resulting from expression of defective gene products (e.g., rare genetic disorders such as alpha1-antitrypsin deficiency or lysosomal storage disorders). For more information, please visit Lab Molinari, X and LinkedIn. 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The term "Fusion protein" has two distinct definitions. One refers to the expression product of two recombined genes obtained through DNA recombinant technology, while the other refers to a group of proteins that mediate the fusion of two cytoplasmic membranes, such as one of the two glycoproteins contained in the outer leaflet of theSendai virus lipid bilayer, which mediates the fusion of the enveloped virus with the host cell cytoplasmic membrane. The other glycoprotein is the erythrocyte agglutinin neuramidase. The two different proteins can be linked into a large molecule either by chemical methods or by the fusion of genes. Fusion protein technology is a purposeful gene fusion and protein expression method to obtain large amounts of standard fusion proteins. Using fusion protein technology, it is possible to construct and express novel target proteins with various functions. Clinical Application of Fusion Proteins1. DNA Vaccines At present, vaccines have gone through three generations: The first generation vaccines activate the immune system with attenuated or killed pathogens; The second generation vaccines are component vaccines developed using biotechnology and recombinant DNA technology to induce an immune response; The third generation vaccines directly inject gene-recombined antigen genes to activate the human immune system, namely DNA vaccines. DNA vaccines have obvious advantages compared to traditional vaccines, such as easy production, strong stability, low cost, and the ability to simultaneously induce both humoral and cellular immune responses. 2. Dual-Function Enzymes (Multi-Function Enzymes) Research has found that in a large enzyme molecule constructed using gene fusion, if the entire encoding sequences of each enzyme molecule used to form the fusion protein are preserved in the new enzyme molecule, then the fusion protein generally retains the enzymatic activity of each of the enzyme molecules it was constructed from. It has also been found that in these newly constructed fusion proteins, the proper folding of proteins and the active sites of each enzyme were not affected. Compared to single enzymes, the specific activity of the enzyme in the fusion protein is 50%-100%. For two or several enzymes that catalyze consecutive reactions, fusion proteins formed by gene fusion methods can produce a "proximity effect". 3. Targeted Drugs Targeted drugs generally consist of two parts: one part is the drug; the other part is a ligand that can bind specifically to the lesion. Through fusion protein technology, these two parts can be fused together to form a protein with unique conformation and function. 4. Gene Expression Gene fusion technology was first used to express exogenous proteins in bacteria (mainly E. coli). For foreign genes (especially eukaryotic genes), fusion expression in E. coli has many advantages. For one, since foreign genes are generally connected to the C-terminal encoding sequence of a suitable fusion protein, there's no need to design SD sequences separately. Also, due to the presence of N-terminal fusion genes, foreign gene expression is relatively easier. Secondly, the expression products of foreign genes are often degraded by the host cell's proteases. When a foreign gene forms a fusion gene with a certain protein of the host itself, such as a part of the encoding sequence of β-galactosidase, its expression as a fusion protein often reduces degradation by the host cell. Common fusion proteins include immunoglobulin (Ig) fusion proteins, parathyroid hormone (PTH) fusion proteins, and recombinant fusion proteins of cytokines. Fusion proteins possess superior pharmacokinetic properties. Therefore, these drugs can be used in lower doses and are more effective compared to their unfused equivalents. So far, Fc fusion and HSA fusion techniques are the most widely used, but in recent years, XTEN fusion, CTP fusion, ELP fusion, and transferrin fusion techniques have made significant progress. Some drugs based on these technologies have already been launched, and a large number of drugs are currently undergoing clinical trials; they hold the promise to produce excellent outcomes, benefiting patients with various diseases worldwide. Fusion protein Competitive LandscapeAccording to Patsnap Synapse, as of 24 Sep 2023, there are a total of 941 Fusion protein drugs worldwide, from 796 organizations, covering 448 targets, 555 indications, and conducting 3659 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications,  targets, organizations, clinical trials, and clinical results related to this drug type.  Approved Recombinant protein Medicinal: NirsevimabNirsevimab is a monoclonal antibody fusion protein drug that targets the RSV F protein. It falls under the therapeutic area of infectious diseases, specifically Respiratory Syncytial Virus (RSV) infections. The drug is developed by AstraZeneca AB, a renowned pharmaceutical organization. As of the highest phase, Nirsevimab has been approved globally. In China, it is currently in the NDA/BLA phase, indicating that it is awaiting approval from the Chinese regulatory authorities. The drug received its first approval globally in October 2022, with the European Union being the first country/location to grant approval. Nirsevimab has undergone various regulatory processes to expedite its development and approval. It has been granted priority review, indicating that it is considered a high-priority drug due to its potential impact on public health. Additionally, it has received designations such as PRIME (PRIority MEdicines) and Fast Track, which aim to accelerate the development and review process for promising drugs. The drug has also undergone accelerated assessment, a regulatory mechanism that allows for a faster evaluation of drugs that address unmet medical needs. Furthermore, Nirsevimab has been designated as a Breakthrough Therapy, indicating its potential to provide significant improvement over existing treatments. Lastly, it has been recognized as a Promising Innovative Medicine, highlighting its innovative nature and potential benefits. In summary, Nirsevimab is a monoclonal antibody fusion protein drug developed by AstraZeneca AB. It targets the RSV F protein and is indicated for the treatment of Respiratory Syncytial Virus (RSV) infections. The drug has received global approval, with the European Union being the first to grant approval. It has undergone various regulatory processes, including priority review, PRIME designation, Fast Track, accelerated assessment, Breakthrough Therapy designation, and recognition as a Promising Innovative Medicine. These regulatory mechanisms aim to expedite the development and review process for drugs that address unmet medical needs and have the potential to provide significant improvements in patient outcomes. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. BenegrastimBenegrastim is a fusion protein drug that targets CSF-3R and is used in the treatment of various diseases. It falls under the therapeutic areas of Nervous System Diseases, Endocrinology and Metabolic Disease, Other Diseases, and Hemic and Lymphatic Diseases. The drug is primarily indicated for the treatment of Neutropenia, Fever, and Parkinson's Disease. Benegrastim is developed by Evive Biopharmaceutical (Beijing) Ltd. and Evive Biotech Co. Ltd., both organizations based in China. It has received approval for use in the global market as well as in China. The drug's highest phase of development is approved, indicating that it has successfully completed clinical trials and met the necessary regulatory requirements. The first approval for Benegrastim was granted in China in May 2023. As a fusion protein drug, Benegrastim is designed to target CSF-3R, a receptor involved in regulating the production and differentiation of white blood cells. Neutropenia, a condition characterized by a low count of neutrophils (a type of white blood cell), is one of the active indications for Benegrastim. By targeting CSF-3R, the drug aims to stimulate the production of neutrophils and restore their levels in the body. In addition to Neutropenia, Benegrastim is also indicated for the treatment of Fever and Parkinson's Disease. The drug's therapeutic areas suggest that it may have potential applications in various diseases affecting the nervous system, endocrine system, metabolism, and the hematopoietic and lymphatic systems. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. Overall, Benegrastim is a fusion protein drug developed by Evive Biopharmaceutical (Beijing) Ltd. and Evive Biotech Co. Ltd. It has received approval for use in China and globally, with its highest phase being approved. The drug targets CSF-3R and is indicated for the treatment of Neutropenia, Fever, and Parkinson's Disease. Its first approval was granted in China in May 2023.