Institut d'Investigació Biomèdica de Bellvitge

Defects in the blood vessel network of the central nervous system have been linked to early symptoms of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). It is this complex vascular network that provides the necessary nutrients -- especially glucose and oxygen -- to activate all neuronal functions. A new study reveals that the TDP-43 protein is essential for forming a stable and mature blood vessel network in the central nervous system. Defects in the blood vessel network of the central nervous system have been linked to early symptoms of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). It is this complex vascular network that provides the necessary nutrients -- especially glucose and oxygen -- to activate all neuronal functions. Now, a study led by the University of Barcelona and the Bellvitge Biomedical Research Institute (IBIDELL) reveals that the TDP-43 protein is essential for forming a stable and mature blood vessel network in the central nervous system. According to the study, featured on the cover of the journal JCI Insight, the TDP-43 protein is also critical in maintaining the integrity of the blood-brain barrier, which prevents toxins and pathogens from reaching the central nervous system. The project is led by Professor Eloi Montañez, from the Faculty of Medicine and Health Sciences of the University of Barcelona and IDIBELL, and involves teams from the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB), the Josep Carreras Leukaemia Research Institute, and the National Centre for Genomic Analysis (CNAG-CRG). What is the role of the TDP-43 protein in the vascular system? The TDP-43 protein is a key factor in nervous system function and neuronal plasticity. It is a DNA- and RNA-binding protein that regulates gene expression, and its dysfunction has been associated with various neurodegenerative disorders. Although much progress has been made recently in understanding the functions of TDP-43 in neurons, its exact role in the endothelial cells that make up the circulatory system, the formation of new blood vessels (angiogenesis) and vascular function was not yet known. "The study reveals for the first time that TDP-43 is essential for the formation and stability of blood vessels in the central nervous system, and for the integrity of the blood-brain barrier," says Professor Montañez, from the UB's Department of Physiological Sciences. The vascularization of the central nervous system and the formation of the blood-brain barrier are regulated by different signalling pathways. For example, the integrin signalling pathway that regulates the interaction of cells with the extracellular matrix and the signalling carried out by the transcription factor β-catenin. "In the study, we found that TDP-43 deficiency alters the extracellular matrix that surrounds blood vessels and reduces β-catenin signalling in endothelial cells," says the researcher. "Thus, mice without endothelial TDP-43 protein show multiple haemorrhages and vascular degeneration in the brain and spinal cord." Vascular defects and inflammatory response in neurosciences The authors also identify TDP-43 in endothelial cells as a potential contributing factor to the vascular defects that trigger the inflammatory response observed in patients diagnosed with TDP-43-associated diseases. "Some alterations in the blood vessels of the central nervous system -- defects in the integrity of the blood-brain barrier or degeneration of endothelial cells -- are associated with inflammatory and immune responses that can cause neuronal loss. This process of neuronal degeneration underlies the origin or progression of various neurological disorders -- stroke, diabetic retinopathy -- and some neurodegenerative diseases such as Alzheimer's disease, ALS or LATE (Limbic-predominant age-related TDP- 43 encephalopathy). The study will help to better understand the molecular mechanisms linking vascular defects and neuroinflammation. "Our goal now is to analyse whether defects in TDP-43 protein function in the endothelium of mature vessels could be involved in ALS or other TDP-43-associated pathologies due to increased vascular permeability or inflammatory processes," Montañez concludes.

An experimental study has shown that a type of skin bacterium can efficiently be engineered to produce a protein to regulate sebum production. This application could treat acne without compromising the homeostasis of the entire skin microbiome. International research led by the Translational Synthetic Biology Laboratory of the Department of Medicine and Life Sciences (MELIS) at Pompeu Fabra University has succeeded in efficiently engineering Cutibacterium acnes -a type of skin bacterium- to produce and secrete a therapeutic molecule suitable for treating acne symptoms. The engineered bacterium has been validated in skin cell lines and its delivery has been validated in mice. This finding opens the door to broadening the way for engineering non-tractable bacteria to address skin alterations and other diseases using living therapeutics. The research team is completed by scientists from the Bellvitge Biomedical Research Institute (Idibell), the University of Barcelona, the Protein Technologies Facility of the Centre for Genomic Regulation, Phenocell SAS, Medizinische Hochschule Brandenburg Theodor Fontane, Lund University, and Aarhus University. Acne is a common skin condition caused by the blockage or inflammation of the pilosebaceous follicles. Its appearance can vary, ranging from whiteheads and blackheads to pustules and nodules, mainly on the face, forehead, chest, upper back and shoulders. Although acne is most common among adolescents, it can affect people of all ages. The most severe cases of acne are treated with antibiotics to kill bacteria living in the follicles, or isotretinoin (known as Accutane), a vitamin A derivative, which induces the death of sebocytes, the epithelial skin cells that produce sebum. However, these treatments can cause serious side effects such as breaking skin microbiome homeostasis -because they are not selectively killing bacteria- or photosensitivity, in the case of antibiotics, or birth defects or extreme scaling of skin, in the case of isotretinoin. The results of the study, published today in Nature Biotechnology, show that researchers have successfully edited the genome of Cutibacterium acnes to secrete and produce NGAL protein known to be a mediator of the acne drug, isotretinoin, that has been shown to reduce sebum by inducing the death of sebocytes. "We have developed a topical therapy with a targeted approach, using what nature already has. We engineered a bacterium that lives in the skin and make it produce what our skin needs. Here, we focused on treating acne, but this platform can be extended to several other indications," says Nastassia Knödlseder, first author of the study. Broadening the way of engineering bacteria "Until now, C. acnes was considered an intractable bacterium. It was incredibly difficult to introduce DNA and get proteins produced or secreted from an element inserted into its genome," explains Knödlseder, who is a postdoc in the UPF Translational Synthetic Biology Laboratory. However, since C. acnes seems an attractive synthetic biology chassis for treating skin diseases due to its niche environment deep inside hair follicles -practically where sebum is released-, its importance for skin homeostasis, its close contact to relevant therapeutic targets, plus the fact that it has been shown to successfully engraft when applied to human skin, led them to insist on editing the genome of this non-engineerable bacterium. To edit the genome of C. acnes, the research team led by Marc Güell has focused on improving DNA delivery to the cell, DNA stability inside the cell, and gene expression. The scientists have considered regulatory measures by developing a biocontainment strategy to avoid the use of elements that generate regulatory concerns such as mobile genetic elements, plasmids or antibiotic resistance. Hence, the resulting synthetic bacterium has safety features to enable "real-life application" and consider it for future human therapeutics. Synthetic C. acnes is able to secrete and produce NGAL to modulate sebum production in cell lines. When applied to the skin of mice -the only animal model able to test engineered bacteria to date- they engraft, live and produce the protein. However, mice skin it is not comparable to humans'. It has more hair, is looser, has less lipids and a different sweat mechanism. Hence the need for an alternative model, better representing human skin, such as 3D skin models. The road to therapeutics "We have developed a technology platform that opens the door to editing any bacteria to treat multiple diseases. We are now focused in using C. acnes to treat acne but we can deliver genetic circuits to create smart microbes for applications related to skin sensing, or immune modulation," points out Marc Güell, who has led the research. Following the same strategy, this research line will continue under the European Project 'SkinDev' in which scientists from the Translational Synthetic Biology lab together with its partners will engineer C. acnes to address atopic dermatitis, a chronic cutaneous inflammatory condition characterized by dry skin, eczema and severe irritation, especially common among young children. Although any living therapeutics strategy should be validated individually, the researchers show their optimism in applying these smart microbes to humans because non-engineered C. acnes has already been tested on the skin of patients safely and effectively.

Two collaborative projects with public research centers with a global budget of 2.3 million eurosOryzon to receive up to 1.4 million eurosFocused on the discovery and validation of novel biomarkers and epigenetic targets for the treatment of neuronal pathologies MADRID, Spain and BOSTON, Oct. 03, 2023 (GLOBE NEWSWIRE) -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today the granting, through a provisional resolution proposal, of two aids within the Spanish research plan 2021-2023 for public-private collaboration projects: the DICTIONIS Project with a budget of 951,000 euros (€) and the MODERN Project with a budget of €1,328,594. The plan is funded by the Spanish State Research Agency and the Ministry of Science and Innovation within the framework of the recovery, transformation and resilience plan financed by the European Union (NextGenerationEU). The DICTIONIS Project will be carried out in collaboration with the Fundació Centre de Regulació Genomica from Barcelona (Spain) and focuses on the diagnosis of chromatinopathies by detecting alterations in histone modifications. The MODERN Project will be carried out in collaboration with the Universitat Autònoma de Barcelona, the Fundació de Institut d'Investigació Biomédica de Bellvitge (IDIBELL) and LEiTAT and focuses on high-throughput technologies for the discovery and validation of new epigenetic targets and inhibitors for the treatment of neuronal pathologies. Both projects started on April 1, 2023 and will have a duration of two years. The projects have an overall budget of €2.3 million euros, of which Oryzon will receive approximately a €1.35 million aid and an additional grant to hire two Ph.D.s. Dr. Jordi Xaus, Oryzon’s Chief Scientific Officer, said: "We thank the Spanish Ministry of Science for these aids that underline the scientific relevance of our research in the epigenetic area in neurological diseases, as well as to reinforce efficiencies and multiply efforts with the national network of public research institutions. These programs are a continuation and complement to our vafidemstat program, which is already in Phase 2 in two highly prevalent psychiatric diseases, borderline personality disorder and schizophrenia, and reinforce the company's leadership in the development of innovative drugs against epigenetic targets useful in the treatment of neurological pathologies, a field of great medical need and with an important commercial opportunity." About OryzonFounded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company and the European leader in epigenetics, with a strong focus on personalized medicine in CNS disorders and oncology. Oryzon’s team is composed of highly qualified professionals from the pharma industry located in Barcelona, Boston and San Diego. Oryzon has an advanced clinical portfolio with two LSD1 inhibitors, vafidemstat in CNS and iadademstat in oncology, in several Phase II clinical trials. The company has other pipeline assets directed against other epigenetic targets. In addition, Oryzon has a strong platform for biomarker identification and target validation for a variety of malignant and neurological diseases. For more information, visit www.oryzon.com About Vafidemstat Vafidemstat (ORY-2001) is an oral, CNS-optimized LSD1 inhibitor. The molecule acts on several levels: it reduces cognitive impairment, including memory loss and neuroinflammation, and at the same time has neuroprotective effects. In animal studies vafidemstat not only restores memory but reduces the exacerbated aggressiveness of SAMP8 mice, a model for accelerated aging and Alzheimer’s disease (AD), to normal levels and also reduces social avoidance and enhances sociability in murine models. In addition, vafidemstat exhibits fast, strong, and durable efficacy in several preclinical models of multiple sclerosis (MS). Oryzon has performed two Phase IIa clinical trials in aggressiveness in patients with different psychiatric disorders (REIMAGINE) and in aggressive/agitated patients with moderate or severe AD (REIMAGINE-AD), with positive clinical results reported in both. Additional finalized Phase IIa clinical trials with vafidemstat include the ETHERAL trial in patients with Mild to Moderate AD, where a significant reduction of the inflammatory biomarker YKL40 has been observed after 6 and 12 months of treatment, and the pilot, small-scale SATEEN trial in Relapse-Remitting and Secondary Progressive MS, where anti-inflammatory activity has also been observed. Vafidemstat has also been tested in a Phase II in severe Covid-19 patients (ESCAPE) assessing the capability of the drug to prevent ARDS, one of the most severe complications of the viral infection, where it showed significant anti-inflammatory effects in severe Covid-19 patients. Currently, vafidemstat is in two Phase IIb trials in borderline personality disorder (PORTICO) and in schizophrenia patients (EVOLUTION). The company is also deploying a CNS precision medicine approach with vafidemstat in genetically-defined patient subpopulations of certain CNS disorders and is preparing a clinical trial in Kabuki Syndrome patients. The company is also exploring the clinical development of vafidemstat in other neurodevelopmental syndromes. FORWARD-LOOKING STATEMENTS This communication contains, or may contain, forward-looking information and statements about Oryzon, including financial projections and estimates and their underlying assumptions, statements regarding plans, objectives, and expectations with respect to future operations, capital expenditures, synergies, products and services, and statements regarding future performance. Forward-looking statements are statements that are not historical facts and are generally identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates” and similar expressions. Although Oryzon believes that the expectations reflected in such forward-looking statements are reasonable, investors and holders of Oryzon shares are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Oryzon that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the documents sent by Oryzon to the Spanish Comisión Nacional del Mercado de Valores (CNMV), which are accessible to the public. Forward-looking statements are not guarantees of future performance and have not been reviewed by the auditors of Oryzon. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date they were made. All subsequent oral or written forward-looking statements attributable to Oryzon or any of its members, directors, officers, employees, or any persons acting on its behalf are expressly qualified in their entirety by the cautionary statement above. All forward-looking statements included herein are based on information available to Oryzon on the date hereof. Except as required by applicable law, Oryzon does not undertake any obligation to publicly update or revise any forward‐looking statements, whether as a result of new information, future events, or otherwise. This press release is not an offer of securities for sale in the United States or any other jurisdiction. Oryzon’s securities may not be offered or sold in the United States absent registration or an exemption from registration. Any public offering of Oryzon’s securities to be made in the United States will be made by means of a prospectus that may be obtained from Oryzon or the selling security holder, as applicable, that will contain detailed information about Oryzon and management, as well as financial statements. IR, USIR & Media, EuropeSpainOryzonAshley R. RobinsonSandya von der WeidPatricia Cobo/Daniel FoleyEmili TorrellLifeSci Advisors, LLCLifeSci Advisors, LLCAtreviaChief Business Officer+1 617 430 7577+41 78 680 05 38+34 91 564 07 25+34 672 447 094+34 93 515 1313arr@lifesciadvisors.comsvonderweid@lifesciadvisors.compcobo@atrevia.comdfoley@atrevia.cometorrell@oryzon.com