KDM6A

It has long been known that viral infections can be more severe in males than females, but the question as to why has remained a mystery -- until possibly now. Researchers have found that female mouse and human Natural Killer cells have an extra copy of an X chromosome-linked gene called UTX. UTX acts as an epigenetic regulator to boost NK cell anti-viral function, while repressing NK cell numbers. It has long been known that viral infections can be more severe in males than females, but the question as to why has remained a mystery -- until possibly now. The key may lie in an epigenetic regulator that boosts the activity of specialized anti-viral immune cells known as natural killer (NK) cells. In a study published March 16 in the peer-reviewed journal Nature Immunology, a collaborative team of UCLA researchers have found that female mouse and human NK cells have an extra copy of an X chromosome-linked gene called UTX. UTX acts as an epigenetic regulator to boost NK cell anti-viral function, while repressing NK cell numbers. "While it is well-known that males have more NK cells compared to females, we did not understand why the increased number of NK cells was not more protective during viral infections. It turns out that females have more UTX in their NK cells than do males, which allows them to fight viral infections more efficiently," said co-senior author Dr. Maureen Su, professor of microbiology immunology and molecular genetics, and of pediatrics, at the David Geffen School of Medicine at UCLA. The researchers noted that this held true whether or not the mice had gonads (ovaries in females; testes in males), indicating that the observed trait was not linked to hormones. Furthermore, female mice with lower UTX expression had more NK cells which were not as capable of controlling viral infection. "This implicates UTX as a critical molecular determinant of sex differences in NK cells," said the study's lead author Mandy Cheng, graduate student in molecular biology at UCLA. The findings suggest that therapies involving immune responses need to move beyond a "one-size-fits-all" approach and toward a precision medicine model, also known as personalized medicine, that tailors treatments that take into account people's individual differences, such as genetics, environment and other factors that influence health and disease risk, the researchers write. "Given the recent excitement with using NK cells in the clinic, we will need to incorporate sex as a biological factor in treatment decisions and immunotherapy design," said co-senior author Tim O'Sullivan, assistant professor of microbiology, immunology and molecular genetics at the Geffen School. The researchers were supported by grants from the National Institutes of Health (AI145997, NS107851, AI143894, DK119445, HD100298), National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR071307), UC CRCC (CRN-20-637105), UCLA CFAR (5P30 AI028697), Department of Defense (USAMRAA PR200530), Ruth L. Kirschstein National Research Service Awards (GM007185 and AI007323), National Organization of Rare Diseases, Whitcome Fellowship from the Molecular Biology Institute at UCLA, and the Warsaw Fellowship from the UCLA Department of Microbiology, Immunology, and Molecular Genetics. Study co-authors are Joey Li, Luke Riggan, Bryan Chen, Rana Yakhshi Tafti, Scott Chin, Feiyang Ma,Matteo Pellegrini, Haley Hrncir, and Arthur Arnold, all of UCLA.

HOPE will be the first clinical trial in precision medicine with vafidemstat in neurodevelopmental diseases Multicentric study to assess the efficacy of vafidemstat in Kabuki syndrome patients Expected to start in early 2022 In collaboration with the Kennedy-Krieger Institute MADRID, Spain and CAMBRIDGE, Mass., Sept. 21, 2021 (GLOBE NEWSWIRE) -- ORYZON Genomics (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that it has received a one million USD grant to support a new clinical trial with our Phase II LSD1 inhibitor vafidemstat in patients with Kabuki syndrome (KS). The grant was awarded by a patient family whose other philanthropic endeavors include founding the Roya Kabuki clinic at Boston Children’s Hospital and sitting on the board of the Kabuki Syndrome Foundation (KSF). The company expects to start a Phase I/II trial, named HOPE, which will be a multicenter, multi-arm, randomized, double-blind and placebo-controlled trial to explore the safety and efficacy of vafidemstat in improving several impairments described in KS patients. The trial will be performed in children older than 12 years and in young adults. The company is finalizing the protocol design for this new trial with researchers from the Kennedy Krieger Institute (KKI), key opinion leaders, regulatory experts in rare diseases and other stakeholders. We expect to start this clinical trial in the first half of 2022 in several hospitals and sites in the United States and, possibly, in Europe. Considering the FDA and EMA precedents in rare diseases and CNS disorders, we believe that if the HOPE trial demonstrates relevant clinical improvements, it may potentially serve as the basis for accelerated approval in the EU and the United States. Janet Lee, Executive Director of the Kabuki Syndrome Foundation, has commented: “This investment is an extraordinary opportunity to support a ground-breaking therapeutic candidate for Kabuki syndrome, to improve the quality of life of children and families around the globe. The Kabuki Syndrome Foundation is proud to partner with Oryzon and key opinion leaders to further our mission of advocating for the advancement of research and therapeutic treatments. We look forward to working with global patient advocacy groups and the broader Kabuki syndrome community on efforts that support clinical trial readiness and enrollment opportunities to ensure the patient voice is at the center of this clinical study.” Dr. Carlos Buesa, President and CEO of Oryzon, said: “We are enormously grateful to this patient’s family for their generous support to this trial and excited to work with the KSF and the scientists from the KKI and the rest of the research community. The scientific literature has shown that LSD1 inhibition may compensate the effects of a number of genetic failures happening in KS and other CNS disorders. HOPE is the first step in a set of innovative personalized medicine trials we are planning with vafidemstat that may bring hope to very much in need patients, in this case KS kids.” There is a strong molecular rationale for LSD1 inhibition as a possible therapy in KS. In type I KS, the loss of one allele of the KMT2D gene produces a hypomethylated status in the chromatin of neuronal cells and an aberrant transcriptional program. LSD1 inhibition can compensate this effect, and apparently many others downstream as a consequence. Researchers at Johns Hopkins University, using a KS mouse model with a mutated KMT2D allele, have shown that the number of histone methyl-marks in the hippocampus is significantly diminished in these KS animals, but when treated with a LSD1 inhibitor, the hippocampus histone methyl-marks recovered to almost normal levels. Remarkably, this normalization of the methyl-marks in the hippocampus also correlated with morphological and functional effects. Neurogenesis deficiency in the hippocampus was rescued and the elongation and branching defects of hippocampal neurons were also restored. Finally, the correlate at morphological level had also a translation in functional readouts like the recovery on the visuospatial learning and memory deficits and the rescue of the immunological impairments in these KMT2D (+/-) KS animals1. Vafidemstat is currently in Phase IIb trials in borderline personality disorder and schizophrenia, and has shown a positive safety and tolerability pro more than 300 subjects dosed up to now, some of them up to 2 years. About Oryzon Founded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company considered as the European champion in Epigenetics. Oryzon has one of the strongest portfolios in the field. Oryzon’s LSD1 program has rendered two compounds, vafidemstat and iadademstat, in Phase II clinical trials. In addition, Oryzon has ongoing programs for developing inhibitors against other epigenetic targets. Oryzon has a strong technological platform for biomarker identification and performs biomarker and target validation for a variety of malignant and neurological diseases. Oryzon has offices in Spain and the United States. Oryzon is one of the most liquid biotech stocks in Europe with +90 M shares negotiated in 2020 (ORY:SM / ORY.MC / ORYZF US OTC mkt). For more information, visit About Vafidemstat Vafidemstat (ORY-2001) is a first-in-class, 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 also 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 protective anti-autoimmune efficacy in several preclinical models of multiple sclerosis (MS). In 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), vafidemstat has shown positive preliminary clinical results. 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 CSF inflammatory biomarker YKL40 has been observed after 6 months of treatment, and the pilot, small scale SATEEN trial in Relapse-Remitting and Secondary Progressive MS. 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. About Kabuki Syndrome Kabuki Syndrome (KS) is an autosomal monogenic disorder characterized by congenital abnormalities that affect the development and function of multiple bodily systems, often manifesting as impaired mental and physical growth and craniofacial and skeletal abnormalities. Patients may also have cardiac malformations and around 30% of patients develop immunological impairments. KS is caused by heterozygous loss-of-function mutations in either of two genes with complementary functions: KMT2D on human chromosome 12 (for KS type I, representing more than 70% of all KS patients) or lysine-specific demethylase 6A. Both genes facilitate the opening of chromatin and promote gene expression. KS occurs in 1/30,000 births. This represents a prevalence of 3,000 and 3,500 patients in the United States and the EU, respectively, who are younger than 25 and are affected by this syndrome. There is currently no approved treatment for this condition. About Kabuki Syndrome Foundation Founded in 2017, the Kabuki Syndrome Foundation ( ) is a 501(c)(3) non-profit corporation whose mission is to drive research efforts that show promise to treat, prevent or cure Kabuki Syndrome through fundraising, knowledge-sharing and collaborating with researchers around the world. 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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, US IR & Media, Europe Spain Oryzon Ashley R. Robinson Sandya von der Weid Patricia Cobo Emili Torrell LifeSci Advisors, LLC LifeSci Advisors, LLC / Carlos C. Ungría BD Director +1 617 430 7577 +41 78 680 05 38 +34 91 564 07 25 +34 93 515 13 13 arr@lifesciadvisors.com svonderweid@lifesciadvisors.com pcobo@atrevia.com cungria@atrevia.com etorrell@oryzon.com 1 Li Zhang, et al., Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome Molecular Therapy - Methods & Clinical Development Volume 20, p779-791, March 12, 2021 doi:10.1016/j.omtm.2021.02.011