Lubs X-Linked Mental Retardation Syndrome

PNRI's Landmark Study Reveals DNA Rearrangement's Role in Genetic Disorders, Paving Way for New Treatments SEATTLE, June 21, 2024 /PRNewswire/ -- Researchers at the Pacific Northwest Research Institute (PNRI) and collaborating institutions have made a groundbreaking discovery that could significantly advance our understanding of genomic disorders. Their latest study, funded by the National Institutes of Health1 and published in Cell Genomics, reveals how specific DNA rearrangements called inverted triplications contribute to the development of various genetic diseases. Understanding the Study Genomic disorders occur when there are changes or mutations in DNA that disrupt normal biological functions. These can lead to a range of health issues, including developmental delays and neurological problems. One type of complex DNA mutation involves a structure known as a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP). This study examines how these complex rearrangements form and their impact on human health. Key Findings The research team, led by PNRI Assistant Investigator Cláudia Carvalho, Ph.D., collaborated with lead author Christopher Grochowski, Ph.D., from the James R. Lupski Lab at Baylor College of Medicine, and other scientists to analyze the DNA of 24 individuals with inverted triplications. They discovered that these rearrangements are caused by segments of DNA switching templates during the repair process. Normally, DNA repair mechanisms use the undamaged complementary strand as a template to accurately repair the damaged DNA. However, sometimes during repair, the repair machinery may inadvertently switch to a different but similar sequence elsewhere in the genome. These switches occur within pairs of inverted repeats—mirror-image DNA sections that confuse the repair machinery. This can lead to using the wrong template, disrupting gene function and contributing to genetic disorders. Structural Diversity: The study found that inverted triplications generate a surprising variety of structural variations in the genome, which can lead to different health outcomes. Gene Dosage Impact: These rearrangements can alter the number of copies of certain genes, known as gene dosage. The correct number of gene copies is crucial for normal human development and function. Changes in gene dosage can cause diseases like MECP2 duplication syndrome, a rare neurodevelopmental disorder. Mapping Breakpoints: By using advanced DNA sequencing techniques, the researchers identified the precise locations where these DNA segments switch templates leading to an altered number of genes including MECP2. Dr. Carvalho and Baylor scientists first observed this pathogenic genomic structure in 2011 while studying MECP2 duplication syndrome. Only recently, with the advent of long-read sequencing technology, has it become possible to investigate in detail how it forms in the genome. Implications for Medical Research and Treatment "This study sheds light on the intricate mechanisms driving genetic rearrangements and their profound impact on rare diseases," said Dr. Cláudia Carvalho, PNRI's lead scientist on the study. "By unraveling these complex DNA structures, we open new avenues for understanding the genetic causes of rare diseases and developing targeted treatments to improve patient outcomes." About PNRI: Pacific Northwest Research Institute (PNRI) is a nonprofit biomedical research institute, where scientists are using innovative approaches in genetics and genomics to tackle some of the most difficult problems in science and medicine. The institute was founded 67 years ago in Seattle, Washington, as a place where scientists were free to pursue discoveries that promised the highest chance of improving human health. The goal was at the beginning, and remains today, to conduct foundational science leading to impactful medical innovations. To learn more, visit pnri.org. 1 Research reported in this press release was supported in part by National Institute of General Medical Sciences of the National Institutes of Health under award number R01132589.

Researchers have uncovered how specific DNA rearrangements called inverted triplications contribute to the development of various genetic diseases. The study reveals that during DNA repair, segments may switch templates within inverted repeats, leading to structural variations and gene dosage alterations, impacting conditions like MECP2 duplication syndrome. This discovery opens new avenues for understanding and treating rare genetic disorders. Researchers at the Pacific Northwest Research Institute (PNRI) and collaborating institutions have made a groundbreaking discovery that could significantly advance our understanding of genomic disorders. Their latest study, funded by the National Institutes of Health and published in the journal Cell Genomics, reveals how specific DNA rearrangements called inverted triplications contribute to the development of various genetic diseases. Understanding the Study Genomic disorders occur when there are changes or mutations in DNA that disrupt normal biological functions. These can lead to a range of health issues, including developmental delays and neurological problems. One type of complex DNA mutation involves a structure known as a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP). This study delves into how these complex rearrangements form and their impact on human health. Key Findings The research team, led by PNRI Assistant Investigator Cláudia Carvalho, Ph.D., collaborated with her lab colleagues, study lead author Christopher Grochowski, Ph.D., from the James R. Lupski Lab at Baylor College of Medicine, and other scientists to analyze the DNA of 24 individuals with inverted triplications. They discovered that these rearrangements are caused by segments of DNA switching templates during the repair process. Normally, DNA repair mechanisms use the undamaged complementary strand as a template to accurately repair the damaged DNA. However, sometimes during repair, the repair machinery may inadvertently switch to a different but similar sequence elsewhere in the genome. These switches occur within pairs of inverted repeats -- sections of DNA that are mirror images of each other. Inverted repeats can confuse the repair machinery, leading to the use of the wrong template, which can disrupt normal gene function and contribute to genetic disorders. Dr. Carvalho and Baylor scientists first observed this pathogenic genomic structure in 2011 while studying MECP2duplication syndrome. Only recently, with the advent of long-read sequencing technology, has it become possible to investigate in detail how it forms in the genome. Implications for Rare Disease Research and Treatment "This study sheds light on the intricate mechanisms driving genetic rearrangements and their profound impact on rare diseases," said Dr. Cláudia Carvalho, PNRI's lead scientist on the study. "By unraveling these complex DNA structures, we open new avenues for understanding the genetic causes of rare diseases and developing targeted treatments to improve patient outcomes." These findings are being applied in a follow-up study led by Baylor's Davut Pehlivan, M.D., investigating how complex genomic structures influence the clinical features of MECP2 duplication syndrome and their impact on targeted therapeutic approaches.

SHANGHAI and REDWOOD CITY, Calif. , May 29, 2024 /PRNewswire/ -- HuidaGene Therapeutics ("HuidaGene"), a global clinical-stage biotechnology company focused on advancing CRISPR-based genomic medicines, and Synthego Corporation ("Synthego"), a leading provider of innovative CRISPR solutions for developing cell and gene therapies, proudly announce a partnered licensing agreement for the high-fidelity Cas12 CRISPR nuclease (hfCas12Max). This partnership underscores the significant clinical utility of hfCas12Max, naturally complementing Synthego's focus on advanced GMP manufacturing capabilities. Under this licensing agreement and pursuant to undisclosed financial terms between HuidaGene and Synthego, HuidaGene grants Synthego manufacturing and commercialization rights for the hfCas12Max nuclease and optimized gRNA for research; HuidaGene also grants Synthego the right to sublicense the nuclease for therapeutic use. This partnership will streamline the development of CRISPR-based therapeutic applications, providing developers with access to highly precise, efficient, and next-generation genome editing tools. Xuan Yao, Ph.D., Co-founder and President of HuidaGene, emphasized the significance of this agreement, stating, "HuidaGene's expansive CRISPR intellectual property portfolio distinguishes it as a vanguard in genomic medicine, with a versatile pipeline targeting critical neurological and ophthalmological conditions. Together with Synthego, we are poised to significantly accelerate the advancement of CRISPR-based therapies and deliver life-altering genomic medicines to patients worldwide." Craig Christianson, CEO of Synthego, expressed enthusiasm about the partnership with HuidaGene on hfCas12Max, stating, "The combination of our advanced CRISPR GMP production capabilities and regulatory expertise with HuidaGene's next-generation nuclease technology is a crucial step toward advancing transformative cell and gene therapies. This partnership underscores Synthego's commitment to CRISPR-based therapeutics, bolstered by our focused investments in GMP manufacturing and comprehensive CRISPR solutions that support therapeutic development. The integration of hfCas12Max naturally aligns with our initiative to enhance the accessibility and efficiency of CRISPR tools." hfCas12Max, a novel CRISPR gene-editing system developed through HuidaGene's HG-PRECISE platform, stands out for its superior on-target editing efficiency and reduced off-target editing activity in mammalian cells. This novel CRISPR gene-editing system also offers the advantage of packaging into a single viral vector, an important requirement for many cell and gene therapies. The commercialization of hfCas12Max will significantly enhance the accessibility of this CRISPR gene-editing system, providing increased freedom-to-operate and facilitating the development of CRISPR-based cell and gene therapies. This partnership reinforces both companies' positions as catalysts for innovation, advancing their shared mission of transforming genomic-based cell and gene therapies and enabling unprecedented therapeutic outcomes. For partnership inquiries, please contact [email protected] and [email protected]. hfCas12Max is a registered trademark in China. About HuidaGene HuidaGene Therapeutics utilizes its proprietary CRISPR-based HG-PRECISE® platform to discover, engineer, and develop potentially curative genomic medicine. The Company is advancing clinical programs of HG004 in RPE65-associated inherited retinal disease (granted both ODD and RPDD), HG202 CRISPR RNA-editing in neovascular age-related macular degeneration, and the preclinical pipeline, including HG204 CRISPR RNA-editing in neurodevelopmental disease of MECP2 duplication syndrome (granted both ODD and RPDD by U.S. FDA and ODD by EMA), HG302 CRISPR DNA-editing for Duchenne muscular dystrophy (granted both ODD and RPDD), and HG303 CRISPR DNA-editing for Amyotrophic Lateral Sclerosis (ALS). The Company's extensive intellectual property portfolio positions it as a leader in unleashing the full potential of genome medicine. Learn more at huidagene.com or on LinkedIn. About Synthego Synthego is a pioneering provider of genome engineering solutions, offering a comprehensive suite of products and services to accelerate CRISPR-based cell and gene therapy development. With a commitment to empowering researchers and innovators, Synthego's cutting-edge CRISPR technologies and expertise drive progress from preclinical to clinical application. Learn more at Synthego.com or on LinkedIn. SOURCE HuidaGene Therapeutics