作者: Emerling, Daniel E ; Williamson, Kevin S ; Jongert, Erik ; Guerrero, Steve ; Jepson, Sofia Z ; Tomaras, Georgia D ; Regules, Jason A ; King, C Richter ; Walker, Michael ; Dutta, Sheetij ; Cavet, Guy ; Smidt, Pauline ; Glanville, Jacob ; Kim, Dongkyoon ; Dennison, S Moses ; Li, Kan ; Ockenhouse, Christian ; MacGill, Randall S ; Lippow, Shaun M ; Robinson, William H ; Wille-Reece, Ulrike ; Mathis-Torres, Shamika ; Williams, Katherine L ; Zavala, Fidel ; Moon, James E ; Flores-Garcia, Yevel ; Siska, Christine ; Ketchem, Randal R ; Chen, Xiaomu ; Tan, Yann Chong

AbstractOver 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO’s preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.

2023-11-07·Circulation

Abstract 12498: AAV-Mediated LINC Complex Uncoupling Ameliorates Pathology in a Mouse Model of LMNA Dilated Cardiomyopathy

作者: Tan, Yann Chong ; Lee, Yin Loon ; Khaing, Nyein Thet ; Ong, Mervyn ; Burke, Brian ; Stewart, Colin ; Russell, David W ; Loh, Connie ; Gan, Esther S ; Zhang, Jinqiu ; Lee, John ; Werner, Hendrikje ; Ng, Jennifer

Mutations in the LMNA gene, encoding lamin A/C, are one of the most frequent genetic causes of dilated cardiomyopathy. While gene therapy using adeno-associated virus (AAV) vectors show promise for the treatment of monogenic diseases, LMNA DCM mutations tend to be autosomal dominant and gain-of-function, precluding typical gene replacement approaches. Lamin A/C forms a filamentous network, the nuclear lamina, underlying the nuclear envelope that is thought to function in maintaining structural integrity of the nucleus by resisting cytoskeletal forces transmitted to the nucleus during cardiac contraction. Our hypothesis is that disruption to the lamin A/C network leads to nuclear envelope rupture as the weakened nuclear lamina cannot resist excess cytoskeletal force. Uncoupling the linkage between the cytoskeleton and nucleus might therefore reduce LMNA -associated pathology. This linkage is known to be mediated by the nuclear envelope-localized linker of nucleoskeleton and cytoskeleton (LINC) complex. Using AAV-mediated expression of a LINC complex uncoupling transgene, GSLA01, we were indeed able to prevent the progression of ventricular dilation, cardiac fibrosis, and decline in ejection fraction observed in a LMNA dilated cardiomyopathy mouse model. We decided to explore structure-function relationships in GSLA01 in our lead optimization studies. We generated a series of truncations of full-length GSLA01 comprising different lengths of its coiled coil domain. In vitro assays indicated that most truncations examined were able to uncouple the LINC complex. Selected truncations were delivered using AAV to LMNA DCM mice after inducing cardiac-specific deletion of Lmna with tamoxifen. Full-length GSLA01 extended the lifespan of LMNA DCM mice from 39 to ~170 days. The truncations mostly performed on par or better than full-length GSLA01 in extending the lifespan of LMNA DCM mice, to more than 250 days for certain constructs. Reducing cytoskeletal force transmission to the nucleus by uncoupling the LINC complex appears to be a viable strategy for treating LMNA -linked pathology, and multiple GSLA01 truncation variants can be used to achieve this effect.

2023-01-06·Human Molecular Genetics

Nesprin-1 LINC complexes recruit microtubule cytoskeleton proteins and drive pathology inLmna-mutant striated muscle

Article

作者: Burke, Brian ; Hong, Wei Liang ; Leong, Ei Leen ; Khaing, Nyein Thet ; Kozlov, Serguei ; Cadot, Bruno ; Wong, Esther Sook Miin ; Stewart, Colin L ; Lee, Yin Loon ; Werner, Hendrikje

AbstractMutations in LMNA, the gene encoding A-type lamins, cause laminopathies—diseases of striated muscle and other tissues. The aetiology of laminopathies has been attributed to perturbation of chromatin organization or structural weakening of the nuclear envelope (NE) such that the nucleus becomes more prone to mechanical damage. The latter model requires a conduit for force transmission to the nucleus. NE-associated Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes are one such pathway. Using clustered regularly interspaced short palindromic repeats to disrupt the Nesprin-1 KASH (Klarsicht, ANC-1, Syne Homology) domain, we identified this LINC complex protein as the predominant NE anchor for microtubule cytoskeleton components, including nucleation activities and motor complexes, in mouse cardiomyocytes. Loss of Nesprin-1 LINC complexes resulted in loss of microtubule cytoskeleton proteins at the nucleus and changes in nuclear morphology and positioning in striated muscle cells, but with no overt physiological defects. Disrupting the KASH domain of Nesprin-1 suppresses Lmna-linked cardiac pathology, likely by reducing microtubule cytoskeleton activities at the nucleus. Nesprin-1 LINC complexes thus represent a potential therapeutic target for striated muscle laminopathies.

项与 Nuevocor Pte Ltd. 相关的新闻（医药）

2024-04-11

·PRNewswire

Nuevocor Strengthens Leadership Team with Appointment of John Lee as Chief Medical Officer

SINGAPORE and PHILADELPHIA, April 9, 2024 /PRNewswire/ -- Nuevocor, a pre-clinical stage biotechnology company dedicated to developing novel medicines to treat cardiomyopathies with aberrant mechanobiology, today announces the appointment of Dr. John Lee, MD, PhD, as its Chief Medical Officer. Dr. Lee is a life science executive with experience spanning from early drug discovery to late-stage clinical development. Dr. John Lee is a board-certified cardiologist who brings over 15 years of clinical development and regulatory expertise to Nuevocor. Dr. Lee was most recently the Chief Medical Officer of PhaseBio Pharmaceuticals, a publicly listed biotech, where he led Phase I-III development of its clinical programs. Prior to PhaseBio, Dr. Lee was the Vice President, Global Head, Cardiovascular Center of Excellence at Quintiles, where he was responsible for developing and implementing the cardiovascular therapeutic area business growth strategy and also represented their cardiovascular therapeutic expertise across the broader enterprise and in the global marketplace. Dr. Lee also served as Executive Director, Discovery Medicine at Bristol-Myers Squibb ("BMS"), where he was responsible for leading the team that provided medical, clinical, scientific, regulatory and R&D advisory expertise in cardiovascular drug development across BMS. Having held key leadership roles in both biotech and pharmaceutical sectors, Dr. Lee is poised to spearhead Nuevocor's clinical development strategy and advance its innovative therapies for LMNA DCM through rigorous clinical development oversight and execution. "Dr. Lee's appointment marks a significant milestone for Nuevocor," said Dr. Yann Chong Tan, PhD, CEO and Co-Founder of Nuevocor. "His extensive experience and proven track record in clinical development make him the ideal candidate to lead our clinical development team. His leadership will be instrumental in furthering our commitment to advancing science and translating it into therapies that will make a real difference in patients' lives." "I am honored to join Nuevocor at this pivotal moment," said Dr. John Lee. "The opportunity to lead the clinical development efforts for the LMNA DCM program is incredibly motivating. I look forward to collaborating with the talented team at Nuevocor to bring potentially life-changing therapies to patients." About Nuevocor Nuevocor is a biotechnology company that is pioneering an innovative pathway-centric approach to developing genetic medicines for heart conditions known as cardiomyopathies. By harnessing our PrOSIA™ mechanobiology platform, Nuevocor designs genetic medicines to target the biomechanical root cause of these diseases. Nuevocor's approach surpasses the limitations of traditional gene therapy, which focuses on individual gene mutations, to treat defects within shared disease pathways across multiple genetic cardiomyopathies. This enables us to extend our impact to broader patient populations. SOURCE Nuevocor

高管变更

2023-11-07

·PRNewswire

Nuevocor presents pre-clinical data at ESGCT and AHA meetings

SINGAPORE, Nov. 7, 2023 /PRNewswire/ -- Nuevocor, a pre-clinical stage biotechnology company focused on developing cardiac genetic medicines through a unique platform to understand the mechanobiological causes of disease, announced today a pair of presentations at two major meetings, the European Society for Gene and Cell Therapy (ESGCT) 30th Annual Congress, and the American Heart Association (AHA) Scientific Sessions 2023. The poster presentations showcase optimization efforts for Nuevocor's first-in-class lead programme using a mechanobiology-based approach to treat LMNA-associated dilated cardiomyopathy. At the ESGCT Congress on 24 – 27 October, 2023 in Brussels, Belgium, Nuevocor co-founder and Chief Executive Officer, Dr. Yann Chong Tan, presented a poster (P613) entitled "An AAV gene therapy for LMNA dilated cardiomyopathy via disruption of the LINC complex." At the AHA Scientific Sessions meeting in Philadelphia, Pennsylvania, USA, Nuevocor Chief Medical Officer, Dr John Lee, will present a poster (Sa3004) entitled "AAV-Mediated LINC Complex Uncoupling Ameliorates Pathology in a Mouse Model of LMNA Dilated Cardiomyopathy" on Saturday, November 11, 2023 11:30 AM - 12:45 PM at Zone 3, Science and Technology Hall, Level 200 of the Pennsylvania Convention Center. For more information on the meetings, please visit the respective conference websites. About Nuevocor Nuevocor is a biotechnology company that is pioneering an innovative pathway-centric approach to developing genetic medicines for heart conditions known as cardiomyopathies. By harnessing our PrOSIA mechanobiology platform, Nuevocor designs genetic medicines to target the biomechanical root cause of these diseases. Nuevocor's approach surpasses the limitations of traditional gene therapy, which focuses on individual gene mutations, to treat defects within shared disease pathways across multiple genetic cardiomyopathies. This enables us to extend our impact to broader patient populations. SOURCE Nuevocor

AHA会议临床研究

2022-12-21

·PRNewswire

Nuevocor to Present at Biotech Showcase during JPM week and at Keystone Symposium on Heart Development and Disease

SINGAPORE, Dec. 21, 2022 /PRNewswire/ -- Nuevocor, a pre-clinical stage cardiac gene therapy company, announced today that it will be presenting at the Biotech Showcase during JPM week, taking place in San Francisco, CA, USA from January 9 to 11, 2023. Nuevocor will also be giving an oral presentation on new pre-clinical data for its LMNA cardiac gene therapy programme at the Keystone Symposium on Heart Development and Disease, taking place in Santa Fe, NM, USA from February 12 to 15, 2023. Details of the presentations are as follows: Biotech Showcase Date: Tuesday, January 10, 2023 Time: 3:00PM PST Location: Hilton San Francisco Union Square, Franciscan B (Ballroom Level) Presenter: Yann Chong Tan, PhD, Founder and CEO, Nuevocor Keystone Symposia on Heart Development and Disease: From Genes to Cures Date: Tuesday, February 14, 2023 Time: 2:30PM MST Location: Eldorado Hotel, Santa Fe Session: Workshop 2 – Resolving the Genotype-Phenotype Conundrum in Congenital Heart Disease and Inherited Cardiomyopathies Title: Targeting the LINC Complex with AAV Gene Therapy Extends Lifespan and Preserves Cardiac Function in a Mouse Model of LMNA Dilated Cardiomyopathy Presenter: Yin Loon Lee, PhD, Founder and Senior Director, Biology, Nuevocor For more information on the meetings, please visit the respective conference websites. About Nuevocor Nuevocor is a biotechnology company developing targeted gene therapies to restore heart function through a deep understanding of fundamental mechanisms underlying genetic cardiac diseases. Nuevocor is founded and advised by leaders in mechanobiology, cardiac disease and gene therapy. Their lead candidate treats the underlying biomechanical cause of LMNA dilated cardiomyopathy, while their PrOSIA mechanobiology platform enables target discovery and validation for additional genetic cardiomyopathies. SOURCE Nuevocor

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