CRISPR Platform Brings C-to-U Base Editing to RNA

Genetic Engineering and Biotechnology News | July 30, 2019

A new tool in the CRISPR toolbox doubles the number of single-base RNA edits on researchers wish lists. The tool aptly named RNA Editing for Specific C-to-U Exchange (RESCUE) can be programmed to convert targeted cytosine bases into uridine bases, complementing existing RNA base editors, which convert targeted adenine bases into inosine bases. RESCUE, its creators declare, is a particularly welcome development because many of the transcript modifications within RESCUE’s purview correspond to protein modifications relevant to cell signaling and cancer-linked pathways. For example, RESCUE enables modulation of more posttranslational modifications, such as phosphorylation, glycosylation, and methylation, as well as expanded targeting of common catalytic residues, disease mutations, and protective alleles. RESCUE was developed by a team of scientists led by Feng Zhang, PhD, an investigator at the McGovern Institute and a core member of the Broad Institute of MIT and Harvard. Zhang and colleagues made use of a deactivated Cas13 to guide RESCUE to targeted cytosine bases on RNA transcripts. Also, the scientists used a novel, evolved, programmable enzyme to convert unwanted cytosine into uridine—thereby directing a change in the RNA instructions.

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Hansa Biopharma and Genethon announce collaboration to develop imlifidase as pre-treatment to gene therapy in Crigler-Najjar syndrome patients

prnewswire | April 28, 2023

Hansa Biopharma AB, "Hansa" a pioneer in enzyme technology for rare immunological conditions, and Genethon, a pioneer and a leader in gene therapy research and development for rare genetic diseases, announced they have entered a research and development collaboration. The collaboration will, in a clinical study, evaluate the safety and efficacy of Hansa's antibody cleaving enzyme imlifidase as a pre-treatment prior to the administration of Genethon's gene therapy product candidate GNT-0003 in Crigler-Najjar syndrome in patients with pre-existing neutralizing antibodies (NAbs) to adeno-associated virus serotype 8 (AAV8). The presence of circulating NAbs today excludes patients from entering clinical studies with potentially curative gene therapy treatments and from future access to approved gene therapies. Søren Tulstrup, President and CEO, Hansa Biopharma stated: "Genethon is a pioneer at the cutting-edge of research and development of gene therapies for rare diseases and we are thrilled to be collaborating with them. This research collaboration further validates Hansa's commitment in gene therapy and underscores the important role that our antibody-cleaving enzyme technology can play in ensuring that even more patients can benefit from life-saving gene therapies". GNT-0003 is currently being evaluated in a pivotal clinical study in France, Italy, and the Netherlands and has received PRIME (PRIority MEdicines) status from the EMA. Through the collaboration announced today, patients with Crigler-Najjar and pre-formed antibodies to AAV8 will be enrolled in a study with similar design where imlifidase is evaluated as a pre-treatment to enable gene therapy treatment with GNT-0003. The outcome of the ongoing clinical study of GNT-0003 could potentially form the basis for a MAA or BLA application in Europe or the US. Crigler-Najjar is a genetic disease-causing bilirubin accumulation which leads to irreversible neurological damage manifested as muscle weakness, lethargy, deafness, mental retardation, and eye movement paralysis. Crigler-Najjar syndrome is an ultra-rare disease affecting less than one case per one million people per year.1 Frédéric Revah, CEO, Genethon added: "Patients with pre-existing neutralizing antibodies against AAV vectors cannot today benefit from gene therapy. This collaboration with Hansa Biopharma is thus an important next step in the development of our gene therapy treatment for Crigler-Najjar syndrome, Hansa Biopharma's proven enzyme technology coupled with its scientific expertise will help us advance the critical research we are conducting in Crigler-Najjar and could enable gene therapy treatment for patients who are today not eligible because of their immunological status". About Hansa Biopharma Hansa Biopharma is a pioneering commercial-stage biopharmaceutical company on a mission to develop and commercialize innovative, lifesaving and life-altering treatments for patients with rare immunological conditions. Hansa has developed a first-in-class immunoglobulin G (IgG) antibody-cleaving enzyme therapy, which has been shown to enable kidney transplantation in highly sensitized patients. Hansa has a rich and expanding research and development program based on the Company's proprietary IgG-cleaving enzyme technology platform, to address serious unmet medical needs in transplantation, autoimmune diseases, gene therapy and cancer. Hansa Biopharma is based in Lund, Sweden, and has operations in Europe and the U.S. The Company is listed on Nasdaq Stockholm under the ticker HNSA.

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INDUSTRY OUTLOOK

Monte Rosa Therapeutics Advances Second Development Candidate, MRT-6160, a Novel, Highly Selective Molecular Glue Degrader Targeting VAV1

Globenewswire | May 29, 2023

Monte Rosa Therapeutics, Inc. a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, announced its second development candidate, MRT-6160, a novel, potent, and selective molecular glue degrader of VAV1. The Company plans to file an Investigational New Drug (IND) application for MRT-6160 in the first half of 2024 and to develop the molecule as a potential treatment for autoimmune diseases. “MRT-6160 is a potent, orally bioavailable MGD designed to degrade VAV1, an important protein involved in the signaling pathways of T and B cells. Our in vitro studies have shown that MRT-6160 selectively degrades VAV1 without detectable effects on other proteins. By targeting VAV1, MRT-6160 attenuates multiple aspects of T- and B-cell function and inhibits disease progression in established in vivo models of autoimmunity,” said Owen Wallace, Ph.D., Chief Scientific Officer of Monte Rosa. “The underlying biology and our preclinical data both demonstrate that MRT-6160 acts as an immune modulator, which has the potential to avoid the broad immune suppression seen with other approaches. We look forward to progressing our clinical plan developed with the goal of providing early insights into safety, PK and PD, and proof of concept regarding differentiated effects on key immunomodulatory signaling pathways.” “Our goal centers on pioneering therapeutically meaningful new drugs for patients with serious diseases. By addressing VAV1, a validated but previously undruggable target, we believe we've created a potentially groundbreaking therapy for patients suffering from a range of serious autoimmune conditions, particularly those involving both T- and B cell-mediated autoimmunity,” said Markus Warmuth, M.D., CEO of Monte Rosa. “MRT-6160 is expected to be our second MGD to enter clinical trials, showcasing the continued productivity of our QuEEN™ platform. We anticipate significant progress and milestones in our portfolio in the upcoming year, including initial clinical data from our GSPT1 MGD, MRT-2359, in the second half of this year and filing of an IND application for MRT-6160 in the first half of next year.” About Monte Rosa Monte Rosa Therapeutics is a biotechnology company developing novel molecular glue degrader (MGD) medicines for patients with serious diseases such as oncology, autoimmune and inflammatory diseases. MGDs are small molecule protein degraders that employ the body’s natural mechanisms to selectively eliminate therapeutically relevant proteins. The Company’s QuEEN™ (Quantitative and Engineered Elimination of Neosubstrates) platform enables it to rapidly identify protein targets and design highly selective degraders by combining diverse libraries of proprietary MGDs with in-house proteomics, structural biology, AI/machine learning, and computational chemistry capabilities.

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INDUSTRIAL IMPACT, DIAGNOSTICS

PathAI and ConcertAI Partner to Create First-in-class Histopathology and Clinical Real-World Data Solutions

Prnewswire | April 26, 2023

PathAI, a global leader in AI-powered pathology, and ConcertAI, a leader in AI software-as-a-service technology and real-world evidence solutions for life sciences and healthcare, today announced a strategic partnership to launch a first-in-class quantitative histopathology and curated clinical real-world data (RWD) solution combining PathAI's PathExplore™ tumor microenvironment panel with ConcertAI's Patient360™ and RWD360™ products. Utilizing real world H&E-stained samples from PathAI's pathology laboratory, PathExplore extracts quantitative measures of the tumor microenvironment, known as human interpretable features (HIFs), from whole slide images. These data are linked to Patient360's reference-standard abstracted clinical EMR, medical claims, and Social Determinants of Health data, allowing direct insights into current standards of care and treatment dynamics. Similarly, the data are also linked to RWD360, which provides scaled insights from structured EMR data, medical claims, and Social Determinants of Health for large populations. "Real world data products include clinical and outcomes data, but are missing a critical component that links these, namely pathology, which has historically been non-standardized or with limited quantification," said Andy Beck, CEO and co-founder of PathAI. "Our collaboration with ConcertAI will offer access to a uniquely linked quantitative pathology dataset, allowing researchers to explore hypotheses far beyond the scope of small, controlled datasets, such as identifying and analyzing novel histological biomarkers correlated with patient treatment and outcomes." "Analysis of tumor microenvironment characteristics is critical to understanding why certain patients respond to a specific therapy and others do not. It further allows the definition of clinical strategies that might increase the numbers of patients benefiting from current medicines and improve the effectiveness of new ones," said Jeff Elton, PhD, CEO of ConcertAI. "With PathAI we are creating the first large scale clinical datasets linking pathology HIFs with EMR-derived clinical data, greatly enhancing the armamentarium of the translational and clinical development research communities." ConcertAI and PathAI will jointly offer these combined solutions to biopharma customers, including translational research and real-world data teams. The initial solutions focus on bladder cancer, colorectal cancer, prostate cancer, and melanoma. For more information, contact us at PathAI or ConcertAI, or visit us at PathAI's exhibit and ConcertAI's exhibit at ASCO in Chicago, IL, on June 2-6, 2023. PathAI and PathExplore are a registered trademark and trademark respectively of PathAI. ConcertAI, Patient360, and RWD360 are registered trademarks or trademarks of ConcertAI. All rights reserved. About ConcertAI ConcertAI is a leader in Real-World Evidence (RWE) and AI Software-as-a-Service solutions for life sciences and healthcare. Our mission is to accelerate insights and advance clinical outcomes for patients through advanced AI technologies, multi-modal real-world data, and scientific expertise in partnership with the leading biomedical innovators, healthcare providers, and medical societies.

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