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December 27th, 2020

Frameshifting ID’d in Protein Synthesis by Ribosomes of Melanoma Cells Missing the Amino Acid Tryptophan; First Time Such Frameshifting Observed in Human Cells; Aberrant Proteins Produced As Result; Findings May Offer Therapeutic Insights

Cancers like melanoma are hard to treat, not least because they have a varied bag of tricks for defeating or evading treatments. A combined research effort by scientists at the Weizmann Institute of Science in Israel and researchers in the Netherlands Cancer Institute in Amsterdam and the University of Oslo, Norway, shows exactly how tumors, in their battles to survive, will go so far as to starve themselves in order to keep the immune cells that would eradicate them from functioning. The new work was published online on December 16 in Nature (https://www.nature.com/articles/s41586-020-03054-1). The article is titled “Anti-Tumour Immunity Induces Aberrant Peptide Presentation in Melanoma.” The immunotherapies currently administered for melanomas work by removing obstacles that keep immune cells called T-cells from identifying and killing tumor cells. Recent research suggested that in melanoma, another blocker could assist the T-cells, this one to stop an enzyme called IDO1 that is overproduced by the cancer cells. IDO1 breaks down an essential amino acid, tryptophan, which is needed to make proteins, in the process leaving behind tryptophan breakdown byproducts that suppress the immune response. But IDO1 blockers did not fare well in clinical trials, suggesting more knowledge was needed--including how the cancer cells, which also require tryptophan, can function after they have destroyed this resource. The research team, including the group of Professor Yardena Samuels (http://www.weizmann.ac.il/mcb/Samuels/) of Weizmann’s Molecular Cell Biology Department, members of the lab of Professor Reuven Agami (https://www.nki.nl/research/research-groups/reuven-agami/) of the Netherlands Cancer Institute; Dr.

PACS-1 Gene Could Help Predict Response to Cervical Cancer Treatment

UCLA researchers have identified a potential diagnostic marker that could help predict how likely someone with cervical cancer is to respond to the standard treatment of chemotherapy and radiation. The scientists found that PACS-1 (phosphofurin acidic cluster sorting protein 1), a gene that resides on a small segment of the long arm of chromosome 11, is overexpressed in cancer tissues, which can result in cancer growth and spread. Further, they discovered that translocation of the PACS-1 protein from outside to inside the cell nucleus — a function required for normal cell growth — plays a role in the development of cervical cancer that is resistant to chemotherapy and radiation. Higher levels of PACS-1 expression in the nucleus could indicate resistance to the treatment, the researchers say. Cervical cancer is the second leading cause of cancer-related death among women worldwide. While infection with human papillomaviruses plays a significant role in cervical cancer development, the presence of a virus alone is not enough to cause cancer; genetics and environmental factors such as smoking and poor eating habits also play a role. Therefore, it is important to identify biological markers as targeting agents for diagnosis and treatment. The researchers performed a Western blot, a technique for detecting specific protein molecules from among a mixture of proteins, on cervical tumors and healthy cervical tissue and discovered an overexpression of PACS-1 in the tumor tissues. The team then developed in vitro human cell line models to assess the protein’s role in cell growth. Finally, they used a fluorescence-activated sorter analysis to help determine if the overexpression of the PACS-1 protein was associated with cancer chemotherapy resistance.

December 26th

Study Identifies Divergent Gene Activity Between Healthy and Damaged Skeletal Muscle in Mouse Model of Duchenne Muscular Dystrophy; Work “Opens Door to New Approaches for Ameliorating the Severe Pathological Consequences of This Disease,” Eric Olson Says

Understanding the activity of genes can shed light on pathologies that affect different tissues in the body. However, says Rhonda Bassell-Duby, PhD, a Professor of Molecular Biology at the University of Texas Southwestern (UTSW), studying skeletal muscle has been a challenge because of a key difference from other tissue types; rather than containing a single nucleus that controls the activity of the genes, a skeletal muscle fiber can contain hundreds of nuclei. And it was unknown which genes were activated in all these nuclei, making it unclear how gene expression differs between healthy skeletal muscle tissue and tissue affected by Duchenne muscular dystrophy (DMD). To answer these questions, Eric Olson, PhD, Chairman and Professor of Molecular Biology at UTSW, Dr. Bassel-Duby, and their colleagues isolated tissue from the tibialis anterior, a muscle in mice similar to one in humans that runs down the shin. They took these samples from both healthy animals and from a mouse model of DMD that they generated using gene-editing technology to introduce a mutation that commonly causes DMD in people. The researchers then isolated muscle tissue from both sets of animals, separated the nuclei, and analyzed their gene activity using a tool known as single-nucleus RNA sequencing. The results were published online on November 4, 2020 in PNAS. The article is titled “Degenerative and Regenerative Pathways Underlying Duchenne Muscular Dystrophy Revealed By Single-Nucleus RNA Sequencing.” In muscle fibers from both groups, the scientists identified 14 types of nuclei based on similar gene profiles. These nuclei appear to perform different jobs based on their predominant gene activity, such as maintaining mature muscle, liaising with neurons or tendons, or regenerating new muscle fibers.

Scientists Develop Molecular Classification of Zebrafish Retinal Ganglion Cells (RGCs) Linking Molecularly Described RGC Type to Specific Structure, Function, and Behavioral Response

Retinal ganglion cells (RGCs) are the bottleneck through which all visual impressions flow from the retina to the brain. A team from the Max Planck Institute of Neurobiology, the University of California (UC) Berkeley, and Harvard University created a molecular catalog that describes the different types of these neurons. In this way, individual RGC types could be systematically studied and linked to a specific connection, function and behavioral response. When zebrafish see light, they often swim towards it. Same with prey, although the signals are entirely different. A predator, on the other hand, prompts the fish to escape. That's good, because a mix-up would have fatal consequences. But how does the brain manage to react to a visual stimulus with the proper behavior? Optical signals are generated by photons that bombard the retina of the eye. Neurons in the retina collect and process these impressions. While doing so, the retina focuses on the important details: Is there contrast or color? Are there small or large objects? Is something moving? Once these details are filtered out, retinal ganglion cells (RGCs) send them to the brain, where they are translated into a specific behavior. As the only connection between the retina and the brain, RGCs play a central role in the visual system. We already knew that specific RGC types sends different details to different regions of the brain. However, it has been unclear how RGC types differ on the molecular level, what their respective functions are, and how they help to regulate context-dependent behavior. To begin to solve this puzzle, a team led by Yvonne Kölsch (photo), PhD, from Herwig Baier's (PhD) laboratory analyzed the genetic diversity of RGCs. Dr. Baier is Director of the Max Planck Institute of Neurobiology.

December 25th

Ocugen & Bharat Biotech to Co-Develop COVAXIN™, A Whole-Virion Inactivated COVID-19 Vaccine Candidate, for US Market; COVAXIN Is in Phase 3 Trial Now in India

On December 22, 2020, Ocugen, Inc., (NASDAQ: OCGN), a leading biopharmaceutical company, and Bharat Biotech, a global leader in vaccine innovation, announced that the companies have signed a binding letter of intent (LOI) to co-develop Bharat Biotech’s COVID-19 vaccine candidate, COVAXIN™, an advanced-stage whole-virion inactivated vaccine candidate, for the United States market. COVAXIN has been evaluated in approximately 1,000 subjects in Phase 1 and Phase 2 clinical trials in India, with promising safety and immunogenicity data. The vaccine candidate is currently part of a Phase 3 clinical trial in India involving 26,000 volunteers. Per the LOI, Ocugen will have US rights to the vaccine candidate and, in collaboration with Bharat Biotech, will be responsible for clinical development, registration, and commercialization for the US market. The companies have begun collaborating and will finalize details of the definitive agreement in the next few weeks. This collaboration leverages Ocugen’s vaccine expertise, and its R&D and regulatory capabilities in the US. In preparation for the development of COVAXIN™ in the US, Ocugen has assembled a Vaccine Scientific Advisory Board featuring leading academic and industry experts to evaluate the clinical and regulatory path to approval in the US market. “COVAXIN™ utilizes a historically proven approach to vaccine design. The adjuvanted inactivated virus vaccine candidate elicited strong IgG responses against spike (S1) protein, receptor-binding domain (RBD) and the nucleocapsid (N) protein of SARS-CoV-2, along with strong cellular responses in Phase 1 and 2clinical trials.

December 24th

New Class of Antibiotics Active Against a Wide Range of Bacteria; Inhibitors of Key Enzyme Kill Bacteria Directly & Also Elicit Rapid Immune Response; “Dual Acting Immuno-Antibiotics” Possible Landmark in World’s Fight Against Antimicrobial Resistance

Wistar Institute (Philadelphia) scientists have discovered a new class of compounds that uniquely combine direct antibiotic killing of pan drug-resistant bacterial pathogens with a simultaneous rapid immune response for combatting antimicrobial resistance (AMR). These finding were published online on December 23, 2020 in Nature. The article is titled “IspH inhibitors Kill Gram-Negative Bacteria and Mobilize Immune Clearance.” The World Health Organization (WHO) has declared antimicrobial resistance (AMR) as one of the top 10 global public health threats against humanity. It is estimated that by 2050, antibiotic-resistant infections could claim 10 million lives each year and impose a cumulative $100 trillion burden on the global economy. The list of bacteria that are becoming resistant to treatment with all available antibiotic options is growing and few new drugs are in the pipeline, creating a pressing need for new classes of antibiotics to prevent public health crises. “We took a creative, double-pronged strategy to develop new molecules that can kill difficult-to-treat infections while enhancing the natural host immune response,” said Farokh Dotiwala, M.B.B.S., Ph.D., Farokh Dotiwala (https://wistar.org/our-scientists/farokh-dotiwala), MBBS, PhD, Assistant Professor in the Vaccine & Immunotherapy Center and lead author of the effort to identify a new generation of antimicrobials named dual-acting immuno-antibiotics (DAIAs). Existing antibiotics target essential bacterial functions, including nucleic acid and protein synthesis, building of the cell membrane, and metabolic pathways. However, bacteria can acquire drug resistance by mutating the bacterial target the antibiotic is directed against, inactivating the drugs, or pumping them out.

Lysine Methyltransferase SETD2 Plays Key Role in Modifying Actin Cytoskeleton; This Has Implications for Two Important Functions of Cancer Cells--Cell Migration & Autophagy; SETD2 Interacts with Huntingtin and Actin-Binding Adapter HIP1R to Modify Actin

SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) is a protein well known as a chromatin remodeler, one that helps turn genes on or off by modifying histone proteins in the nucleus of the cell. When researchers discovered that SETD2 is mutated or lost in several cancer types, most commonly a type of kidney cancer called clear-cell renal cell carcinoma, all eyes turned toward SETD2 function in the nucleus of the cell to explain these cancers. In 2016, the lab of Cheryl Walker (photo), PhD, Director of the Center for Precision Environmental Health at Baylor College of Medicine, made the unexpected discovery that SETD2 not only remodels chromosomes in the nucleus, but also microtubules of the cytoskeleton outside the nucleus. The cytoskeleton is a dynamic network of interlinking protein thread-like structures, including filaments and microtubules that extend throughout the cell. It gives a cell its shape and internal organization and provides mechanical support that enables cells to carry out essential functions like division and movement. The Walker team found that SETD2 tags cytoskeleton microtubules with a methyl group. Loss of SETD2 resulted in defective delivery of chromosomes and problems with the separation of daughter cells during cell division. "Our findings suggested that defects in SETD2 could not only affect gene expression but also functions controlled by the cytoskeleton, such as movement, metastasis, and migration, which are very important for cancer cells," Dr. Walker said. "We wondered whether SETD2 might target other cytoskeletal proteins." Actin proteins, which form the filaments of the cytoskeleton, stood out as a prime target for SETD2.

December 23rd

French Exosome Company CILOA Creates GMP-Compliant Production Unit; This Unit Ensures Autonomy of CILOA in Development of Its Biomanufacturing Infrastructuren and Progress Toward Future Clinical Studies of Exosome-Based Vaccines & Biomedicines

On December 8, 2020, Ciloa, a pioneer French company specialized in the in-vivo customization of exosomes, announced the implementation of a production unit designed to meet GMP (Good Manufacturing Practices) standards. This new unit will allow Ciloa to have a complete manufacturing control and independence, starting by the initiation of the clinical phases. Ciloa’s future biomedicines and vaccines based on exosomes (TEM image here) will thus comply with the requirements of the regulatory agencies. Since its foundation in 2011 by Dr. Robert Mamoun, former Director of Research at INSERM, and Dr. Bernadette Trentin, both experts in molecular virology, Ciloa has been developing its expertise in the customization, production, and purification of exosomes. Stemming from two families of patents from the CNRS (French National Centre for Scientific Research) and the University of Montpellier, this breakthrough technology positions Ciloa as a precursor in the fast-evolving field of exosome innovation. Exosomes are natural nanovesicles secreted by cells into the extracellular medium. They can act as intercellular messengers and deliver specifically functional proteins (and other molecules) to targeted cells. Moving throughout the body, they can transmit natural signals that can be used therapeutically to regenerate, modify, multiply, or induce apoptosis of the targeted cells. The technology developed by Ciloa acts on the cellular machinery involved in exosome production. It is the sole technology that allows the in-vivo production of exosomes customized with any proteins.

New Drug Inhibits Growth of Cancer Cells; Small Molecule Blocks Gene Expression in Mitochondria in Mice & Stops Cancer Cells from Growing; Article Published in Nature

A newly developed compound starves cancer cells by attacking their "power plants"--the so-called mitochondria (image). The new compound prevents the genetic information within mitochondria from being read. Researchers from the Max Planck Institute for Biology of Ageing in Cologne, the Karolinska Institute in Stockholm, and the University of Gothenburg report in their study that this compound could be used as a potential anti-tumor drug in the future; not only in mice, but also in human patients. The article describing this work was published in the December 16, 2020 issue of Nature (https://www.nature.com/articles/s41586-020-03048-z). The article is titled “Small Molecule Inhibitors of Human Mitochondrial DNA Transcription.” Mitochondria provide our cells with energy and cellular building blocks necessary for normal tissue and organ function. For a long time, the growth of cancer cells was assumed to be independent of mitochondrial function. However, this long-standing dogma has been challenged in recent years. Especially, cancer stem cells are highly dependent on mitochondrial metabolism. Due to the central role of mitochondria for normal tissue function, and because drugs that target mitochondrial functions are usually very toxic, it has so far proven difficult to target mitochondria for cancer treatment. Now an international team of researchers has found a way to overcome these difficulties. "We managed to establish a potential cancer drug that targets mitochondrial function without severe side effects and without harming healthy cells", explains Nina Bonekamp, PhD, one of the lead authors of the study. Mitochondria contain their own genetic material, the mitochondrial DNA molecules (mtDNA), whose gene expression is mediated by a dedicated set of proteins.

December 22nd

FDA Resumes eIND Approval for Severe-to-Critical COVID-19 Patients Use of Vyrologix™ (Leronlimab) Following Full Enrollment in CytoDyn’s Phase 3 Trial for Severe-to-Critical COVID-19

On December 22, 2020, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing Vyrologix™ (leronlimab-PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced that a treating physician has received authorization from the U.S. Food and Drug Administration (“FDA”) to administer leronlimab for a COVID-19 patient under emergency investigational new drug IND (eIND) authorization. Nader Pourhassan, PhD, President and Chief Executive Officer of CytoDyn, commented, “We are very thankful the FDA is allowing severe-to-critical COVID-19 patients access to Vyrologix™ (leronlimab) again under eIND while we await the unblinding of data from our recently completed Phase 3 registrational trial. We are receiving daily requests from families seeking our drug for a loved one with COVID-19. In recent months, leronlimab received more than 60 eIND authorizations from the FDA, and during the pendency of our COVID-19 trials, we deferred seeking authorizations for eINDs in order to accelerate the pace of enrollment. Now that enrollment has been completed, we are pleased to be able to assist once again and remain hopeful the upcoming results of our Phase 3 trial will enable leronlimab to be more readily available for severe-to-critical COVID-19 patients.” CytoDyn’s Phase 2b/3 trial to evaluate the efficacy and safety of leronlimab for patients with severe-to-critical COVID-19 indications is a two-arm, randomized, double-blind, placebo-controlled, adaptive design multicenter study. Patients are randomized to receive weekly doses of 700 mg leronlimab, or placebo. Leronlimab and placebo are administered via subcutaneous injection. The study has three phases: Screening Period, Treatment Period, and Follow-Up Period. The primary outcome measured in this study is: all-cause mortality at Day 28.