Institute of Bioengineering & Nanotechnology

A study of the genetic variation that makes mice more susceptible to bowel inflammation after a high-fat diet has identified candidate genes which may drive inflammatory bowel disease (IBD) in humans. A study of the genetic variation that makes mice more susceptible to bowel inflammation after a high-fat diet has identified candidate genes which may drive inflammatory bowel disease (IBD) in humans. The findings are published as a Reviewed Preprint in eLife. Described by the editors as a fundamental study, the work provides a framework for using systems genetics approaches to dissect the complex mechanisms of gut physiology. The authors show how it is possible to use genetically diverse but well-characterised mice to interrogate intestinal inflammation and pinpoint genes influenced by the environment - in this case, a high-fat diet - and identify potential treatment targets for IBD in mice and humans. The editors describe the strength of the analyses as compelling and add that, as a resource, it will be useful for linking genetic variations and diet to gut-related disorders. It is well established that a high-fat diet can increase the risk of IBD. However, the impact of diet varies between individual people, suggesting an interplay with genetic factors. More than 200 risk genes have been identified for IBD, but there is still no effective treatment, and it is therefore important to understand the gene-by-environment interactions underpinning the inflammation that eventually evolves into IBD. "Differences in the clinical presentation of IBD among patients, as well as diversity in diet and lifestyle, render human genetic studies challenging," explains lead author Xiaoxu Li, a Doctoral Research Assistant at the Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Switzerland. "Genetically diverse populations of mice allow us to mirror the differences in human populations, while controlling several environmental factors, such as temperature and diet, when exploring the genetic modulators of IBD in the laboratory." Li and colleagues used mouse genetic reference populations (GRPs) to map the genetic factors that are important in IBD induced by a high-fat diet. They measured the levels of gene expression in the colons of 52 mice fed with either a chow or a high-fat diet and identified a subset of mice that were more susceptible to high-fat-diet-induced intestinal inflammation. Moreover, they found that levels of a pro-inflammatory cytokine called interleukin-15 were increased in the mice more likely to develop IBD, while levels of the anti-inflammatory cytokine, Interleukin-10, were decreased. This indicates that changes in the levels of genes associated with IBD reflect the general inflammatory status of mice. After classifying different mouse strains based on their likelihood of developing IBD-like genetic signatures, the team explored this further using gene co-expression network analysis. This identified two distinct modules (clusters) of genes that are related to known genetic signatures of human IBD. Next, they looked at the function of these genes and how they are controlled. Both IBD-associated modules largely consisted of immune response-related genes, including those known to be involved in Crohn's disease, and the team identified the likely regulators of the expression of these genes. But the genetic drivers behind the different susceptibility in the mice were still elusive. To find the candidate genes that influence gut inflammation specifically following a high-fat diet, they performed QTL analysis to identify quantitative trait loci (QTL) - regions of genes that interact with the environment to impact the observable trait data. This revealed a QTL that is related to chronic intestinal inflammation in mice. To see whether genes under this QTL could play a role in human IBD, the team then cross-checked their findings with risk genes for IBD by conducting an analysis using genome-wide association study data from UK Biobank*. They identified two plausible gene candidates, called EPHA6 and MUC4. In addition, using publicly available genetic variation data for IBD, Crohn's disease and ulcerative colitis, they found evidence to suggest that increased expression of the MUC4 gene in part of the colon may increase the risk of IBD in humans. A limitation of this analysis is that there were no mechanistic investigations or studies that directly provide a causative link between the candidate genes and IBD. The results are primarily observational and correlative, but they provide a dataset that generates hypotheses that can be studied further. "Our results point to important potential roles of two gene candidates in gut chronic inflammation that may lead to inflammatory disorders," says senior author Johan Auwerx, a Professor at the Institute of Bioengineering, EPFL. "Our systems genetics approach using GRP mice where the genetic backgrounds are known and the environment can be controlled enables the prioritisation of candidate genes in a complex disease which, when combined with human genome-wide association studies from UK Biobank, are generalisable to human patients and may have clinical value."

Please check out the biopharma industry coronavirus (COVID-19) stories that are trending for March 31, 2020. News information is not all-inclusive. Please check back for updates. FDA Actions EUA for Hydroxychloroquine Sulfate and chloroquine Phosphate : On March 28, 2020, the FDA issued an Emergency Use Authorization for hydroxychloroquine sulfate and chloroquine phosphate products donated to the Strategic National Stockpile (SNS) to be distributed and used for certain hospitalized patients with COVID-19 EUA for Battelle Decontamination System : The FDA adjusted the EUA for the Battelle Decontamination System for use to decontaminating N95 respirators. Those respirators would then be able to be reused by health care professionals during the COVID-19 pandemic. Warning Letters for Two Companies: The FDA and FTC issued warning letters to both Corona-cure.com and Carahealth for using misleading claims of prevention and/or treatment of COVID-19 for their products. Updated Guidance : The FDA updated guidance for “Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic.” Diagnostics Update : The FDA has worked with more than 230 test developers who plan to submit EUA requests to detect COVID-19. Also, 20 EUAs have been issued. The FDA has also announced an expedited review of diagnostic tests . Diagnostics Alberta Health Services (AHS): AHS has partnered with Spartan Bioscience to create a rapid testing device . The company is creating a handheld device that can detect the COVID-19 virus in less than one hour and may help eliminate the need for lab samples. Luminex received FDA EUA for its NxTAG CoV Extended Panel test for SARS-CoV-2. It can diagnose up to 96 patients in about 4 hours. It can be run in parallel with the NxTAG Respiratory Pathogen Panel (RPP). Thermo Fisher Scientific : Thermo Fisher announced the availability of Thermo Scientific AcroMetrix Coronavirus 2019 (COVID-19) RNA Control. This quality control product will be used to monitor and validate COVID-19 molecular diagnostic tests. Testing Therapies, Antivirals and Vaccines BioSpace’s Genetown Hotbed is at the very heart of the biopharma industry in the United States, largely in the Boston area. As the biopharma industry responds to the COVID-19 pandemic, some of the area’s companies are at the very frontlines of drug development against the disease , while others play supporting roles for the entire industry. Generation Bio / Vir Biotechnology: Both companies announced a collaborative research agreement to examine the potential for Generation Bio’s non-viral gene therapy platform to encompass the impact of Vir Biotechnologies’ human monoclonal antibodies (mAb) to help fight SARS-CoV-2. Clara Biotech: Clara Biotech, based out of Lawrence, KS indicated it has developed a way to target infected lunch tissue using exosomes . Clara Biotech is in the process of seeking clinical trials for the therapy that could reduce more complicated symptoms of COVID-19. Cue Health was awarded a $13 million contract to accelerate the development, validation and FDA clearance of a portable molecular diagnostic test for COVID-19 in less than 25 minutes. Vaxart produced 5 COVID-19 vaccine candidates for testing in its preclinical models. The development has started on its development program for cGMP production of the vaccine with Emergent BioSolutions and expects to initiate a Phase I trial in the second half of 2020. Bionano Genomics launched the largest study to date to identify genomic variants and novel active substances that influence resistance or sensitivity to the novel coronavirus that causes COVID-19. The first study is underway in Wuhan, China. The Hannover Medical School is now launching a study involving 1,000 patients and controls. BioMedInnovations: A North Carolina life science startup, BioMedInnovations has designed a low-cost device used to help people breathe . The company shifted its focus from making equipment to prolong organ life for transplants to respiratory medical devices due to the COVID-19 pandemic. Bermuda-based Kiniksa Pharmaceuticals saw early evidence treatment response from its experimental drug mavrilimumab in the care of COVID-19 patients. Mavrilimumab is an investigational fully-human monoclonal antibody that targets granulocyte macrophage colony-stimulating factor receptor alpha (GM-CSFRα). Patients treated with the asset had pneumonia and hyperinflammation associated with COVID-19. To date, six patients have been treated with mavrilimumab in the treatment protocol. All patients showed an early resolution of fever and improvement in oxygenation within 1-3 days. None of these patients have progressed to require mechanical ventilation. Mavrilimumab has been well-tolerated. China’s Sartorius is teaming up with Tianjin CanSino Biologics and the Institute of Bioengineering at the Academy of Military Medical Sciences in China to develop a vaccine candidate against COVID-19. CanSinoBIO and the Institute of Bioengineering used Sartorius’ BIOSTAT STR single-use bioreactor system for the upstream preparation of the recombinant vaccine, thus ensuring the rapid linear amplification of the adenovirus vector, Ad5-nCoV. ViGene Biosciences is providing 2020 GMP manufacturing slots now to help manufacture the vaccines for COVID-19. The company’s manufacturing is aimed at three different categories: Adenovirus GMP production expressing certain COVID-19 antigen ; GMP AAV-delivered COVID-19 vaccine ; and GMP Plasmid or Bacmid based COVID-19 vaccine . San Diego-based Arcturus Therapeutics is working with Duke University to develop a vaccine for COVID-19. Duke-NUS, a partnership between Duke and the National University of Singapore, developed a process to track genetic changes and their correlations that augment testing of vaccines. These gene expression changes can be measured within the first 5 days following vaccination and the data may also guide dose selection. Researchers in Australia are looking at a potential treatment for COVID-19 and are turning to another older treatment , a vaccine once used to prevent tuberculosis (TB) called the bacillus Calmette-Guerin (BCG), which has been used for about 100 years. Company Actions Reata: Due to the COVID-19 pandemic and after consulting with the trial’s Data Safety Monitoring Board (DSMB), Reata has halted the Phase III CATALYST trial of bardoxolone methyl in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) . These patients have compromised cardiopulmonary function often treated with immunosuppressants, putting them at high risk of infections. Reata decided that it was an unacceptable risk bringing these patients to clinics or in-person visits during the pandemic. Amgen is evaluating how the COVID-19 pandemic is affecting its operations, supply chain and clinical trial programs. The Phase II trial of AMG 510 in lung cancer is continuing uninterrupted, as is its Phase III trial with AstraZeneca of tezepelumab in asthma, which is also fully enrolled and the company does not expect delays. And, the Phase III heart failure trial in collaboration with Cytokinetics of omecamtiv mecarbil is also fully enrolled and expected to continue uninterrupted. Exicure updated its response to the COVID-19 pandemic. Its Phase Ib/II trial of AST-008 in Merkel cell carcinoma and in cutaneous squamous cell carcinoma is beginning the Phase II, which is continuing as expected. HiFiBIO Therapeutics is running experiments with researchers at ESPCI Paris – PSL and others to identify immune system activity to COVID-19 at the cellular level with its CelliGO platform, a novel droplet-based microfluidics technology. As the COVID-19 pandemic continues, Moderna, Inc. said it remains committed to its clinical development plans and is using a risk-based framework to evaluate new participant enrollment and new site initiation on a case-by-case basis. The pandemic has caused the company to pause enrollment in a Phase I rare disease trial for its pediatric respiratory vaccine. It is also suspending new enrollment of participants in the on-going hMPV/PIV3 study. Moderna has also paused enrollment in other trials. It is monitoring its Phase II CMV and Phase I Zika trials, both of which have been fully-enrolled. The company’s work on mRNA-1273, its vaccine candidate against the novel coronavirus continues to progress, Moderna said. While much of the company has gone to a remote-work situation, Moderna said essential in-person laboratory, manufacturing and related functions continue on site. Other Industry News The pandemic has forced pharma sales teams to harness virtual platforms since face-to-face interactions have been halted due to concerns over the spread of the virus. Could an increased reliance on virtual meetings last beyond the pandemic? Time will tell.

A summary of daily biopharma industry news. Please check out stories that are trending on March 25, 2020. News information is not all-inclusive. Please check back for updates. FDA Actions Access to Blood Donated by COVID-19 Survivors : The FDA is aiding access to convalescent plasma, antibody-rich blood products. This blood, donated from COVID-19 survivors, could shorten the length, or lessen the severity of the virus. Action to Increase U.S. Supplies : The FDA took action to increase U.S. supplies to help the U.S. with COVID-19. This action provided instructions to manufactures importing personal protective equipment and other devices. Vaccine Development : The FDA is working with both local and international experts to find vaccines to treat COVID-19. The FDA is collaborating with the EMA to facilitate SARS-CoV-2 vaccine development. Filtering Facepiece Respirator Shortages (FFRs) : The FDA has states that certain imported disposable FFRs that are not NIOSH-approved are appropriate to protect the publish health or safety. Center for Devices and Radiological Health (CDRH) Steps to Prioritize Work : The FDA has issued a Letter to Industry that includes steps the CDRH has taken to address the impact of COVID-19 public health emergencies on day-to-day operations in both the CDRH and in the medical device industry. The FDA has created a COVID-19 Diagnostic Tests Hotline for test developers and laboratories who have questions about the EUA process or who identify shortages of testing supplies. They also have a toll-free 24-hour phone line, 1-888-INFO-FDA. Diagnostics PerkinElmer announced the U.S. Food and Drug Administration (FDA) had granted its New Coronavirus RT-PCR test Emergency Use Authorization (EUA). The company joins a growing list of firms that have been granted EUA for COVID-19 testing The first was Roche , which was granted use for its fully automated cobas 6800 and 8800 Systems, approved on March 13. Heat Biologics and the University of Miami are collaborating on the development of a point-of-care diagnostic test. The test will require a pharyngeal throat swab to deliver on-the-spot results on a paper strip in under 30 minutes. This will vastly improve the four-to-five hour timeline for current tests that require blood draws to detect antibodies. Preliminary research suggests the new test is specific to the novel coronavirus, with no cross-reaction to previous coronavirus subtypes, the company said. The test is designed to enable cost-effective manufacturing amenable for mass production and deployment around the world. Minnesota-based Bio-Techne Corporation’s Ella Automated Immunoassay Platform is being used by hospitals in the United States and Italy to monitor individual immune responses to COVID-19. Specifically, the Ella Cytokine Storm Panel is being used to detect an immune response known as Cytokine Release Syndrome (CRS) in real-time. CRS represents a critical point in individuals with severe COVID-19 disease where immune molecules, called cytokines, attack the patient’s organs, representing a critical and potentially fatal point in disease management. Bio-Techne is investing in both near-term and long-term efforts to enable broader clinical adoption of Ella and is looking to partner with clinical research customers to pursue Emergency Use Authorization status for COVID-19 testing in key regions, as well as investing in manufacturing and quality control systems required for diagnostic products. Testing Therapies, Antivirals and Vaccines Gilead has submitted a request to the U.S. Food and Drug Administration (FDA) to rescind the orphan drug designation it was granted for remdesivir for the treatment of COVID-19. The FDA said Tuesday that it will allow physicians to use what is referred to as convalescent plasma collected from recovered COVID-19 patients in an attempt to treat patients who are critically ill from the virus that was declared a pandemic. China’s Sartorius is teaming up with CanSino Biologics and the Institute of Bioengineering at the Academy of Military Medical Sciences in China to develop a vaccine candidate against COVID-19. CanSinoBIO and the Institute of Bioengineering used Sartorius’ BIOSTAT STR single-use bioreactor system for the upstream preparation of the recombinant vaccine, thus ensuring the rapid linear amplification of the adenovirus vector, Ad5-nCoV. San Francisco-based Vir Biotechnology indicated it has identified several human monoclonal antibody (mAb) candidates against SARS-CoV-2, the virus causing COVID-19. In the interest of saving time, the company’s lead development was transferred to WuXi Biologics and Biogen several weeks ago with human trials likely to begin in the next three to five months. Cambridge, Mass.-based AlloVir , an immunotherapy company, teamed up with Baylor College of Medicine to discover and develop off-the-shelf, virus-specific T-cell therapies to combat SARS-CoV-2. With AlloVir’s proprietary technology, in addition to targeting SARS-CoV-2, the investigational virus-specific T-cell therapy may also address other coronavirus (CoV) strains including SARS-CoV, MERS-CoV, and also the endemic CoVs that commonly afflict immunocompromised patients, the company said. AlloVir aims to develop a therapy for CoVs that can be used as a stand-alone treatment or incorporated into the company’s multi-respiratory virus investigational therapy, ALVR106, which is designed to address other devastating and life-threatening community-acquired respiratory viruses. CHF Solutions announced the use of its Aquadex therapy for treating COVID_19 in New York City and in Georgia. The Aquadex SmartFlow system is a way of removing excess fluid from patients suffering from fluid overload. NeuroClear Technologies acquired the rights to develop a novel pharmaceutical to treat Covid-19 from BioSig Technologies . The product, Vicromax, has completed Phase I and three Phase II trials for other indications. In a preliminary internal review, Vicromax showed strong activity against COVID-19 in cell cultures. NeuroClear is a majority-owned subsidiary of BioSig. It intends to develop Micromax and take it through clinical trials under a new NeuroClear subsidiary, ViralClear Pharmaceuticals . Company Actions Immuron provided an update to the market regarding the current and future impact of COVID-19 . Immuron’s Board has moved quickly to address the present situation and have mentioned radical cost-cutting and deferring certain research and development activities. As a major first step in this process, Immuron’s CEO, Gary S. Jacob, has resigned as CEO and member of the Board of Immuron. DermTech International has implemented a work-from-home policy for much of its staff, however, the company said its laboratory remains fully-operational due to the necessity of providing results for early melanoma detection. While the company is taking every precaution due to the pandemic, it maintains that assessing an atypical mole for melanoma should be considered essential, and as such is “evaluating all opportunities to make our test available to patients and ensure timely results.” The California-based company noted that its patient-focused teams continue to operate normally and are following appropriate safety procedures including, social distancing, proper respiratory etiquette and hand hygiene, staggered shifts, requiring sick employees to stay home, and frequent environmental cleaning. The company suspended face-to-face interactions between its sales team and healthcare clinicians. Eloxx Pharmaceuticals paused enrollment in its Phase II trials for ELX-02 in cystic fibrosis in response to the COVID-19 pandemic. Takeda Pharmaceutical is donating more than $6.25 million to organizations in the U.S. impacted by COVID-19. The American Red Cross will receive $4 million. It will match employee donations to the American Red Cross dollar for dollar, up to a collective total of $500,000. The City of Cambridge Mayor’s Relief Fund will receive $2 million and the Town of Lexington’s Emergency Assistance Fund will receive $250,000. Applied Biosciences Corporation , a company focused on the development of synthetic cannabinoid therapeutics, has diverted its manufacturing resources to build products that will help battle the spread of the coronavirus. The company said it is prioritizing the development of additional products to complement its hand sanitizer line and anticipates launching them within the coming weeks, which will include, a travel-sized sanitizing spray, anti-bacterial hand soap and bottles of Isopropyl Alcohol. Other Industry News Hours before the U.S. Food and Drug Administration granted Emergency Use Authorization to California-based Cepheid’s rapid Xpert Xpress SARS-CoV-2 point-of-care diagnostic, Jeff Hawkins, chief executive officer of Truvian Sciences, noted that in all of the industry response to the pandemic , approval of such a device was still missing. On Tuesday, the former Food and Drug Administration Commissioner, Scott Gottlieb, told CNBC that the pandemic is going to be a long fight and the U.S. officials shouldn’t consider lifting stringent mitigation measures.