Category Archives: Cell Medicine

In 2004, Dr. Michael Ackerman got an unexpected phone call.

On the other end of the line was a medical examiner in Kentucky who had recently performed a befuddling autopsy on a 12-year-old Amish girl.

He was perplexed why this seemingly healthy Amish child died suddenly during play, said Ackerman, a genetic cardiologist at Mayo Clinic who studies why some young people die unexpectedly. And he says, I have DNA for you.

Ackerman, who also leads Mayos Windland Smith Rice Sudden Death Genomics Laboratory, pioneered a postmortem test to detect genetic causes behind sudden death. The medical examiner in Kentucky had heard about his work.

That phone call would ignite more than a decade of genetic sleuthing across multiple states to understand why a healthy Amish child had died without an obvious explanation. The mystery of her death and later, the deaths of more than a dozen other Amish children would vex researchers and clinicians for years, until Ackerman and his colleagues finally made a breakthrough in their Mayo lab.

Those findings were recently published in the JAMA Cardiology medical journal. Now, those same researchers are working to find a treatment.

Not long after the medical examiners call in 2004, Ackerman and his team were just beginning their research into the girls DNA when tragedy struck again. Four months after losing their daughter, the family lost her 10-year-old sister under similar circumstances suddenly, while she was outside playing.

Ackerman said his research team had a hunch the siblings deaths involved a gene called RYR2. When there's a single error on the gene, it causes an irregular heart rhythm that often reveals itself in the form of fainting spells while exercising. It can be fatal.

But that was more than 15 years ago, and medical research tools hadnt quite caught up to the teams needs.

Back then, it was painfully slow. It sort of was one gene at a time, Ackerman said.

After extensive testing of the girls' DNA, the Mayo researchers still had no answers.

We basically had a project that was stalled and would stay stalled until we would have evolution of technology, Ackerman said.

Over the next decade, 16 more Amish children died while exercising, without warning. The same family that lost their daughters in 2004 lost two more children under similar circumstances. Amish children in other states died, too.

While Mayos research languished, more than a thousand miles away, doctors at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., encountered a similarly tragic story.

In 2005, a young, apparently healthy Amish child was playing and died suddenly. The autopsy revealed no obvious cause. Several years later, the girls sister experienced cardiac arrest but survived and she is still living, 15 years later.

This started a trend, essentially, in their family, said Kristi Fitzgerald, a genetic counselor at Nemours and an author of the JAMA paper. Its not just a fluke chance, a terrible, tragic event. Now with two girls in one family, the presumption was that this probably was a genetic cause, something to do with a genetic arrhythmia.

But just as in Ackermans lab in Rochester, Minn., genetic testing at Nemours turned up nothing.

Over the years, Nemours staff collaborated with Mayo staff, and in the process learned that the sisters who had died in Kentucky were from the same extended family as the child who had died in Delaware.

Researchers also identified additional relatives in Iowa who have the same genetic defect. To date, no members of Amish communities in Minnesota appear to have the condition.

Clinicians at Mayo and elsewhere are fiercely protective of the families affected, and declined to identify them to maintain their privacy.

In Rochester, Ackerman and his staff continued to collect DNA samples from the children who died in this perplexing way, hoping someday to figure out the cause of their death.

They just needed the technology to catch up. In 2016, it started to.

Ackerman said new testing techniques revealed that the sudden deaths weren't caused by just one error on the RYR2 gene they were caused by 300,000 of them.

What's more, the risk of sudden death came only when the children inherited that faulty gene from both parents.

"We basically did genomic triangulation and figured that all of these sudden deaths and all of these different Amish communities were happening for the exact same reason: a double whammy, a double hit of this exact same duplication, Ackerman said.

Nemours pediatrician Matthew Demczko has made a career working with Amish children who live with an array of genetic abnormalities.

He said the genetic heart defect detected by the Mayo team is likely unique to the Amish community. Thats because researchers think people with the defect are all connected to a small number of people who established a particular Amish community from which the children affected were all descended. Those people are what Demczko calls "founder individuals."

Their genetic information has now become sort of the genetic thumbprint of the entire community, he said.

Demczko said Amish communities tend to be small and insular, and members of the community typically marry and have children with people who are also Amish.

That factor on top of the idea that from a cultural perspective, very few individuals come into the Amish community, there's really no introduction of new genetic material, he said.

Beating heart cells engineered from blood donated by two people living with a condition that has caused the sudden deaths of Amish children are shown on a microscope screen inside of the Mayo Clinic's Windland Smith Rice Sudden Death Genomics Laboratory.

Evan Frost | MPR News

Fitzgerald, Demczkos colleague, is on the front lines of screening members of Amish communities in their region for the defect. She said that Nemours positive reputation in nearby Amish communities helps in her work.

Word of mouth is important, she said. I think that's a great source of referral, to have a patient to say, We had a good experience. This went well.

Fitzgerald said her Amish patients ask the same questions about genetic testing as other families do: What will the test tell them? Why is the test important? What will they do with the information if they test positive?

And she said it's a misconception that Amish people shun medicine.

The families shes worked with, she said, have been open to testing and treatment.

"Parents want what's best for their child. It's about building a relationship, you know, with the family, she said. Most are not at all skeptical."

Fitzgerald said that some parents whose children have tested positive for the condition have opted to get an implantable defibrillator, which is the only available treatment.

But many Amish families dont carry health insurance, so that solution is not only invasive, but can be prohibitively expensive.

Back at Mayo, researcher Dave Tester is trying to better understand the genetic defect he helped discover. Now that theyve pinpointed the cause of the childrens sudden death, theyre trying to find a more affordable and accessible treatment.

"This is sort of phase 2 in this study, said Tester, who also authored the JAMA article.

To do that, the researchers turned to another novel approach: They engineered beating heart cells from blood samples donated by two people living with the condition.

He points to a cluster of heart cells undulating rhythmically under a microscope.

"These cells have the same exact genetic background that our patient does, he said. Here we can understand, at least from this patient's perspective what is the cell doing?"

Beating heart cells from blood samples donated by two people living with a condition that has caused the sudden death of Amish children.

Evan Frost | MPR News

In the coming months, Tester and his staff will perform a battery of tests on these cells, looking for clues that point them toward a better treatment.

But in the meantime, Mayo and Nemours continue to collaborate to understand just how common the condition is and how widespread. Their network has also extended to Iowa, where a genetic counselor is working with nearby Amish communities.

To ease that process, Mayo has made the test free for Amish families who may be affected.

Fitzgerald, the genetic counselor, is hopeful additional screening in Delaware and in other Amish communities will reveal more information about the condition.

And while she may not be able to offer her families a perfect solution today, at least they're starting to get some answers.

We don't want to give false hope, but I think it is important to tell families how far we come, she said. We tell people Hold on, stay tuned.

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Amish kids were dying mysteriously. Mayo scientists solved it. But can they treat it? - Minnesota Public Radio News

Sanaz Mansouri,1,* Behzad Khansarinejad,2,* Ghasem Mosayebi,2 Aziz Eghbali,3 Mahdieh Mondanizadeh1,4

1Department of Biotechnology and Molecular Medicine, Arak University of Medical Sciences, Arak, Iran; 2Department of Microbiology and Immunology, Arak University of Medical Sciences, Arak, Iran; 3Department of Pediatrics, School of Medicine, Arak University of Medical Sciences, Arak, Iran; 4Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran

*These authors contributed equally to this work

Correspondence: Mahdieh MondanizadehDepartment of Biotechnology and Molecular Medicine, Arak University of Medical Sciences, Arak, IranTel/Fax +98-8634173526Email m_mondanizadeh@yahoo.com

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and malignant neoplasm that arises from the hematopoietic T-cell precursors. Inactivation of FBXW7 gene is frequently observed in T-cell acute lymphoblastic leukemia, suggesting a significant tumor-suppressive role for FBXW7 in the pathobiology of this leukemia. Considering the role of microRNAs in cell proliferation and regulation of apoptosis, the aim of this study was to identify novel oncogenic microRNAs that suppress FBXW7 in patients with T-ALL.Patients and Methods: The expression levels of two bioinformatically predicted microRNAs miR-32 and miR-107 were compared in patients with T-ALL and a control group. A total of 80 plasma samples were subjected to RNA extraction, and the microRNA expression profiles were assessed by the RT-qPCR. The expression level of miR-103 was used as the endogenous reference for normalization of quantitative data.Results: The plasma levels of miR-32 and miR-107 in patients with T-ALL were significantly higher (5.65, P< 0.001) and lower (0.432, P= 0.002), respectively. On the other hand, the expression levels of FBXW7 gene were significantly downregulated by 76.9 fold in T-ALL patients (P< 0.001). The results of the ROC curve analysis indicated that overexpression of miR-32 might be used to distinguish T-ALL patients with reasonable sensitivity and specificity.Conclusion: miR-32 is considered as a novel oncomir that targets FBXW7 and might have a role in the etiology or progression of T-ALL. Furthermore, miR-32 can potentially serve as a non-invasive biomarker for detection of T-ALL.

Keywords: biomarker, FBXW7, T-ALL, microRNA

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Alteration in Expression of miR-32 and FBXW7 Tumor Suppressor in Plasm | CMAR - Dove Medical Press

Scientists have created a detailed map of breast cancer ever achieved, revealing how genetic changes shape the physical tumour landscape, according to research funded by Cancer Research UK and published in Nature Cancer.

An international team of scientists, brought together by an ambitious 20m Grand Challenge award from Cancer Research UK, has developed intricate maps of breast tumour samples, with a resolution smaller than a single cell.

These maps show how the complex cancer landscape made up of cancer cells, immune cells and connective tissue varies between and within tumours, depending on their genetic makeup.

This technique could one day provide doctors with an unparalleled wealth of information about each patients tumour upon diagnosis, allowing them to match each patient with the best course of treatment for them.

In the future, it could also be used to analyse tumours during treatment, allowing doctors to see in unprecedented detail how tumours are responding to drugs or radiotherapy. They could then modify treatments accordingly, to give each patient the best chance of beating the disease.

Dr Raza Ali, Lead Author of the study and Junior Group Leader at the Cancer Research UK Cambridge Institute, said: At the moment, doctors only look for a few key markers to understand what type of breast cancer someone has. But as we enter an era of personalised medicine, the more information we have about a patients tumour, the more targeted and effective we can make their treatment.

The researchers studied 483 different tumour samples, collected as part of the Cancer Research UK funded METABRIC study, a project that has already revolutionised our understanding of the disease by revealing that there are at least 11 different subtypes of breast cancer.

The team looked within the samples for the presence of 37 key proteins, indicative of the characteristics and behaviour of cancer cells. Using a technique called imaging mass cytometry, they produced detailed images, which revealed precisely how each of the 37 proteins were distributed across the tumour.

The researchers then combined this information with vast amounts of genetic data from each patients sample to further enhance the image resolution. This is the first time imaging mass cytometry has been paired with genomic data.

These tumour blueprints expose the distribution of different types of cells, their individual characteristics and the interactions between them.

By matching these pictures of tumours to clinical information from each patient, the team also found that the technique could be used to predict how someones cancer might progress and respond to different treatments.

Professor Carlos Caldas, Co-Author of the study from the Cancer Research UK Cambridge Institute, said: Weve shown that the effects of mutations in cancer are far more wide-ranging than first thought.

They affect how cancer cells interact with their neighbours and other types of cell, influencing the entire structure of the tumour.

The research was funded by Cancer Research UKs Grand Challenge initiative. By providing international, multidisciplinary teams with 20m grants, this initiative aims to solve the biggest challenges in cancer.

Dr David Scott, Director of Grand Challenge at Cancer Research UK said: This team is making incredible advances, helping us to peer into a future when breast cancer treatments are truly personalised.

Theres still a long way to go before this technology reaches patients, but with further research and clinical trials, we hope to unlock its powerful potential.

The researchers where based at the Cancer Research UK Cambridge Institute, University of Cambridge, the University of Zrich, Switzerland and the British Columbia Cancer Research Centre, Canada.

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Map of breast cancer reveals how mutations shape the tumour landscape - Pharmafield

New York, Feb. 17, 2020 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Cell Expansion Market to 2027 - Global Analysis and Forecasts By Product ; Cell Type ; Application ; End User, and Geography" - https://www.reportlinker.com/p05862085/?utm_source=GNW

Cancer is one of the major cause of human death worldwide.In recent years, the cases of cancer have been increasing tremendously and the trend is anticipated to remain the same in the upcoming years.

According to the World Health Organization in 2018, approximately 9.6 million deaths across the globe were due to cancer. Furthermore, the National Cancer Institute predicted that in 2018, approximately 1,735,350 new cancer cases would be diagnosed in the US.

Changes in lifestyle have resulted in more exposure to oncogenic factors.Cancer can be cured if diagnosed and treated at an initial stage.

Cancer sequencing using next-generation sequencing (NGS) methods provides more information. Additionally, cell expansion related procedures also aids in research, diagnostics and treatment of cancer.Furthermore, Asia Pacific region is also facing the problem of the growing prevalence of cancer.The top 15 countries with Cancer prevalence are Japan, Taiwan, Singapore, South Korea, Malaysia, Thailand, China, Philippines, Sri Lanka, Vietnam, Indonesia, Mongolia, India, Laos, and Cambodia.

According to the National Institute of Cancer Prevention and Research (NICPR), in 2018, in India, total deaths due to cancer were 784,821.

The global Cell Expansion market is segmented by product, cell type, application, end user.Based on product, the cell expansion market is segmented into consumables and instruments.

In 2018, the consumables accounted for the largest market share in the global cell expansion market by product.These consumables are essential components of any laboratory experiment hence they are expected to witness significant growth during the forecast period.

Based on cell type, the cell expansion market has been segmented into human cell and animal cell.Furthermore based on application the cell expansion market has been segmented into Regenerative Medicine And Stem Cell Research, Cancer And Cell-Based Research and Other Applications.

Based in end user market is segmented into Biopharmaceutical And Biotechnology Companies, Research Institutes, cell banks and others.

Some of the essential primary and secondary sources included in the report are the National Institute of Cancer Prevention and Research (NICPR), Association for Management Education and Development, Center for Cancer Research, International Society for Stem Cell Research (ISSCR), American Association of Blood Banks (AABB), National Institute of Cancer Prevention and Research and others.Read the full report: https://www.reportlinker.com/p05862085/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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The global cell expansion market is projected to reach US$ 42,837.11 Mn in 2027 from US$ 11,929.43 Mn in 2018 - GlobeNewswire

The mechanism that prevents destruction of cancer cells by CAR T-cell therapy has been identified by researchers in Pennsylvania.

Chimeric antigen receptor (CAR) T-cell therapy has been hailed as a breakthrough in cancer treatment; modifying a patients own immune T cells to seek and destroy cancer cells. However, a significant proportion of patients have cancer that still evades destruction and new research from the Abramson Cancer Center of the University of Pennsylvania is helping to explain why.

Researchers have described how a death receptor pathway in the cancer cell itself plays a central role in determining its response to CAR T cells. This first-of-its-kind study has shown that natural cancer features can influence response to CAR T cells, and that cancer cells can drive the development of CAR T-cell dysfunction.

In acute lymphoblastic leukaemia (ALL), between 10 and 20 percent of patients have disease that is resistant to CAR T cells, but until now, researchers did not understand why.

Most theories have centred around a defect in the T cells, but what weve shown here is that the problem originates in an important death signalling pathway in the cancer cell itself, which prevents the T cell from doing its job, said the studys co-senior author Marco Ruella, MD, an assistant professor of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania and a member of the Center for Cellular Immunotherapies in Penns Abramson Cancer Center. Ruellas co-senior author is Saar Gill, MD, PhD, an assistant professor of Hematology-Oncology at Penn.

Researchers first performed a genome-wide CRISPR/Cas9-based screen of an ALL cell line known as Nalm6 to isolate pathways associated with resistance. Cells were edited for loss of function of single genes and combined with CAR T cells for 24 hours to identify the pathway driving the primary resistance.

The team discovered that in ALL cells resisting CAR T attack, there was depletion of genes involved in activating the cell death pathway (FADD, BID, CASP8 and TNFRSF10B) and enrichment of genes required for resisting the cell death pathway (CFLAR, TRAF2 and BIRC2). When they tested this in animal models, the effect was even greater than what had been observed in vitro. The researchers were initially mystified by this discrepancy, prompting them to study the effect of the cancer on the T cells trying to kill it. This led them to observe that prolonged survival of cancer cells led to T cell dysfunction.

Most theories have centred around a defect in the T cells, but what weve shown here is that the problem originates in an important death signalling pathway in the cancer cell itself

The team then explored the clinical relevance of these findings using paediatric patient samples from previous CAR T trials by analysing the genes in leukaemia cells and in T cells pre- and post-infusion from responders and non-responders. They found that the previously identified signalling pathways in cancer cells were directly associated with responses to CAR therapy in the patients from two clinical trials, further suggesting that death receptor signalling is a key regulator of primary resistance to CAR T-cell therapy in ALL.

We now know that resistance occurs in two phases: the cancer cells initial resistance to death, followed by the cancers ability to impair T-cell function, said co-first author Nathan Singh, MD, MS, who led the work while he was a post-doctoral researcher with Carl June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies. Singh is now an assistant professor of Medicine at Washington University School of Medicine in St. Louis and a research member of Siteman Cancer Center. Together, this leads to CAR T-cell failure that allows the disease to progress.

Researchers say these findings suggest the use of healthy donor T cells for CAR T manufacturing may face the same barriers as cells used from the patient.

This will also inform future research investigating new and improved CAR T cells that have the ability to overcome this resistance, along with therapies that target the defective signalling pathway in cancer cells, Gill said.

These findings were published inCancer Discovery.

Link:
Precise features of CAR T cell-resistant cancer have been identified - Drug Target Review

MEDFORD/SOMERVILLE, Mass. (February 4, 2020)Researchers led by biologists at Tufts University have discovered that the brains of developing embryos provide signals to a nascent immune system that help it ward off infections and significantly improve the embryos ability to survive a bacterial challenge. Using frog embryos, which continue to develop with their brains removed, the researchers found that embryos without a brain are not able to marshall the forces of immune cells to an injury or infection site, leading the embryo to succumb to an infection more quickly. By contrast, the presence of a brain crucially helps direct immune cells to the site of injury to overcome the bacterial threat. The study was published today in NPJ Regenerative Medicine.

In a developing embryo, both brain and immune system are not fully formed. The immune system, for its part, consists mostly of an innate system of cells that respond immediately to infection and do not require training or produce antibodies. Nevertheless, these cells require signals that prompt them to move toward an infection site and trigger a response.

The research team found that the brain appears to contribute to the signals that guide the nascent immune system. When brainless frog embryos were infected with E. coli, only about 16% of embryos survived, while the presence of a brain protected more than 50% from the infection. By following markers of immune cells, researchers confirmed that the effect is not due to the missing brain somehow hampering immune system development because the composition of the immune cells remained the same with or without a brain. Instead, they found that the effect was due to the brain sending signals to the immune cells to move toward the site of an infection.

We found that macrophages innate immune system cells that can swallow up bacteria and destroy them to reduce the burden of an infection do not migrate appropriately without the presence of the brain said Michael Levin, Vannevar Bush Professor of Biology at Tufts Universitys School or Arts and Sciences and Associate Faculty at Harvards Wyss Institute, director of the Allen Discovery Center at Tufts and corresponding author of the study. Without the brain and its neurotransmitter signals, gene expression and innate immune system activity go awry, resulting in increased susceptibility to bacterial pathogens.

Other roles for the embryonic brain signaling during infection may include inducing cellular responses, for example preventing cell death or reducing inflammation, that help protect against the harmful effects of the infection.

Immune system abberations were also observed in brainless embryos that were further developed. When the researchers tracked myeloid cells, a class of immune cells that includes macrophages, neutrophils and others, after an injury, they found that the myeloid cells in brainless embryos gathered in locations far from the injury site. By contrast, myeloid cells in normal embryos with intact brains would pile up at the injury site to assist in healing. In fact, in the brainless embryo, the myeloid cells tended to cluster around abnormal, disorganized peripheral nerve networks, also a by-product of brain absence, as demonstrated in earlier studies.

An examination of aberrations in genetic expression in brainless embryos also pointed to the reduction of the neurotransmitter dopamine (a signaling chemical used in the brain for learning and motivation), and that dopamine may play a role in activating immune cells to migrate in the early stages of an infection. The absence of an immune cell quorum at the infection site leads the brainless embryos to become more susectible to its lethal effects.

Our results demonstrate the deep interconnections within the bacteria-brain-body axis: the early brain is able to sense the pathogenic bacteria and to elaborate a response targeted to fight against the cellular and molecular consequences of the infection, said Celia Herrera Rincon, Research Scientist II at the Allen Discovery Center at Tufts, and first author of the study.

Other authors of this study include: Jean-Francois Par, Christina Harrison, Alina Fischer, and Sophia Jannetty at the Allen Discovery Center at Tufts; Christopher Martyniuk, associate professor in the Department of Physiological Sciences at University of Florida; and Alexandre Dinis and Vishal Keshari, graduate students, and Richard Novak, senior staff engineer at the Wyss Institute for Biologically Inspired Engineering, Harvard Universiy.

This research was supported by the Templeton World Charity Foundation Independent Research Fellowship (TWCF0241) and the Allen Discovery Center program through The Paul G. Allen Frontiers Group (12171), as well as The Defense Advanced Research Projects Agency(DARPA, W911NF-16-C-0050), and the National Institutes of Health (AR055993, AR061988). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Herrera-Rincon, C., Par, J-F, Martyniuk, C.J., Jannetty, S.K., Harrison, C., Fischer, A., Dinis, A., Keshari, V., Novak, R., and Levin, M. An in vivo brainbacteria interface:

the developing brain as a key regulator of innate immunity. NPJ Regenerative Medicine (31 Jan 2020) DOI: 10.1038/s41536-020-0087-2

###

About Tufts University

Tufts University, located on campuses in Boston, Medford/Somerville and Grafton, Massachusetts, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university's schools is widely encouraged.

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Brain links to embryonic immunity, guiding response of the troops that battle infections - Tufts Now

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Signals that cause damage blocked in mice

Inner hair cells of the cochlea (green and blue) excite auditory nerve fibers (red) by releasing glutamate, a chemical signal that helps convert sound waves into electrical signals that travel to the brain. But too much glutamate can be harmful, leading to noise-induced hearing loss. Studying mice, researchers at Washington University School of Medicine in St. Louis and their colleagues have shown that a drug compound can block damage caused by too much glutamate signaling, raising the possibility of medication that prevents noise-induced hearing loss.

Loud noise can damage the inner ear and cause hearing loss. Studying mice, researchers at Washington University School of Medicine in St. Louis and the University of Iowa have shown that a drug compound can block damage caused by loud noise, raising the possibility of medication that prevents noise-induced hearing loss.

The study is published the week of Feb. 3 in the Proceedings of the National Academy of Sciences.

The spiral-shaped cochlea of the inner ear is responsible for detecting sound. Inner hair cells lining the cochlea transform the mechanical vibrations of sound waves into chemical signals. These chemicals primarily one called glutamate are then released from the hair cells and received by glutamate receptors on the auditory nerve fibers that then send electrical impulses to the brain. There, the signals are interpreted as language, music or signs of danger, for example.

The junction between a hair cell and a nerve fiber is called a synapse. Loud noise can release too much glutamate, overwhelming the glutamate receptors, which leads to loss of synapses and, eventually, a condition called sensorineural hearing loss. More than 460 million people worldwide live with hearing loss that negatively impacts their daily lives, according to the World Health Organization. By 2050, that number is projected to increase to more than 900 million.

Sensorineural hearing loss is the most common sensory deficit worldwide, and there are no medicinal treatments for preventing it, said co-author Mark A. Rutherford, PhD, an assistant professor of otolaryngology at Washington University. Glutamate receptors are essential for hearing, but overstimulating them can lead to irreversible damage to synapses. What we have found is that glutamate receptors are not all the same, allowing us to block some while leaving others unblocked. When we blocked one subclass of glutamate receptor while leaving the other active, we prevented the damage while maintaining hearing function.

These two different types of receptors those that allow calcium to pass through and those that dont are present at the same synapses. Normally, both are activated when transmitting sound information to the auditory nerve. Rutherford and his collaborators at the University of Iowa found that a compound called IEM-1460 blocks the portion of these receptors that allows more calcium to pass through. In doing so, they prevent the damage, but the receptors that are not blocked allow hearing to continue.

Blocking all of the receptors would, in theory, protect hearing but also cause temporary deafness perhaps similar to the effect of wearing ear plugs. This perhaps would be helpful for long-term hearing preservation but not ideal in situations where people are exposed to dangerous levels of noise but still need to hear what is happening around them.

For military personnel going into combat, for example, its important to find a way to protect hearing from noise damage while still allowing them to hear in that moment, Rutherford said. We showed that this compound selectively blocks the receptors responsible for the damage, while allowing other receptors to continue working normally so there is little interference with the hearing function.

Said senior author Steven H. Green, PhD, of the University of Iowa: Even moderate noise can cause damage to these synapses, and the damage accumulates as we age. With our aging population, the number of people living with disabling hearing loss is increasing rapidly. This is the motivation behind our labs collaboration: We are seeking preventive therapies that can protect this vital sensory function in the setting of damaging noise levels while still letting people hear as they normally would.

For this preliminary study in mice, a surgical procedure was used to apply the drug directly into the inner ear in a continuous flow. With potential therapies in mind, future work involves examining whether delivery of the drug by injection or orally or by placing it into the ear canal, in the form of ear drops, for example, or some combination of delivery methods could achieve the same effect. The IEM-1460 compound has never been tested in people, but it has been safely administered to small mammals as well as nonhuman primates in other types of neurobiology research, according to the investigators.

This work was supported by the National Institutes of Health (NIH), grant numbers DC002961 and DC014712; the Department of Defense (DOD), grant number W81XWH-14-1-0494; and the American Hearing Research Foundation.

Hu N, Rutherford MA, Green SH. Protection of cochlear synapses from noise-induced excitotoxic trauma by blockade of Ca2+-permeable AMPA receptors. Proceedings of the National Academy of Sciences. Feb. 3, 2020.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Noise-induced hearing loss blocked with drug compound - Washington University School of Medicine in St. Louis

NEW YORK, Feb. 4, 2020 /PRNewswire/ --Hoth Therapeutics, Inc. (NASDAQ:HOTH), a biopharmaceutical company focused on unique targeted therapeutics for patients suffering from dermatological indications ranging from atopic dermatitis, psoriasis and acne along with gene therapy treatment for asthmatics, is pleased to announce the initiation of a preclinical study for the treatment of asthma and allergic inflammation in collaboration withNorth Carolina State University(NC State).

The study has begun thedelivery and distribution of nebulized particleswhich willenable the therapeutic oligonucleotide (oligo), short DNA and RNA molecules that have a wide range of applications in gene testing.Hoth has appointed Dr. Glenn Cruse to its Scientific Advisory Board and will oversee the Company's gene therapy programs advancements.

Mr.Robb Knie, Chief Executive Officer of Hoth Therapeutics, Inc. commented,"We are extremely pleased that our gene therapy program with NC State has officially begun and that Dr. Cruse who is overseeing the advancement ofexperimentshas joined our Scientific Advisory Board. Commencement of this initiative is an important step in the development and growth of our company. Dr. Cruse's expertise asa leading mast cell biologist in allergic and inflammatory diseases will be invaluable for the preclinical development of Splice-switching oligonucleotides (SSOs) for asthma."

In November 2019 Hoth entered into a licensing agreement with North Carolina State University (NC State) to study NC State's Exon Skipping Approach for Treating Allergic Diseases. This Exon Skipping Approach was developed by Dr. Glenn Cruse, Principal Investigator and Assistant Professor in the Department of Molecular Biomedical Sciences at the NC State College of Veterinary Medicine. During Dr. Cruse's research, a new approach for the technique of antisense oligonucleotide-mediated exon skipping to specifically target and down-regulate IgE receptor expression in mast cells was identified. These findings set a breakthrough for allergic diseases as they are driven by the activation of mast cells and the release of mediators in response to IgE-directed antigens.

Glenn Cruse completed his Ph.D. at Glenfield Hospital, The University of Leicester, UK in 2009. He then moved to the National Institutes of Health in Bethesda, Maryland in January 2010 to start a visiting postdoctoral fellowship in the Laboratory of Allergic Diseases, NIAID, In January 2015, Dr. Cruse was appointed as a Research Fellow in the same laboratory. Dr. Cruse joined the Department of Molecular Biomedical Sciences at NC State in January 2016 as an Assistant Professor.

Dr. Cruse is a mast cell biologist that has authored and co-authored over 30 publications including articles in top journals such as the New England Journal of Medicine, Proceedings of the National Academy of Sciences USA and Immunity. The Cruse lab is interested in the role that mast cells play in allergic and inflammatory diseases and identifying novel therapeutics that target mast cells. Since mast cells act as sentinel cells that participate in both innate and acquired immunity, particularly at biological barriers, emphasis on diseases in tissues at the interface with the environment such as the lung, skin, gastrointestinal tract and even the neuro-immune axis are the main focus of the lab.

About Hoth Therapeutics, Inc.Hoth Therapeutics, Inc. isa clinical-stage biopharmaceutical company focused on developing new generation therapies for dermatological disorders. HOTH's pipeline has the potential to improve the quality of life for patients suffering from indications including atopic dermatitis, chronic wounds, psoriasis, asthma and acne. To learn more, please visitwww.hoththerapeutics.com.

Forward Looking StatementsThis press release includes "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements in this press release include, but are not limited to, statements that relate to the advancement and development of the BioLexa Platform, the commencement of clinical trials, the availability of data from clinical trials and other information that is not historical information. When used herein, words such as "anticipate", "being", "will", "plan", "may", "continue", and similar expressions are intended to identify forward-looking statements. In addition, any statements or information that refer to expectations, beliefs, plans, projections, objectives, performance or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking. All forward-looking statements are based upon Hoth's current expectations and various assumptions. Hoth believes there is a reasonable basis for its expectations and beliefs, but they are inherently uncertain. Hoth may not realize its expectations, and its beliefs may not prove correct. Actual results could differ materially from those described or implied by such forward-looking statements as a result of various important factors, including, without limitation, market conditions and the factors described under the caption "Risk Factors" in Hoth's Form 10K for the period endingDecember 31, 2018, and Hoth's other filings made with the Securities and Exchange Commission. Consequently, forward-looking statements should be regarded solely as Hoth's current plans, estimates and beliefs. Investors should not place undue reliance on forward-looking statements. Hoth cannot guarantee future results, events, levels of activity, performance or achievements. Hoth does not undertake and specifically declines any obligation to update, republish, or revise any forward-looking statements to reflect new information, future events or circumstances or to reflect the occurrences of unanticipated events, except as may be required by law.

ContactsInvestor Relations Contact:Phone: (646) 756-2997Email:investorrelations@hoththerapeutics.comwww.hoththerapeutics.com

KCSA Strategic CommunicationsValter Pinto(212) 896-1254Hoth@kcsa.com

View original content to download multimedia:http://www.prnewswire.com/news-releases/hoth-initiates-preclinical-gene-therapy-program-with-nc-state-for-the-treatment-of-asthma-and-allergic-inflammation-300998521.html

SOURCE Hoth Therapeutics, Inc.

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Hoth Initiates Preclinical Gene Therapy Program with NC State for the Treatment of Asthma and Allergic Inflammation - BioSpace

Injecting a swarm of nanoparticlesinto the blood of someone who has suffered a brain injury may one day help tolimit the damage if experimental results in mice can be translated to humans. In mice, these nanoparticlesseemed to reduce dangerous swelling by distracting immune cells from rushing to aninjured brain.

The results, describedonline January 10 in the Annals ofNeurology, hint that the inflammation-fighting nanoparticles might somedaymake powerful medicine, says John Kessler, a neurologist at NorthwesternMedicine in Chicago. All the data we have now suggest that theyre going to besafe, and theyre likely to work for people, Kessler says. But we dont knowthat yet.

After an injury, tissueoften swells as immune cells flock to the damage. Swelling of the brain can be dangerousbecause the brain is contained within the skull and theres no place to go, Kesslersays. The resulting pressure can be deadly.

But nanoparticles might serveas an immune-cell distraction, the results in mice suggest.

Headlines and summaries of the latest Science News articles, delivered to your inbox

Two to three hours after ahead injury, mice received injections of tiny biodegradable particles made ofan FDA-approved polymer the same sort thats used in some dissolving sutures. Instead of rushing towardthe brain, a certain type of immune cell called monocytes began turning theirsights on these invaders. These monocytes engulfed the nanoparticles, and thecells and their cargo got packed off to the spleen for elimination, theresearchers found. Because these nanoparticles are quickly taken out ofcirculation, the researchers injected the mice again one and two days later, inan effort to ease inflammation that might crop back up in the days after theinjury.

Mice that received the nanoparticles fared better after their brain injuriesthan mice that didnt get the nanoparticles. Ten weeks after the injury, thedamaged spots themselves were about half as big as the spots in mice thatdidnt receive the treatment, suggesting the damage was stalled in the micethat got nanoparticles.

Other tests showed that bothbrain swelling and scarring were less severe in mice that had receivednanoparticles. Mices vision cells performed better in response to light. And behaviorimproved, too. Mice were able to walk better across a ladder if they had receivedthe nanoparticle decoys. The scope of the animals improvements was a muchbigger effect than you actually expected or hoped for, Kessler says.

Other potential nanoparticle therapies rely on tethering drugs or other cargo to thenanoparticles themselves (SN: 3/7/19).But in this study, the nanoparticles were bare. Thats different from what wetypically think of as a nanoparticle treatment, says Forrest Kievit, abiomedical engineer at the University of NebraskaLincoln. That simplicity might make the manufacturingof these particles more straightforward than other, more complicatednanoparticles, a benefit for potential clinical trials.

Kievit cautions, however,that there are many differences between mice and human brain injuries: the typeand severity of the injuries and the timelines for recovery are different, forinstance. And the ways that the brain suffers after a hard hit involves morethan just a harmful immune response. Toxic substances can accumulate and spreadto unaffected areas, for instance.

Still, Kessler is optimisticthat these nanoparticles hold promise not just for treating brain injuries, butalso for a wide range of ailments that involve a potentially damaging immuneresponse. In 2014, researchers found that nanoparticlesdistracted monocytes from causing inflammation in other circumstances in mice. Similar nanoparticles seemed toimprove mices heart health after undergoing a blockage that mimics a heartattack. Nanoparticles also seemed to ease signs of inflammatory bowel disease,and boosted survival of mice infected with West Nile virus.

There are few ways to treat traumaticbrain injuries, Kessler says. Theres nothing thats really been able to makea dent in this disease. Thats why it would be so exciting if it really works.

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Injecting nanoparticles in the blood curbed brain swelling in mice - Science News

Q4 2019 Vertex Pharmaceuticals Inc Earnings Call

Cambridge Feb 4, 2020 (Thomson StreetEvents) -- Edited Transcript of Vertex Pharmaceuticals Inc earnings conference call or presentation Thursday, January 30, 2020 at 9:30:00pm GMT

TEXT version of Transcript

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Corporate Participants

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* Charles F. Wagner

Vertex Pharmaceuticals Incorporated - Executive VP & CFO

* Jeffrey Marc Leiden

Vertex Pharmaceuticals Incorporated - Chairman, CEO & President

* Michael Partridge

Vertex Pharmaceuticals Incorporated - SVP of IR

* Reshma Kewalramani

Vertex Pharmaceuticals Incorporated - Chief Medical Officer

* Stuart A. Arbuckle

Vertex Pharmaceuticals Incorporated - Executive VP & Chief Commercial Officer

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Conference Call Participants

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* Alethia Rene Young

Cantor Fitzgerald & Co., Research Division - Head of Healthcare Research

* Brian Corey Abrahams

RBC Capital Markets, Research Division - Senior Biotechnology Analyst

* Cory William Kasimov

JP Morgan Chase & Co, Research Division - Senior Biotechnology Analyst

* Konstantinos Biliouris

Morgan Stanley, Research Division - Research Associate

* Liisa Ann Bayko

JMP Securities LLC, Research Division - MD and Senior Research Analyst

* Michael Jonathan Yee

Jefferies LLC, Research Division - Equity Analyst

* Paul Andrew Matteis

Stifel, Nicolaus & Company, Incorporated, Research Division - Co-Head of the Biotech Team, MD & Senior Analyst

* Philip M. Nadeau

Cowen and Company, LLC, Research Division - MD & Senior Research Analyst

* Robyn Kay Shelton Karnauskas

SunTrust Robinson Humphrey, Inc., Research Division - Research Analyst

* Salveen Jaswal Richter

Goldman Sachs Group Inc., Research Division - VP

Story continues

* Whitney Glad Ijem

Guggenheim Securities, LLC, Research Division - Senior Analyst of Biotechnology

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Presentation

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Michael Partridge, Vertex Pharmaceuticals Incorporated - SVP of IR [1]

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Good evening. Welcome to the Vertex Full Year and Fourth Quarter 2019 Financial Results Conference Call. This is Michael Partridge, Senior Vice President of Investor Relations for Vertex. Making prepared remarks on the call tonight, we have Dr. Jeff Leiden, Chairman and CEO; Dr. Reshma Kewalramani, Chief Medical Officer; Stuart Arbuckle, Chief Commercial Officer; and Charlie Wagner, Chief Financial Officer. We recommend that you access the webcast slides on our website as you listen to this call. This conference call is being recorded, and a replay will be available on our website.

We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed CF medicines, our pipeline and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

I will now turn the call over to Dr. Jeff Leiden.

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Jeffrey Marc Leiden, Vertex Pharmaceuticals Incorporated - Chairman, CEO & President [2]

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Thanks, Michael. Good evening, everyone. We saw many investors and analysts at the JPMorgan Conference 2 weeks ago. So I'll spend just a few moments highlighting our 2019 achievements in what we believe sets Vertex apart for the future.

2019 was a truly remarkable year for Vertex. All parts of our business met or exceeded the goals we set at the start of the year. And as a result, we are very well positioned to bring our CF medicines to many more people and to advance our broad pipeline in additional diseases in 2020.

In cystic fibrosis, the U.S. approval of TRIKAFTA for patients 12 and older in October, 5 months ahead of our PDUFA date, was the most significant milestone to date in our efforts to bring new CF medicines to all people with this disease. TRIKAFTA is a remarkable medicine that holds the potential to treat up to 90% of all people with CF. As you'll hear from Stuart, the U.S. launch of TRIKAFTA in patient ages 12 and older is off to a very strong start. There's clear interest in TRIKAFTA across all groups of eligible patients, and the early feedback from both patients and doctors is highly positive.

Outside the U.S., in 2019, we reached a number of key reimbursement agreements for our CF medicines that will allow many thousands of new patients to begin treatment with our CFTR modulators in countries, including England, France, Spain, Australia and many others throughout 2020.

We're also making excellent progress advancing and broadening our pipeline beyond CF. As we enter 2020, we are now in the clinic with multiple new medicines in 5 diseases outside of CF. We continue to implement our strategy of advancing a portfolio of medicines into clinical development for each of the disease areas. Key programs include alpha-1 antitrypsin deficiency. Our AAT program, where we have multiple small molecule correctors in the clinic, aimed at addressing the underlying cause of disease in both the liver and the lung. These include VX-814, which has recently entered Phase II clinical development.

Beta-thalassemia and sickle cell disease, where we announced clinical data for 2 patients treated with CTX001, a onetime CRISPR-Cas9 ex vivo gene editing therapy, which suggest that we may be able to functionally cure these diseases.

FSGS, where our first small molecule aimed at halting the progression of the disease will move into Phase II development in 2020. And type 1 diabetes, where we are developing an autologous islet transplantation therapy with cells alone and a second with a combination of cells and a device to correct islet cell function and potentially transform the treatment of this disease.

Importantly, these pipeline programs now span multiple modalities, including small molecules where Vertex has excelled in the past, but also new approaches such as cell and genetic therapies. For these new modalities, we've acquired or partnered with leading companies who have the best teams and unique expertise to manufacture and deliver transformational therapies for diseases that fit our strategy.

And in business development, we completed more transactions in 2019 than in the 4 prior years, including our acquisitions of Semma with a leading cell therapy approach for type 1 diabetes, and Exonics, the leader in gene editing for DMD and DM1.

In summary, 2019 was the combination of almost a decade of focused execution against our strategy of discovering and developing transformative medicines for serious diseases in specialty areas, by focusing on validated targets and predictive biomarkers that will improve the probability of clinical success. Our strategy is playing out exactly as we had planned and will position us for continued short-term and long-term growth. The company has never been stronger or better positioned for future success in CF and beyond.

Let me now turn the call over to Reshma, who will talk in more detail about the year ahead.

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Reshma Kewalramani, Vertex Pharmaceuticals Incorporated - Chief Medical Officer [3]

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Thanks, Jeff. Our 2019 progress has positioned us for continued growth in 2020 and for many years to come. We are focused on bringing our CF medicines to more people, advancing our pipeline and building financial strength to support continued investment in internal and external innovation. In 2020, we expect to gain approval for the triple combination in Europe in patients 12 years and older and to submit TRIKAFTA for approval in the U.S. for children ages 6 to 11.

Beyond CF, we are advancing multiple molecules in our pipeline through late preclinical and early clinical development and are now entering a period of multiple proof-of-concept data readouts and clinical advances with potentially transformative medicine. With our AAT program, we recently initiated a Phase II proof-of-concept study of the small molecule corrector VX-814 in patients with 2 copies of the Z mutation and expect data from the study in 2020. In APOL1-mediated FSGS, we completed a Phase I study of VX-147 in late 2019 and expect to initiate an open-label Phase II proof-of-concept study in 2020 to evaluate the reduction in protein levels in the urine with VX-147.

In pain, having established proof-of-concept data from NaV1.8 inhibition with VX-150 in multiple Phase II studies, our focus is now to find the optimal molecule or molecules to advance into mid- and late-stage studies. We are continuing to advance a portfolio of medicines into clinical development, and we'll be advancing an additional molecule into Phase I development in the first half of 2020. We have discontinued Phase I development of VX-961 because it did not display an optimal PK and tolerability profile.

Beyond our small molecule programs, we've made significant progress in building and progressing a portfolio of cell and genetic therapies in line with our research strategy, primarily through our business development activities. We are highly encouraged by our recent clinical data for our CRISPR-Cas9 ex vivo gene editing treatment, CTX001, for beta-thalassemia and sickle cell disease. Both studies continue to enroll, and we expect to provide additional data for this program in 2020.

I'd also like to highlight our cell therapy approach for Type 1 diabetes. This program comes to us from our acquisition of Semma Therapeutics in October of 2019. The team of scientists at Semma have cracked the biology on both the production and scale-up of fully mature islet cells and has developed a novel implantable device to protect these cells from the immune system, while preserving cell health and function. We have set an ambitious goal to progress this program into clinical development in late 2020 or early 2021.

In summary, we've made outstanding progress in CF and multiple other diseases in 2019. And I look forward to updating you on our progress over the coming months and years.

I'll now turn the call over to Stuart.

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Stuart A. Arbuckle, Vertex Pharmaceuticals Incorporated - Executive VP & Chief Commercial Officer [4]

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Thanks, Reshma. I am pleased to review with you this evening, our strong commercial performance for 2019. Our full year 2019 CF revenues were $4 billion, up from $3 billion in 2018, which represents year-over-year growth of 32%. This growth in total revenues was driven primarily by the full year impact of the SYMDEKO launch in the U.S. and Germany, label expansions for our CF medicines globally and the early approval and launch of TRIKAFTA in the U.S.

The launch of TRIKAFTA is off to a very strong start. Our fourth quarter total CF product revenues were approximately $1.25 billion, including TRIKAFTA revenues of $420 million, making TRIKAFTA already our top-selling medicine. I would note that our fourth quarter revenues include, as expected, launch-related stocking of approximately $100 million. Approximately 18,000 patients are eligible for TRIKAFTA in the U.S., which represents the largest patient population eligible for one of our CF medicines at the time of approval and launch. For 6,000 of these people, this is the first time they have had a medicine to treat the underlying cause of their CF. We are seeing strong interest from all groups of eligible patients, including new initiations as well as patients transitioning from our other CFTR modulators.

Our commercial supply, market access, patient support, marketing and field teams were ready for an early approval. And since October, these teams have been doing a phenomenal job with CF centers and commercial and government payers. The centers and their multidisciplinary teams have done a remarkable job responding to the high patient demand. And while still early in the launch, we are on track to obtain broad reimbursement for TRIKAFTA in the U.S., similar to what we have seen for our other CF medicines. Together, these factors have combined to produce the strong start to the launch.

Outside the U.S., we reached multiple reimbursement agreements in 2019 in key countries, which will enable many thousands of patients to initiate treatment with certain Vertex medicines for the first time. While TRIKAFTA will be the main driver of Vertex's revenue growth in 2020, we also expect an increase in international revenues based on more patients initiating treatment with our medicines outside the U.S.

In summary, I am pleased that we are bringing our medicines to many more patients around the globe.

And with that, I'll now turn the call over to Charlie.

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Charles F. Wagner, Vertex Pharmaceuticals Incorporated - Executive VP & CFO [5]

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Thanks, Stuart. I will provide additional remarks this evening regarding our 2019 financial results, and I will also discuss our 2020 financial guidance. All of the results and guidance I will discuss are non-GAAP.

As Stuart mentioned, we had fourth quarter total CF product revenues of approximately $1.25 billion, a 45% increase compared to 2018. Our fourth quarter 2019 combined R&D and SG&A expenses were $496 million, including the operating expenses of Exonics and Semma compared to $400 million in the fourth quarter of 2018. Significant growth in revenues and disciplined spending in the fourth quarter resulted in operating income of $593 million, a 70% increase compared to the fourth quarter of 2018.

Net income for the fourth quarter of 2019 was $444 million compared to $337 million for the fourth quarter of 2018. Our full year financial results reflect a similar story of strong revenue growth and disciplined spending, resulting in exceptional operating income growth.

Our total CF revenues for 2019 were $4 billion, a 32% increase over full year 2018. Our 2019 combined R&D and SG&A expenses were $1.69 billion compared to $1.53 billion for 2018. Our full year operating income was $1.79 billion for 2019 compared to $1.11 billion for 2018, a year-over-year increase of more than 60%.

As our profitability and cash flow increased as a result of treating more CF patients globally, we have deliberately reinvested in both internal and external innovation to create future medicines. In 2019, we invested approximately $1.6 billion in external innovation through new acquisitions and collaborations. Even with the significant BD activity, we ended the year with approximately $3.8 billion in cash and marketable securities compared to $3.2 billion at the end of 2018. As we look ahead to 2020 and beyond, we expect continued increases in cash flow to provide more flexibility for additional investments to fuel our long-term growth.

Now on to 2020 guidance. Today, we're providing 2020 financial guidance for total CF product revenues as well as for combined non-GAAP R&D and SG&A expenses and our anticipated effective tax rate. The strong uptake of TRIKAFTA and the recent completion of reimbursement agreements outside the U.S. have positioned Vertex for continued strong revenue growth in 2020. Our 2020 guidance for total CF product revenues is $5.1 billion to $5.3 billion, which at the midpoint reflects approximately 30% growth over 2019.

I would note a few dynamics that are reflected in our 2020 guidance. As part of the strong launch of TRIKAFTA, that Stuart mentioned, we saw an expected launch-related inventory build of approximately $100 million in the fourth quarter that we do not expect to repeat in 2020. Also, as we move through 2020, as with all of our CFTR modulators, persistence and compliance dynamics will affect TRIKAFTA revenues, and therefore, our experience with our other CF medicines is factored into our guidance.

Lastly, we expect gross to net adjustments of 13% to 14% for 2020. Focusing in on Q1 2020, we expect our revenues to be modestly higher than Q4 2019 revenues. This reflects the impact of the fourth quarter inventory build as well as gross-to-net adjustments in the first quarter of each year that are generally higher relative to the previous quarter.

We expect 2020 combined R&D and SG&A expenses of $1.95 billion to $2 billion. The increase compared to 2019 is primarily driven by the launch of TRIKAFTA globally and the expansion of our R&D pipeline into additional diseases. Our R&D expense growth includes increased investment to advance our programs and selling genetic therapies, including type 1 diabetes and DMD.

Now to tax guidance, where we expect our full year non-GAAP tax rate to be 21% to 22%. The tax rate may fluctuate quarter-to-quarter, with the highest rate occurring in the fourth quarter. The vast majority of our tax provision will be noncash expense until we fully use our net operating losses. As Jeff noted, Vertex has a unique long-term growth potential that is based on continued revenue growth in CF and an expanding pipeline, and with continued spending discipline, we expect operating margins, earnings and cash flow to continue to increase.

Now back to Jeff for a few concluding comments.

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Jeffrey Marc Leiden, Vertex Pharmaceuticals Incorporated - Chairman, CEO & President [6]

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Edited Transcript of VRTX earnings conference call or presentation 30-Jan-20 9:30pm GMT - Yahoo Finance