Category Archives: Gene Medicine

DURHAM, N.C. and SEATTLE, Dec. 2, 2021 /PRNewswire/ -- Tune Therapeutics, a biotechnology company pioneering the creation of epi-therapeutic medicines, launched today with its powerful and precise genetic tuning platform, TEMPO. This cutting-edge technology dials gene expression up or down to desired levels with the potential to reverse pathways of cancer, genetic disease, and aging by changing cell fate and function at will.

"Genetic medicine is at a tipping point," said Matt Kane, CEO of Tune Therapeutics. "We now understand that the driving force of human health and disease is not our genes, but the epigenomic elements that shape and control them. Until now, scientists and bioengineers lacked the combined understanding, clinical expertise, and technology needed to make epigenomic therapies a practical reality. Now, we have all three."

TEMPO Platform

Tune's proprietary TEMPO platform can rapidly target and adjust the epigenomic machinery of the cell, which shapes DNA and controls gene expression. By varying specific control modules in an iterative process, TEMPO can fine-tune expression toward healthy levels even in diseases involving multiplex or polygenic interactions.

Unlike genome editing, the tuning process does not generate double- or single-strand breaks in DNA and makes no permanent changes to the DNA sequence. This de-risks the precise targeting of entire gene networks, allowing Tune to simultaneously turn silenced genes on and dial over-expressed genes down, in a practical, therapeutic context.

Tune has already shown that TEMPO can locate epigenomic elements involved in several intractable genetic conditions revealing targets and networks that would be invisible or inaccessible to gene editing approaches. Moreover, Tune can optimize TEMPO to command expression of individual genes or networks with remarkable specificity and precision. This opens the door to an entirely new class of epi-therapeutics.

"The exciting challenge in front of us is taking these transformative advances in technology and extending their potential for our greater society," said Charlie Gersbach, PhD, Acting Chief Scientific Officer, Tune Therapeutics. "From proof of concept in rare, single-gene disorders to common conditions that aren't linked to a single gene mutation but are treatable through epigenomic control and constitute the vast majority of human diseases."

Veteran Genomic Medicine Leadership Team

Tune is launching with a veteran leadership team, endowed with deep expertise in gene and cell therapy, genome editing, and epigenetics.

In addition, Tune's Board of Directors includes Mr. Kane, Dr. Gersbach, Ali Behbahani, M.D., (New Enterprise Associates), and co-founder Dan McHugh (Emerson Collective).

Drawing upon deep, local talent pools in Durham and Seattle, Tune has assembled two highly seasoned discovery and development teams, secured foundational intellectual property from Duke University, and raised $40 million from top-tier investors including co-leads New Enterprise Associates and Emerson Collective, with Hatteras Venture Partners, Mission BioCapital, and others joining the round. This financing will enable Tune to rapidly advance its preclinical research, attract top-tier talent, and further develop its therapeutic platform.

"Tune is effectively pioneering a brand-new therapeutic modality," said Dr. Behbahani. "With the unbound potential of this approach, and their collective successes in the field, Tune is primed to become a transformative presence in modern biomedicine."

About Tune Therapeutics

Tune Therapeutics, Inc. is orchestrating the power of the epigenome to treat complex, pervasive diseases that have long eluded treatment. With its versatile and powerful TEMPO epigenomic control platform, Tune's experienced team is pioneering a new therapeutic modality that can fine-tune any gene network. In breaking free from the limitations of traditional gene and cell therapies, Tune is developing solutions for even the most challenging and intractable diseases and building the capacity to transform human health and medicine.

SOURCE Tune Therapeutics

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Tune Therapeutics Launches with Pioneering Epigenomic Control Platform to Master Gene Networks, Treat Broad Range of Diseases - PRNewswire

-- RareStone to seek marketing authorization for IMCIVREE to treat obesity due to biallelic POMC, PCSK1 and LEPR deficiencies and Bardet-Biedl and Alstrm syndromes in mainland China, Hong Kong and Macau ---- Rhythm to receive $12 million upfront in cash and equity, up to $63.5 million in future milestone payments and sales royalties --

BOSTON, Dec. 06, 2021 (GLOBE NEWSWIRE) -- Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a biopharmaceutical company aimed at developing and commercializing therapies for the treatment of rare genetic diseases of obesity, and RareStone LTD, formerly Citrine Medicine, a China-based rare disease company, today announced an exclusive licensing agreement for the development and commercialization of IMCIVREE (setmelanotide) in China, including mainland China, Hong Kong and Macau. This licensing agreement marks the first expansion of Rhythms pipeline into Asia and is designed to accelerate patient access to IMCIVREE where there remains significant unmet need to address the severe, early-onset obesity and hyperphagia that characterize both acquired and genetic diseases of the melanocortin-4 receptor (MC4R) pathway.

According to the terms of the agreement, RareStone will seek local approvals to commercialize IMCIVREE for the treatment of obesity and hyperphagia due to biallelic proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency, as well as Bardet-Biedl and Alstrm syndromes. Additionally, RareStone will fund efforts to identify and enroll patients from China in Rhythms global EMANATE trial, a Phase 3, randomized, double-blind, placebo-controlled trial to evaluate setmelanotide in five independent sub-studies in patients with obesity due to a heterozygous variant of POMC/PCSK1 or LEPR; certain variants of the SRC1 gene, certain variants of the SH2B1 gene, or PCSK1 N221D deletions within the MC4R pathway.

RareStone, a company committed to treating rare diseases, is well-positioned to leverage its network of hospitals and key opinion leaders, deep regulatory experience and community-building infrastructure to advance IMCIVREE through clinical development and regulatory approvals in China, said David Meeker, M.D., Chair, Chief Executive Officer and President of Rhythm. We are thrilled to enter into this agreement, which substantially accelerates our ability to address the needs of patients living in China and potentially make IMCIVREE available to many more patients with rare genetic diseases of obesity.

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RareStone was founded in 2019 with funding from leading health care investors, including Eight Roads, F-Prime Capital, Vivo Capital, Quan Capital, 3H Health Investment and WU Capital. The Shanghai-based company is focused on building an ecosystem to support patients and families living with rare diseases in Greater China and has dedicated itself to improving the lives of patients with rare and intractable diseases by making diagnosis and essential treatments available and accessible to those who need them.

There is a significant need in China for a therapeutic option to treat patients with early-onset, severe obesity and hyperphagia caused by variants in genes of the MC4R pathway, said Shawn Xiang, Ph.D., CEO of RareStone. Rhythms precision medicine, IMCIVREE (setmelanotide), approved by FDA and authorized by the European Commission and Great Britains Medicines & Healthcare Products Regulatory Agency, has transformed the treatment paradigm for rare genetic diseases of obesity. We are eager to deliver the proven clinical benefit of IMCIVREE to patients in China and plan to pursue local approvals rapidly in five initial indications, while supporting Rhythms ongoing clinical development efforts more broadly.

According to the terms of the licensing agreement, RareStone will make an upfront payment to Rhythm of $7 million and issue $5 million in equity to Rhythm. Rhythm will be eligible to receive development and commercialization milestones of up to $63.5 million, as well as tiered royalty payments on annual net sales of IMCIVREE.

About Rhythm PharmaceuticalsRhythm is a commercial-stage biopharmaceutical company committed to transforming the treatment paradigm for people living with rare genetic diseases of obesity. Rhythms precision medicine, IMCIVREE (setmelanotide), was approved in November 2020 by the U.S. Food and Drug Administration (FDA) for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to POMC, PCSK1 or LEPR deficiency confirmed by genetic testing and in July and September 2021, respectively, by the European Commission (EC) and Great Britains Medicines & Healthcare Products Regulatory Agency (MHRA) for the treatment of obesity and the control of hunger associated with genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. IMCIVREE is the first-ever FDA-approved and EC- and MHRA-authorized therapy for patients with these rare genetic diseases of obesity. The Company submitted a supplemental New Drug Application (sNDA) to the FDA, which was accepted for filing in November 2021 and assigned a Prescription Drug User Fee Act (PDUFA) goal date of March 16, 2022. Rhythm also submitted a Type II variation application to the European Medicines Agency in October 2021 seeking regulatory approval and authorization for setmelanotide to treat obesity and control of hunger in adult and pediatric patients 6 years of age and older with BBS or Alstrm syndrome in both the United States and European Union. Additionally, Rhythm, along with its partners, is advancing a broad clinical development program for setmelanotide in other rare genetic diseases of obesity and is leveraging the Rhythm Engine, the largest known obesity DNA database -- now with approximately 45,000 sequencing samples -- to improve the understanding, diagnosis and care of people living with severe obesity due to certain genetic deficiencies. Rhythms headquarters is in Boston, MA.

About RareStone LTD.RareStone, formerly Citrine Medicine, is dedicated to improving the lives of patients with rare and intractable diseases by making diagnosis and essential treatments available and accessible to those who need them in Greater China. Our mission is to build the first rare disease ecosystem in China, and in doing so, enable people with rare diseases to live more normal lives. In addition to developing and marketing rare disease drugs, RareStone aims to establish a patient-centric platform which educates people on rare diseases, trains doctors on diagnosis and treatment, and helps doctors develop a full disease management protocol. RareStones lead product candidate, Wakix (pitolisant), is an investigational oral drug in development for the treatment of narcolepsy and obstructive sleep apnea in China. RareStone also recently announced two strategic partnerships that will gives the company exclusive Greater China rights to develop, register, and commercialize Alkindi for pediatric congenital adrenal hyperplasia (CAH) patients and Efmody for adolescent and adult CAH and adrenal insufficiency patients. RareStone is headquartered in Shanghai, China and has other offices in Beijing, China and Cambridge, Mass. For more information, visit http://www.rarestonegroup.com

IMCIVREE (setmelanotide) IndicationIn the United States, IMCIVREE is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by an FDA-approved genetic test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).

In the EU and Great Britain, IMCIVREE is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. IMCIVREE should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology.

Limitations of UseIMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective:

Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign;

Other types of obesity not related to POMC, PCSK1 or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity.

Important Safety Information

WARNINGS AND PRECAUTIONS

Disturbance in Sexual Arousal: Sexual adverse reactions may occur in patients treated with IMCIVREE. Spontaneous penile erections in males and sexual adverse reactions in females occurred in clinical studies with IMCIVREE. Instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention.

Depression and Suicidal Ideation: Some drugs that target the central nervous system, such as IMCIVREE, may cause depression or suicidal ideation. Monitor patients for new onset or worsening of depression. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors.

Skin Pigmentation and Darkening of Pre-Existing Nevi: IMCIVREE may cause generalized increased skin pigmentation and darkening of pre-existing nevi due to its pharmacologic effect. This effect is reversible upon discontinuation of the drug. Perform a full body skin examination prior to initiation and periodically during treatment with IMCIVREE to monitor pre-existing and new skin pigmentary lesions.

Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants: IMCIVREE is not approved for use in neonates or infants.

ADVERSE REACTIONS

The most common adverse reactions (incidence 23%) were injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection.

USE IN SPECIFIC POPULATIONSDiscontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

Treatment with IMCIVREE is not recommended for use while breastfeeding.

To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at +1 (833) 789-6337 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

See U.S. Full Prescribing Information, EU SmPC and MHRA SmPC for IMCIVREE.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding activities in connection with the exclusive licensing agreement with RareStone and potential payments thereunder, the potential, safety, efficacy, and regulatory and clinical progress of setmelanotide, including the anticipated timing for initiation of clinical trials and release of clinical trial data and our expectations surrounding potential regulatory submissions, approvals and timing thereof, and our business strategy and plans, including regarding commercialization of setmelanotide. Statements using word such as expect, anticipate, believe, may, will and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including, but not limited to our ability to enroll patients in clinical trials, the design and outcome of clinical trials, the impact of competition, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, our liquidity and expenses, the impact of the COVID-19 pandemic on our business and operations, including our preclinical studies, clinical trials and commercialization prospects, and general economic conditions, and the other important factors discussed under the caption Risk Factors in our Quarterly Report on Form 10-Q for the quarter ended September 30, 2021 and our other filings with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this release or to update them to reflect events or circumstances occurring after the date of this release, whether as a result of new information, future developments or otherwise.

Corporate Contact:David ConnollyHead of Investor Relations and Corporate CommunicationsRhythm Pharmaceuticals, Inc.857-264-4280dconnolly@rhythmtx.com

Investor Contact:Hannah DeresiewiczStern Investor Relations, Inc.212-362-1200hannah.deresiewicz@sternir.com

Media Contact:Adam DaleyBerry & Company Public Relations212-253-8881adaley@berrypr.com

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Rhythm Pharmaceuticals and RareStone Ltd. Announce Exclusive Licensing Agreement for the Development and Commercialization of IMCIVREE (setmelanotide)...

Never in recent history has the world been so engrossed by the most mundane stages of the scientific process. But for the last two years, each incremental step in sciencefrom lab research to understand the evolution of COVID-19 and develop a vaccine to fight it, to clinical trials, to pharmaceutical approvalmeant one thing: Hope. And thats what this list of the years best health innovations highlights. In addition to two novel vaccines released to combat the most deadly pandemic of our time, the world also saw the first-ever drug approved to treat rare progeria, a new insulin formulation that might finally make the life-saving therapy affordable for all, and a malaria vaccine decades in the making.

Looking for the complete list of 100 winners? Check it out here.

A pair of COVID-19 vaccines, which are highly effective at preventing COVID-19, were authorized for emergency use in 2021. Pfizer/Moderna

To pull humankind out of the COVID-19 pandemic, doctors and public health experts knew we would need a safe and effective vaccine. Pharmaceutical companies around the world have raced to characterize the SARS-CoV-2 virus, understand how it invades our immune systems, and develop a targeted injection to prevent it. As of November 2021, at least 28 promising vaccines have been trialed in humans, and 15 have been authorized for emergency use around the world. But two stood out enough to win our top award: Pfizers Comirnaty, developed in partnership with Germany-based biotechnology company BioNTech, and Modernas SpikeVax, which the Cambridge, Mass., company developed with the help of the National Institutes of Allergy and Infectious Disease.

The jabs are unlike any other inoculation on the market today. They are the first so-called mRNA vaccinesa technology that has been in development for decades. They work by harnessing messenger RNA, the genetic bits of code that tell our cells how to make proteins. The vaccines carry mRNA with instructions for making a protein found on the outside of SARS-CoV-2, the novel virus that causes COVID-19. Our bodies quickly destroy the errant mRNA instructions, but not before our cells build the corresponding proteins. Those proteins then attach to specialized immune cells, triggering the system to recognize them as invaders and develop antibodies against their ilk. If a vaccinated person comes into contact with SARS-CoV-2, those antibodies can spring into action, reproduce, and destroy the virus before it replicates out of control, thwarting the disease.

This duo of shots also work remarkably well. In clinical trials, both of the two-dose regimens were at least 94 percent effective at preventing symptomatic cases of COVID-19. The vaccines also fended off hospitalization nearly 100 percent of the time. While a multitude of inoculation options were crucial to curbing the spread of the virus, these two mRNA therapies are especially poised to change the course of the pandemicand the future of preventative medicine.

Zokinvy is the first FDA-approved treatment for Hutchinson-Gilford progeria syndrome, a rare disease that causes premature aging. Eiger Pharmaceuticals

People diagnosed with Hutchinson-Gilford progeria syndrome rarely live beyond 15 years of age, and until now treatments could only target its symptoms and complications. The disease occurs when a genetic mutation changes the shape of a protein in the nuclei of a carriers cells. The faulty protein, called progerin, causes cells to prematurely die. Zokinvy prevents the buildup of defective progerin, thereby minimizing the damage it can do. In addition to prolonging lifespan by several years, the new drug also reduces symptoms of heart and bone problems associated with the rare condition, which affects roughly 400 children worldwide.

In a first, researchers successfully treated a genetic liver disease by injecting the CRISPR gene editing tool directly into a persons body. Intellia Therapeutics

Since 2012, researchers have been tweaking CRISPR, the gene-editing tool that easily edits the human genome, to treat diseases caused by DNA mutations. But until this year, the method, which involves injecting a patient with tweaked stem cells, had only been used to treat conditions whose mutations are in the bloodstream, such as sickle-cell anemia.In August of 2021, researchers published the results of a six-person clinical trial in which doctors attempted to fix a genetic defect that causes a rare liver condition called transthyretin amyloidosis. Packaged inside a tiny blob called a lipid nanoparticle, the gene-editing tech made its way to the liver, where it went to work correcting defective cells. Theres still a long way to go before this treatment, which is still in the first phase of clinical trials, finds its way to the market. But, if successful, it could pave the way for healing a wide variety of genetic conditions.

The FDA approved a number of monoclonal antibody treatments this year, including Regenerons Inmazeb. Regeneron Pharmaceuticals, Inc.

When infected with Zaire ebolavirus, people can experience high fevers, severe bleeding, and organ failure, which is fatal in half of cases. Researchers at biotech company Regeneron have now created monoclonal antibodieslab-crafted molecules that mimic the work of the immune systems natural defenses to help take down invadersto target the illness. Inmazeb is a combination of three antibodies that target a protein on the surface of the Ebola virus. In a clinical trial, 66.2 percent of the 154 people who received Inmazeb survived, compared to only 49 percent of the 153 people who didnt. While not a surefire cure, monoclonal antibodies have been crucial in treating many viral diseases. The FDA gave an emergency-use authorization to two monoclonal antibody therapies for COVID-19 in 2021, and approved another one to treat Ebola as well.

Ellume delivers a result in as little as 20 minutes. Ellume

Vaccines greatly reduce the risk of acquiring and spreading COVID-19, but theyre not perfect. Breakthrough cases will continue to emerge even among highly vaccinated communities. Thats where testing comes in. The Ellume at-home COVID-19 test was the first of its kind to get FDA authorization, allowing consumers to check their COVID-19 status without going to the doctor. The test consists of a nasal swab, a dropper, processing fluid, and an analyzer. An app takes you through step-by-step instructions: Connect the analyzer via Bluetooth, empty the processing fluid into the dropper, swab both nostrils, attach the swab to the dropper, squeeze five drops onto the analyzer, and wait 15 minutes for your results. Ellume reports that the test identifies positive cases 95 percent of the time and negative ones 97 percent of the time.

The Bridge-Enhanced ACL Restoration Implant by Miach Orthopaedics offers a less invasive way to repair a persons ACL. Boston Childrens Hospital

The ACL, or anterior cruciate ligament, stretches diagonally across the middle of the knee and is vital in keeping our bodies upright and stable. Its also prone to failure; according to a 2016 report in the Journal of Clinical Orthopedics and Trauma, its the most common source of significant knee injury. Repairing a torn ACL requires surgery, and sometimes reconstructionan invasive procedure where a piece of tendon and bone is taken from another part of the body, or from a donor, to rebuild the torn ligament. The newly FDA-approved BEAR Implant takes the place of that material. Made of bovine collagen, its secured in place between the two torn ends of the ACL to bind them together. The patients body absorbs the device within a few months, by which time, new, healthy tissue has grown in its place.

The sharpest, clearest CT scanner, yetSiemens

CT scans provide detailed images of the inside of the human body that help diagnose and track disease and injury. Conventional scanners create images by combining the total energy from several x-rays. During this process, some energy from the x-ray is lost, leading to lower resolution. Siemens new scanner, called the Naeotom Alpha, uses detectors that count photons to measure every particle of light that comes through, leading to sharper, higher contrast images of the inner workings of your body.

An insulin product that everyone can afford. Viatris, Inc

Some 34 million people live with diabetes in the United States alone. For many of them, insulina hormone usually produced in the pancreas that helps process glucoseis necessary for survival. Despite this, insulin remains an extremely expensive product, even for those who are fully insured. Semglee could change that. Its an interchangeable, biosimilar insulin productthe first of its kind to gain recognition from the FDA. A biosimilar is a biological therapy (hormones and vaccines are examples) that has no meaningful difference from one thats already FDA-approved and on the marketthink of it as a generic medication that pharmacists can swap for a name-brand drug, but that doesnt require prior approval from a doctor to make the switch. Semglee, which comes in 10 mL vials and 3 mL prefilled pens and is administered subcutaneously once daily, is medically identical to Lantus, the name brand for insulin.

Mosquirix, developed to prevent malaria, is also the first vaccine to prevent a parasitic disease. GlaxoSmithKline

By some estimates malaria kills about half a million people worldwide every year. GlaxoSmithKlines Mosquirixa vaccine decades in the makinggenerates an immune response against Plasmoduim falciparum, which is among the most deadly of the fiveparasites that cause malaria, and the most prevalent strain throughout Africa. The vaccine received an endorsement from the World Health Organization; a distinction that gives it the go-ahead for wider distribution and use. While the inoculation is only about 50 percent effective against severe malaria, with a significant drop in efficacy after a year, its still one of the best ways to prevent the deadly disease.

The first new antifungal in decades treats vaginal yeast infections. SCYNEXIS, Inc.

According to the CDC, about 1.4 million people in the US go to the doctor for vaginal yeast infections each year. While over-the-counter treatments often work just fine, more stubborn cases can resist. Brexafemme is the first novel antifungal in more than two decades, representing an entirely new class called triterpenoids. It works by blocking an enzyme that helps create a protective coating around Candida fungi, which cause vaginal yeast infections. Without this covering, the microbe quickly dies off. The two-tablet formulation starts working within a few days, and remains in a persons system for as long as two weeks to prevent a resurgence.

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The top 10 health and medicine breakthroughs of 2021 - Popular Science

Introduction

Intracranial aneurysm (IA) is a complex disease characterised by pathological dilatation of the cerebral arteries. IA may rupture, leading to subarachnoid haemorrhage (SAH) and significant morbidity and mortality, one of the most devastating neurological events.1 Although the pathogenesis of IA has been explored for many years, the mechanisms of its formation, growth, and rupture remain largely unknown. Various theories have been proposed to develop IA, which is generally believed to be a multifactorial disorder that occurs due to the interaction of environmental and genetic factors.2,3 Environmental factors, such as alcohol consumption, smoking, sex, and hormonal background of the patient, and hypertension seem to be common risk factors.4,5 In addition, there have been many studies on genetic markers for the risk of IA,6,7 which vary according to ethnicity and may not be generalisable to different populations.

Extracellular matrix (ECM) remodelling plays an important role in maintaining the structure and integrity of intracranial arteries. Disruption of the ECM of the arterial wall is a likely factor in the pathogenesis of IA.8 The VCAN gene, located at 5q12-q14, has 15 exons encoding a large 372.82 kDa chondroitin sulphate proteoglycan in the ECM, which plays a key role in maintaining ECM function.9 It has also been implicated in cell proliferation, cell adhesion, cell migration, and invasion. The VCAN gene produces four subtypes, V0, V1, V2, and V3, by alternate splicing of exons 7 and 8. The two largest exons, 7 and 8, encode glycosaminoglycan (GAG) attachment sites, GAG alpha and GAG beta, respectively.9,10 The latter contains a proteoglycan class with heparin sulphate. The loss of function of similar protein-binding domains may lead to the rupture of these components in certain proteins in the ECM, softening the artery wall, forming an aneurysm.

VCAN is a candidate gene for IA because it plays a vital role in ECM assembly and is localised in a previously implicated locus for IA on chromosome 5q.11 However, polymorphisms can have various effects in these gene regions that can be race-specific (since polymorphisms are known to be race-specific). Previous linkage studies have indicated that the three VCAN SNPs, rs251124, rs173686, and rs2287926, are associated with aneurysms.10,12,13 Nevertheless, replication studies in different ethnicities have provided conflicting results regarding IAs.10,12,14,15 Considering the genetic differences among different races and regions and the uncertainty of the correlation between VCAN gene polymorphism and IA incidence in the Chinese population, we aimed to explore the association of the VCAN gene variants rs251124, rs173686, and rs2287926 with IA prevalence in the Eastern Chinese population.

This study complied with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board and Ethics Committee of the First Affiliated Hospital of Anhui University of Science and Technology. All participants provided written informed consent (Approval No. 2019B20,2019-1-1).

This case-controlled prospective study included 162 patients with sporadic IAs and 182 age-matched controls admitted to the First Affiliated Hospital of Anhui University of Science and Technology between January 2017 and December 2020. All cases with confirmed IAs based on digital subtraction angiography (DSA) were retrospectively confirmed by a neuroradiologist and two highly qualified cerebrovascular neurosurgeons. Patients were excluded if they had a family history of IA, fusiform and dissection aneurysms, or traumatic and infectious aneurysms. A total of 182 controls were symptomatically normal and did not have a medical or family history of IA or SAH. Controls subjects were sex- and age-matched individuals, diagnosed negative for IA by DSA or CTA from the same hospital, and matched to IA patients for the area of residence to eliminate the effect of population stratification by heterogeneity.

Candidate SNPs were selected by searching for SNPs in previous studies and genome-wide association studies (GWAS) that showed significant associations with IA. DNA was extracted from peripheral blood leukocytes using the TIANamp Blood DNA Extraction Kit (TIANGEN Biotech Co., Ltd., Beijing, China). The DNA samples were stored at 80 C until use. SNP genotyping for rs251124, rs2287926, and rs173686 was performed using Kompetitive Allele Specific PCR (KASP). The SNP data were analysed with CFX Manager Software version 3.1 (Bio-Rad).

General clinical features of the case and control groups were described as mean standard deviation (SD) and compared using Students t-test for continuous variables. Genotype and allele frequencies were computed and checked for deviation from the HardyWeinberg equilibrium (ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl). Categorical variables were presented as proportions and were compared using the chi-square test or Fishers exact test (two-tailed). Further stratification of the patients based on sex and aneurysm rupture status was performed to understand the role of the VCAN variant within the sexes and between the ruptured aneurysm and non-ruptured aneurysm groups. The association of SNPs with the risk of sporadic IA was investigated using logistic regression analysis. Statistical significance was set at P<0.05. All statistical analyses were performed using GraphPad Prism 8.02 (San Diego, CA, USA) and SPSS software (version 21.0; IBM Corp., Armonk, NY, USA).

A total of 162 IA patients and 182 control subjects were included in this study. The demographic characteristics of patients and controls are shown in Table 1. In the case group, 72.8% of the patients had a single aneurysm. The aneurysms were primarily located in the internal carotid artery (38.3%), followed by the middle cerebral artery (19.1%), anterior communicating artery (13.6%), and other locations. Additional details are provided in Table 2.

Table 1 Characteristics of Cases vs Controls

Table 2 Clinical Characteristics of Intracranial Aneurysm

The distribution of the SNP genotypes was consistent with the HardyWeinberg equilibrium. As shown in Table 3, there were significant differences in the genotype and allele frequency distributions of rs251124 and rs173686 between the IA cases and controls (P<0.05). A significant association was observed with rs251124 at the allelic (OR=1.489, CI: 1.0892.044; P=0.0137) and genotypic (P=0.0415) levels. The frequency of rs251124-TT in IA patients was higher than in controls (2= 6.364, P=0.0415). The risk allele frequencies of rs173686 were significantly different between patients with IA and controls (OR=1.558, CI: 1.1152.171; P=0.0096). For SNP rs2287926, there was no statistically significant difference in genotype or allele frequencies between the patient and control groups (Table 3).

Table 3 Genotype and Allele Frequencies of SNPs of VCAN

Table 4 shows the genotypes of the SNPs and their associations with IA. Logistic regression analysis showed that the T/T genotype and T allele of rs251124 were independent risk factors for IA (OR=1.726, 95% CI: 1.1362.263; P=0.011). Similarly, for the SNP rs173686, G allele carriers were also at a significantly higher risk of IA (OR=2.52, 95% CI: 1.2615.037; P=0.009).

Table 4 Logistic Regression Model of Genotype Analysis

Table 5 shows no significant difference in genotype frequencies between the ruptured and unruptured aneurysm groups at either of the two SNPs rs251124 and rs173686 (P>0.05).

Table 5 Genotypic Results of Ruptured and Unruptured Aneurysms

Table 6 shows no significant difference in genotype frequencies among aneurysm groups at either of the two SNPs rs251124 and rs173686 (P> 0.05).

Table 6 Genotype Frequencies of SNPs rs251124 and rs173686 at Different Locations

Table 7 suggests that the rs251124 T allele and rs173686 G allele contribute to a significantly higher risk for males and females at both allelic and genotypic levels when stratified based on sex (P<0.05).

Table 7 Comparison of the Genotype and Allele Frequencies of rs251124 and rs173686 Within Males and Females in Cases and Control

There are various theories about the development of aneurysms, most of which reflect an imbalance in the ECM remodelling. ECM remodelling plays an important role in maintaining the structure and integrity of intracranial arteries and its reduction is a prominent feature of cerebral aneurysms. The VCAN gene localised on 5q12q14 has 15 exon codes9 for a large 372.82 kDa chondroitin sulphate proteoglycan found abundantly in the ECM and plays various roles in maintaining ECM functions. Some studies have shown that a decreased density of smooth muscle cells results in decreased production of CSPG2 (also known as versican), which in turn weakens the vascular wall. VCAN (CSPG2) also plays an important role in the assembly of ECM, and diminished maintenance of the ECM has been increasingly regarded as an important factor in the development of IA.16

This study investigated the associations between three SNPs in the VCAN gene and IA susceptibility in the Eastern Chinese population. The results showed that rs251124T/T genotype and T allele and rs173686 G/G genotype and G allele increased the risk of IA formation. No significant differences in genotype or allele frequencies between the case and control groups were detected at the rs2287926 SNP. Our findings further support the VCAN gene as an IA susceptibility gene.

The VCAN gene (also known as chondroitin sulphate proteoglycan [CSPG2]) predicts the risk of aneurysm development and subsequent rupture.12,15,16 Nevertheless, the association between the SNPs of VCAN and the risk of IA remains controversial due to contrary reports. For example, Sathyan et al10 found that the minor allele T of rs251124 showed an increased risk of IA. The CT genotype has been defined as a risk factor for the occurrence and rupture of aneurysms in a South Indian population. In addition, rs2287926 further substantiates the potential role of VCAN in the pathogenesis of IA.

Moreover, no confirmed association between rs173686 at genotypic and allelic levels and IA in the South Indian population has been reported. However, in a Dutch population, the VCAN (CSPG2) genes were identified as susceptibility genes for IA, and the rs173686 polymorphism has also been linked to IA.12 The association between the rs173686 polymorphism and IA risk has also been observed in a Kazakh population.14 Similarly, another study replicated the association of rs251124 with the risk of IAs in a Japanese IA population.15 In contrast, replication studies reported a lack of association between the CSPG2 variants (rs173686 and rs251124) with IA susceptibility.15 The above studies suggest that race and geography may influence these contradictory results. On the other hand, this may be explained by the heterogeneity of ethnic origin and/or small sample size.

Consistent with previous studies and meta-analyses,10,12,13 we found that rs251124 was associated with sporadic IAs, and rs251124T/T genotype and T allele were risk factors for IA in the Eastern Chinese population, but not in agreement with the results of Sun et al,15 who found no confirmed association in a study of Han Chinese. Additionally, our study found that the rs173686 G/G genotype and G allele significantly increased the risk of IA formation, which was similar to the results of studies conducted among European,12 Kazakh,13 and Japanese populations,14 but inconsistent with the results of Sun et al.15 The contrary results indicate that individuals from the same ethnic group also have different susceptibilities. Sun et al15 reported that the two SNPs rs173686 and rs251124 of the CSPG2 gene were not susceptible to IAs in Northern Chinese (Beijing) Han nationality. Alternatively, we observed that rs173686 and rs251124 highly increased the risk of IA formation in the Eastern Chinese population. To the best of our knowledge, the occurrence of IA is the result of the combined effects of genetic and environmental factors. One of the underlying causes of this discrepancy might be regional differences. Our research subjects included patients from eastern China; the possibility of different genetic backgrounds and surroundings caused by ethnic and regional differences might affect the experimental results. In addition, our study group was relatively small; therefore, our results require validation in a large-scale population. Overall, it has been hypothesised that genetic heterogeneity among diverse populations can lead to such paradoxical results.

In addition, our study included patients with ruptured and unruptured IAs. For either of the two SNPs rs173686 and rs251124, there was no statistically significant difference in genotype or allele frequencies between the two groups studied, suggesting that no associations were found in the SNPs rs173686 and rs251124 with IA rupture susceptibility in the Eastern Chinese population. To the best of our knowledge, this is the first study to investigate the association between the VCAN gene and IA rupture in a Chinese population.

Moreover, our study found no significant difference in genotype frequencies among aneurysm groups at either SNP rs251124 or rs173686 (P> 0.05). This suggests that the locations of aneurysm distribution may have nothing to do with SNP variation. Furthermore, subgroup analysis by sex showed that rs251124 T allele and rs173686 G allele contributed to high risk for both males and females at both allelic and genotypic levels, implying that sex has no significant effect on SNP variation. Another possible reason for this result is that the sample size was small.

This study had some limitations. It included only Eastern Chinese patients; therefore, the sample size was relatively small and may not be adequate for assessing the effect of these SNPs on the formation of IAs. Thus, additional studies using different populations are warranted to further validate ethnic and regional differences in the impact of the VCAN polymorphism on IA risk. Moreover, molecular biology experiments and reliable animal models are required to explore the specific mechanisms further.

This study revealed that rs251124 and rs173686 are genetic risk factors for IA formation in the Eastern Chinese population. No association was found between SNP rs2287926 and IA. Our findings suggest that the VCAN gene is an IA susceptible gene, which warrants further study as a screening marker for intracranial aneurysms.

The authors thank Key project of Education Department of Anhui Province (KJ2019A0096) and Huainan science and technology planning project (2016A26(3)) for supporting this work.

The authors report no conflicts of interest in this work.

1. Hitchcock E, Gibson WT. A review of the genetics of intracranial berry aneurysms and implications for genetic counseling. J Genet Couns. 2017;26(1):2131. doi:10.1007/s10897-016-0029-8

2. Boehme AK, Esenwa C, Elkind MS. Stroke risk factors, genetics, and prevention. Circ Res. 2017;120(3):472495. doi:10.1161/CIRCRESAHA.116.308398

3. Ruigrok YM, Rinkel GJ. From GWAS to the clinic: risk factors for intracranial aneurysms. Genome Med. 2010;2(9):61. doi:10.1186/gm182

4. Cho SM, Marquardt RJ, Rice CJ, et al. Cerebral microbleeds predict infectious intracranial aneurysm in infective endocarditis. Eur J Neurol. 2018;25(7):970975. doi:10.1111/ene.13641

5. Chen Y, Zhang Y, Chao YJ, et al. Stent-assisted coiling embolization of middle cerebral artery trifurcation wide-necked aneurysms. Eur Rev Med Pharmacol Sci. 2017;21(19):43464349.

6. Tromp G, Weinsheimer S, Ronkainen A, Kuivaniemi H. Molecular basis and genetic predisposition to intracranial aneurysm. Ann Med. 2014;46(8):597606. doi:10.3109/07853890.2014.949299

7. Bourcier R, Redon R, Desal H. Genetic investigations on intracranial aneurysm: update and perspectives. J Neuroradiol. 2015;42(2):6771. doi:10.1016/j.neurad.2015.01.002

8. Ruigrok YM, Rinkel GJ, Wijmenga C. Genetics of intracranial aneurysms. Lancet Neurol. 2005;4:179189. doi:10.1016/S1474-4422(05)70021-1

9. Iozzo RV, Naso MF, Cannizzaro LA, et al. Mapping of the versican proteoglycan gene (CSPG2) to the long arm of human chromosome 5 (5q125q14). Genomics. 1992;14(4):845851. doi:10.1016/S0888-7543(05)80103-X

10. Sathyan S, Koshy LV, Balan S, et al. Association of Versican (VCAN) gene polymorphisms rs251124 and rs2287926 (G428D), with intracranial aneurysm. Meta Gene. 2014;2:651660. doi:10.1016/j.mgene

11. Onda H, Kasuya H, Yoneyama T, et al. Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet. 2001;69(4):804819. doi:10.1086/323614

12. Ruigrok YM, Rinkel GJ, Wijmenga C. The versican gene and the risk of intracranial aneurysms. Stroke. 2006;37(9):23722374. doi:10.1161/01.STR.0000236499.55301.09

13. Zholdybayeva EV, Medetov YZ, Aitkulova AM, et al. Genetic risk factors for intracranial aneurysm in the Kazakh population. J Mol Neurosci. 2018;66(1):135145. doi:10.1007/s12031-018-1134-y

14. Ruigrok YM, Rinkel GJ, Wijmenga C, et al. Association analysis of genes involved in the maintenance of the integrity of the extracellular matrix with intracranial aneurysms in a Japanese cohort. Cerebrovasc Dis. 2009;28(2):131134. doi:10.1159/000223438

15. Sun H, Zhang D, Zhao J. Chondroitin sulfate proteoglycan 2 (CSPG2) gene polymorphisms rs173686 and rs251124 are not associated with intracranial aneurysms in Chinese Han nationality. Ups J Med Sci. 2007;112(3):289295. doi:10.3109/2000-1967-201

16. Ruigrok YM, Rinkel GJ, Vant Slot R, et al. Evidence in favor of the contribution of genes involved in the maintenance of the extracellular matrix of the arterial wall to the development of intracranial aneurysms. Hum Mol Genet. 2006;15:33613368. doi:10.1093/hmg/ddl412

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SNPs rs251124, rs2287926, and rs173686 with IA | NDT - Dove Medical Press

A study from the Yale Cancer Center potentially introduces a drug design platform to fight drug resistance for patients with HER2-positive breast cancer and ovarian cancer.

A therapeutic strategy that targets cancer-associated gene amplifications via triplex-forming oligonucleotides (TFOs) demonstrated in vivo efficacy, which compared favorably to current precision medicines in patients with HER2-positive breast and ovarian cancer, potentially introducing an alternative option to combat drug resistance in these patient populations, according to research published in Nature Biotechnology.1

In addition to its in-vivo efficacy, investigators reported that TFOs targeting HER2 yielded copy numberdependent DNA double strand breaks (DSBs) and were successful in activating p53-independent apoptosis in HER2 cancer cell and human xenograft models. Overall, treatment of HER2-positive breast cancer xenografts with a TFO, HER2-205, resulted in a 52% reduction in tumor volume when compared with untreated control groups. The finding is comparable with a 58% reduction garnered from treatment with trastuzumab (Herceptin).

Our findings are exciting as they offer a new option to fight breast and ovarian cancers as effectively as clinically utilized drugs now targeting the HER2 protein, senior author Faye Rogers, PhD, associate professor of Therapeutic Radiology at Yale Cancer, said in a press release.2 A number of anticancer therapies have been developed to inhibit the protein products of amplified cancer driver genes, but have met drug resistance.

The research teams goal was to develop a potential drug platform that could directly convert amplified oncogenic driver genes into DNA damage to ultimately induce cell death. The strategy utilizes TFOs that are capable of recognizing unique polypurine sites within the amplified chromosomal region to provoke apoptosis.

After assessing the correlation between level of triplex-induced DNA damage and increased gene copy numbers via a neutral comet assay, the team observed that HER2-205 better induced DNA damage than HER2-1. Moreover, HER2-205 induced significantly more DSBs than HER2-1 in cell lines that contained multiple copies of the HER2 gene.

When looking at HER2-targeting TFOs, the results suggest triplex-induced apoptosis may provide the foundation for potential therapeutic options capable of targeting cancers that develop from gene amplification and sparing tissues that are not gene amplified.

We plan to extend this platform, particularly focusing on cancers with limited precision medicine options, Rogers explained. We will also focus our efforts on drug delivery, since inadequate bioavailability to the tumor can significantly impact therapeutic effect.

Additional findings from the study indicated that tumor growth reduction was observed with intraperitoneal administration of HER2-205. Additionally, investigators reported a tumor tripling time of 29 5.7 days following initial dosing with HER2-205 compared with a of 24 2.1 days in tumors treated with trastuzumab. Moreover, control oligonucleotide MIX24 (ANOVA) did not appear to impact BT474's tumor growth vs the control buffer alone, investigators reported a tumor tripling time of 15.7 4.9 days for control tumors vs 16.3 6.6 days in tumors treated with MIX24 (P = .99).

We envision the use of this drug design platform as a treatment option for several cancers with gene amplification and resistance to current therapies, the investigators concluded.

See more here:
Potential New Therapeutic Option May Combat Drug Resistance in HER2+ Breast Cancer and Ovarian Cancer - Cancer Network

On a brisk Sunday morning in October, a normally quiet grassy area outside the Chemistry Laboratories on Penns campus was filled with shrill cries.

Can anyone help me?!

It burns!

I cant hear out of this ear!!

Dozens of emergency workers jogged purposefully in and out of the lab building, some carrying backboards, others checking medical records, and still others triaging distressed students.

The pleas for help and bustling emergency workers would have been cause for alarmhad they not been part of a simulation intended to provide training for the Medical Emergency Response Team (MERT), a student-run service organization that provides emergency medical services to the Penn community. Begun in 2006, MERT is on call from 5 p.m. to 7 a.m. weeknights and 24 hours on weekends, responding to needs in concert with the Division of Public Safety (DPS) and the Philadelphia Fire Department (PFD). MERT is also supported by the Undergraduate Assembly, the Fox Leadership Program, and Student Health Service.

The simulated mass casualty incident, which mimicked the fallout from a mock explosion and chemical fire in two laboratories, involved 42 student EMTs, 44 volunteer victims, as well as observers from DPS and PFD. Its just one way that MERT goes above and beyond to serve the campus community, says Joshua Glick, an assistant professor of emergency medicine at the Perelman School of Medicine, MERTs medical director, and a MERT alum.

These students have taken it upon themselves to have essentially a full-time job on top of being an undergraduate student, which is a tremendous amount of work, its a tremendous amount of energy, he says. Being a student undergoing a medical emergencywhich can be really scarytheres something comforting about seeing your peers responding to you and helping you.

An interest in medicine is what draws many members of MERT to participate. But becoming involved with MERT is not something Penn students do on a whim. To join requires an internal application process after which members who arent already licensed must obtain certification as an EMT, either externally or through a semester-long training course sponsored by the group.

Emily Kopp, a senior neuroscience and economics double major in the College of Arts and Sciences from Scarsdale, New York, who now serves as MERTs chief, took the course in the spring of her first year at Penn. Me and about 15 or 20 other freshmen and sophomores would spent eight hours every Saturday learning materials, practicing skills, she says. By the end of the semester we were ready to take our licensing exams.

Learning is a continual focus for MERT. Weekly general body meetings allow members to maintain and improve skills in particular areas. Additional formal training happens each August during New Student Orientation, helping the EMTs brush up on competencies, including how to navigate their MERT-issued bikes around campus with up to 30 pounds of emergency equipment attached. Once each semester they strive to hold a mass casualty simulation. And during shifts, crews debrief after each call.

We talk about what we did well, what we didnt do well, what we need to work on, lingering questions, sometimes difficult emotions, says Kopp.

These students have taken it upon themselves to have essentially a full-time job on top of being an undergraduate student, which is a tremendous amount of work, its a tremendous amount of energy. Joshua Glick, an assistant professor of emergency medicine at the Perelman School of Medicine and MERTs medical director

Each MERT EMT is required to commit to 24 hours on shift each month. But many commit far more time. Youll find members of the board or those who are are at higher clinical ranks, like a leader or crew chief, will be taking on 40, 50, 70, up to 100-plus hours a month, says MERT Captain Mariana Restrepo, a senior neuroscience major from Boca Raton, Florida. Its not easy balancing it all, but doing so offers excellent time management skillsgood practice for the future, she says. Id say 80 to 90% of us are involved in extra research, plus seeing our friends, keeping sane.

I think most of our friends wonder how we do it, adds Kopp. From the outside, its a lota lot of hours, a lot of late nights, 100% worthwhile.

The MERT response zone mirrors the DPS patrol area, spanning from 30th to 43rd streets and from Market Street to Baltimore Avenue. During the teams service hours, when an emergency call requiring medical response comes into DPS PennComm Operations Center, the student EMTs on duty are called into action.

Every time they respond they are responding with the Philadelphia Fire Department and with the Penn Police, who establish a safe scene and a perimeter around the scene, says Gene Janda, chief of fire and emergency services in DPS. MERT students then treat patients and prepare them to be transported to the hospital by the PFD.

Janda, who was involved in helping students launch MERT 15 years ago, has seen the benefits of having this campus-based squad. Years ago, he recalls a student member on their way to chemistry class who helped deliver a baby. Another time, a crew assisted a student who fell through an attic floor and required careful handling to avoid further injury before being transported to the hospital.

It could be any situation, he says. It could be some type of trauma, or cardiac arrest; theyre trained for it.

Though MERT began purely as an emergency response service, the organization has since expanded in how it supports the Penn community. Beyond their shift work, MERT members now also coordinate training workshops for Penn faculty, staff, and students in CPR, first aid, stop the bleed injury response, and Narcan administration for opioid overdoses. Many members also do work in the community to promote health and safety.

Kopp, whose role entails coordinating MERTs activities with that of other partners, DPS primary among them, says that the organization works seamlessly with DPS and PFD first responders.

We are all able to work as a team and make sure this campus is really prepared for anything, Kopp says.

Each EMT that is part of MERT could easily point to numerous occasions when their emergency response training was put into meaningful action. For Restrepo, a particularly powerful memory is of administering Narcan to a person in the West Philadelphia community. I walked away from that call, that patient, knowing I saved his life, she says. I think that was the first time I saw the direct impact of our role. We are in the community to save lives.

Restrepo is now in the midst of applying to medical school. And Kopp, too, plans to attend, as do many MERT members. Glick offers living proof of how service with MERT can translate to a career in medicine.

I hit the ground running in medical school, Glick says, who often tells MERT students that the organization equips them with three intangible qualities: a sense of teamwork, great communication skills, and adaptability. Always being comfortable in the uncomfortable, he says, is a skill helpful both in medicine and in life.

I think most of our friends wonder how we do it. From the outside, its a lota lot of hours, a lot of late nights, 100% worthwhile. Senior Emily Kopp, MERTs chief

That embrace of on-the-fly learning was on full display at the mass casualty training event earlier this fall. As MERT team members triaged volunteer patients complaining of head trauma and burn woundsand one even acting out a mental health emergencythey contended with challenges they hadnt anticipated. Despite moment of hesitation and uncertainty, the MERT students eventually ensured that all victims were evacuated from the labs, effectively triaged, and, where needed, transported to the hospital (or back to a dining hall for late-morning bagels and coffee).

To bring the simulation to a close, Lilian Zhang, MERTs disaster response team officer, radioed to her peers, The drill is now completed. But the morningand the learningwasnt quite over. MERT team members filed into the Chemistry building auditorium for a hotwash, a postmortem evaluation of their performance where DPS and other observers offered constructive feedback.

A major takeaway, according to James Taylor, a paramedic and 26 year veteran of the PFD? MERT members took on the simulations challenges with energy, zeal, and readiness. They got the job done.

Learn more on the MERT website.

View allsimulated mass casualty incident photos on Flickr.

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Penn's Medical Emergency Response Team, 'prepared for anything' | Penn Today - Penn Today

THURSDAY, Nov. 18, 2021 (HealthDay News) -- Gene therapy might soon offer a new option for children with a rare genetic disorder that damages tissues throughout the body, researchers are reporting.

In a study of eight children with the condition, called Hurler syndrome, researchers found that the gene therapy was safe over two years. It also showed potential for beating the current standard treatment, stem cell transplantation.

If the gene therapy proves safe and effective in the longer term, experts said, it may well replace stem cell transplants in the future.

"I do think this is a triumph," said Dr. Christopher Dvorak, who co-wrote an editorial published with the study Nov. 18 in the New England Journal of Medicine.

"It's likely to change lives in the not-too-distant future," said Dvorak, a specialist in pediatric stem cell transplantation at the University of California, San Francisco.

Hurler syndrome is one of about 50 genetic diseases known as lysosomal disorders, where children are born lacking key enzymes needed for body cells to function normally.

Hurler syndrome arises when a child inherits a flawed copy of a gene called IDUA from each parent.

The IDUA gene governs an enzyme that breaks down certain complex sugars. In children with Hurler syndrome, those sugars accumulate in cells, causing damage throughout the body, including the brain, eyes, heart and bones.

Enzyme replacement therapy can help with some of those issues, but it does not cross into the brain, said Dr. Walla Al-Hertani, director of the lysosomal disease program at Boston Children's Hospital.

So doctors have turned to stem cell transplants.

The process involves using chemotherapy to deplete a child's own blood-forming stem cells, and replacing them with healthy stem cells from a donor, often from umbilical cord blood. Those healthy cells provide a supply of the needed enzyme, including into the brain.

However, there are downsides.

Even after a transplant, both eye and joint disease can continue to worsen because those areas have a lesser blood supply, explained Al-Hertani, who was not involved in the new study.

And because the treatment involves donor cells, there is a risk of serious immune system reactions, which means ongoing immune-suppressing medication.

Gene therapy could potentially address those issues. For the new study, an international research team tested the approach in eight children with Hurler syndrome, who were about 2 years old, on average.

The tactic involved removing a sample of the children's own blood-forming stem cells, then using a safety-modified virus to deliver a functioning IDUA gene to the cells. After the children had chemotherapy to deplete their remaining blood stem cells, the gene-corrected cells were infused back into their bodies.

Within a month, the researchers found, the children were showing high IDUA activity in their blood three to 12 times higher than what's seen in healthy donors and a sharp reduction in abnormal sugar accumulation.

That high IDUA activity is key, according to lead researcher Dr. Bernhard Gentner of San Raffaele Hospital in Milan, Italy.

Gentner said it suggests that gene therapy might allow more efficient "cross correction" of cells in various body tissues, including the bones where stem cell transplantation is not effective.

At this point, Gentner's team reports, the children have shown normal growth, and are stable in their learning and thinking skills, and stable or "improved" in imaging of the brain and spine.

Al-Hertani said the children need to be followed longer to see whether their enzyme activity remains high, and whether the gene therapy is, in fact, more effective than standard transplants.

But in general, Al-Hertani said she believes gene therapy is "the future" when it comes to treating these rare genetic disorders.

"Our goal," Gentner said, "is to make this new treatment available to patients as soon as possible."

To that end, he added, U.K.-based Orchard Therapeutics has been granted a license to further develop the gene therapy. A phase 2 study is in the "advanced" planning stages, Gentner said.

Dvorak said he does have some concerns about equitable availability should gene therapy become a standard treatment for Hurler syndrome.

In theory, any medical center that treats the condition should be able to offer gene therapy. But it's possible it will roll out in a more limited way, according to Dvorak.

"It's also going to be quite pricey," he said. "I do have concerns that there could be socioeconomic disparities in access to it."

Hurler syndrome affects an estimated one in 100,000 newborns, according to the U.S. National Institutes of Health. The disorder is part of newborn screening in some U.S. states, Dvorak said, but not all.

More information

Boston Children's Hospital has more on Hurler syndrome.

SOURCES: Bernhard Gentner, MD, hematologist, stem cell transplantation unit, San Raffaele Hospital, Milan, Italy; Walla Al-Hertani, MD, MSc, director, lysosomal disease program, Boston Children's Hospital, assistant professor, pediatrics, Harvard Medical School, Boston; Christopher Dvorak, MD, chief, pediatric allergy, immunology and bone marrow transplant division, Benioff Children's Hospitals, University of California, San Francisco; New England Journal of Medicine, Nov. 18, 2021

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Gene Therapy May Reverse Hurler Syndrome, a Rare and Severe Illness in Kids - HealthDay

Meanwhile, Mellins extracted human leucocyte antigen (HLA) profiles from the genetic data of 20 lung disease patients and found that more than half shared the same genetic signature. HLAs are the proteins on cell surfaces that distinguish self from nonself tissues.

I picked up the phone and called Jill Hollenbach, an immunogeneticist at UCSF, and she said, This is remarkable, Mellins said. Hollenbach thought that the results indicated a severe drug reaction rather than a genetically linked feature of Stills disease.

The researchers realized that patients with the lung problems met criteria for drug reaction with eosinophilia and systemic symptoms, or DRESS, a type of severe, delayed medication reaction. Although features of DRESS, easily missed with Stills disease, began soon after the drug was started, on average it took 14 months on the drugs for patients severe lung disease to become apparent.

The researchers compared 66 Stills disease patients who had DRESS with 65 patients who did well on the drugs. Among other problems, three-quarters of the patients with DRESS, with or without lung disease, had liver enzyme levels indicating serious liver dysfunction, and 64% developed a cytokine storm.

The reactions were not always recognized by the patients physicians. Patients who were taken off and kept off the drugs did well. Tragically, of 33 patients who kept taking the medications after their reactions began, nine died.

This [drug reaction] is a very, very complicated signal, and its hard for clinicians to realize that stopping the drug is what you do, especially if there is organ involvement, such as lung or liver dysfunction, Saper said.

The genetic signature that confers higher risk is found in 20% of the population at large and in 80% of patients in the study who had DRESS. Blood testing for HLA markers is available in clinical labs. Since the gene test did not predict all who reacted, this study indicates that physicians should watch carefully for DRESS reactions to inhibitors of IL-1 and IL-6.

Two of the immune-blocking medications, tocilizumab and anakinra, have recently been used in patients experiencing cytokine storms due to severe COVID-19.

This worries the research team because the risky HLA markers are quite common. A recent scientific report on 24 very ill COVID-19 patients treated with tocilizumab noted that six patients died. The Stanford researchers suggest caution in using this drug for COVID-19.

Theres all this circumstantial evidence in COVID patients, but it requires more investigation, Saper said.

Meanwhile, the researchers hope the findings will quickly prompt HLA testing of Stills patients.

One imperative we have is, The right drug, for the right person, at the right time, Saper said. In Stills disease, for most people these drugs are exactly right. But weve been able to identify a simple genetic test that could tell if this is not the right drug for you.

The papers other Stanford authors are research associate Gonzalo Montero-Martin, PhD; Serena Tan, MD, assistant professor of pathology; postdoctoral scholars Vamsee Mallajosyula, PhD, Debopam Ghosh, PhD, and Jianpeng Xu, PhD; Lu Tian, PhD, professor of biomedical data science; and Marcelo Fernandez-Vina, PhD, professor of pathology.

Tian and Mellins are members of the Stanford Maternal and Child Health Research Institute, Mellins is a member of the Interdisciplinary Program in Immunology and the Wu Tsai Neurosciences Institute at Stanford, and Tian is a member of the Stanford Cardiovascular Institute.

Among the contributors areother scientists from UCSF and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, as well as scientists from UC-San Diego, Emory University School of Medicine and Childrens Healthcare of Atlanta, the University of Pittsburgh, the University of Washington, the National Human Genome Research Institute, the University of Pennsylvania, Pennsylvania State University College of Medicine, Yale University Medical School and the University of Hong Kong, also contributed to this research.

The research was funded by the Lucile Packard Foundation for Childrens Health, the Stanford Maternal and Child Health Research Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant Z01-AR041198), the National Human Genome Research Institute (grant Z01-HG200370), the Gordon and Marilyn Macklin Foundation, the RK Mellon Institute for Pediatric Research and the Marcus Foundation Inc.

Some of the authors received personal fees, grants or both from Novartis, which makes canakinumab.

Read more here:
Immunosuppressants linked to severe reactions in people with common genetic profile - Stanford Medical Center Report

Identifying tumor-specific clues of potential poor outcomes could one day lead to improved treatments for metastatic breast cancer. At Baylor College of Medicine, Dr. Matthew J. Ellis and his colleagues are gaining ground in that direction with the discovery of a genetic signature that can provide specific details about a tumor that could guide physicians in the selection of more effective treatments.

About 80% of all breast cancers depend on the hormone estrogen to grow. The hormone promotes tumor growth by binding to the estrogen receptor (ER), said Ellis, professor and director of the Lester and Sue Smith Breast Center and a McNair scholar at Baylor.

Disrupting the estrogen-ER interaction is a key therapeutic approach. Drugs such as tamoxifen and fulvestrant target the ER this way, but tumor cells learn to evade this attack and become resistant to these drugs.

One of the predominant ways ER+ breast cancer cells evade treatment is by creating mutant ERs that no longer can be recognized and targeted by ER-targeting cancer drugs and therefore are unsusceptible to current therapies directed at disrupting estrogen-fueled tumor growth, said first author Xuxu Gou, a graduate student in the Ellis lab.

The team has been studying ESR1 gene translocations, which refer to the ER gene swapping a part of its sequence with genetic information from another gene. ER gene translocations create chimeric ER proteins, meaning the protein contains only half of the ER protein and the other half comes from different protein.

Some of the ER chimeras are extreme versions of mutant ERs because the drug-binding region, which is the same region estrogen binds to, is completely replaced with a region derived from another protein, to which neither the drug nor estrogen can bind. These ER chimeras trigger cancer activity in the absence of hormone.

Not all ER translocations are active some drive metastasis and resistance to treatment, but others do not, Gou said. To be able to determine whether any particular ESR1 translocation can promote disease progression, we developed a diagnostic genetic signature that detects the presence of an active ESR1 chimeric protein.

With support from the National Cancer Institutes PDXnet program, the team used genomics and transcriptomics to annotate 20 mouse models of ER+ patient-derived tumors that demonstrated different degrees of dependence on estrogen for growth. In this data set, a 24-gene signature detected the presence of an active ESR1 fusion, but interestingly also common point mutations in ESR1. These findings were replicated in data from a human metastatic breast cancer cohort. The team therefore called their 24-gene signature the MOTERA score for Mutant or Translocated Estrogen Receptor Alpha.

This work is significant in the area of precision medicine, as it can provide specific details about a tumor that can help guide a more precise selection of personalized, tumor-specific treatments.

In the future, a patients cancer cells could be analyzed and, once the MOTERA score indicates the presence of an ER mutation or translocation, then the tumor cells would be further studied to more precisely determine what kind of ER mutant or translocation is present. This would help guide the selection of a personalized, optimal treatment, said co-author, Dr. Charles E. Foulds, assistant professor at Baylors Lester and Sue Smith Breast Center.

The findings are published in Cancer Research.

Ellis and Foulds are members of the Dan L Duncan Comprehensive Cancer Center at Baylor. Other contributors to this work include Meenakshi Anurag, Jonathan T. Lei, Beom-Jun Kim, Purba Singh, Sinem Seker, Diana Fandino, Airi Han, Saif Rehman, Jianhong Hu, Viktoriya Korchina, Harsha Doddapaneni, Lacey E. Dobrolecki, Nicholas Mitsiades, Michael T. Lewis, Alana L. Welm, Shunqiang Li and Adrian V. Lee. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Yonsei University Wonju College of Medicine, University of Cambridge, University of Utah, Washington University School of Medicine in St. Louis, University of Pittsburgh and University of Michigan.

See the publication for a complete list of the sources of support for this work.

By Ana Mara Rodrguez, Ph.D.

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Gene signature may give an upper hand in metastatic breast cancer - Baylor College of Medicine News

A lengthy video posted on TikTok that makes a host of unfounded claims about COVID-19 vaccines all of which have been repeatedly debunked originated with InfoWars, a website renowned for sowing conspiracy theories.

The viral video claims that COVID-19 vaccines "failed miserably" in animal trials and are "a type of gene therapy that several top scientists warn will kill you." It includes hashtags like #truthcomesout and #firefauci.

The video appeared on Facebook, where it was flagged as part of Facebooks efforts to combat false news and misinformation on its News Feed. (Read more about our partnership with Facebook.)

COVID-19 vaccines did not fail in animal trials or result in the death of the animals tested. The vaccines are not a form of gene therapy, which modifies a persons genes to replace or fix mutations that lead to diseases. The scientists cited in the video have spread misinformation about the vaccines.

The footage is an excerpt from a longer video posted online Oct. 13 called "Kill Shot," by Greg Reese, an editor and producer for the website InfoWars, which has spread other vaccine misinformation. Most recently, InfoWars was in the news because its founder and host, Alex Jones, was found liable for defamation against the families of victims from the 2012 Sandy Hook Elementary School shooting, which Jones has portrayed as a hoax.

In the TikTok video, a narrator says that 22 months into the COVID-19 pandemic, "We have all the information needed to paint a clear picture of whats going on." The narrator then recites a laundry list of false claims about Dr. Anthony Fauci, PCR tests, the ingredients of vaccines and more.

The narrator says, "The COVID vaccines are not vaccines but rather highly controversial mRNA tech that failed miserably on its animal trials, a type of gene therapy that several top scientists warn will kill you," a statement that contains multiple falsehoods.

First, COVID-19 vaccines did not fail animal trials. Fact checkers have debunked this claim, noting that the two vaccines most widely used in the U.S. Pfizer and Moderna produced desirable outcomes in animal testing. Results from Modernas animal testing were published in the New England Journal of Medicine after monkeys had a robust immune response to the vaccine.

Animals also did not die during the vaccine trials. Full Fact reported that had any animals died, human trials that were running concurrently would have been halted, which they were not.

Next, COVID-19 vaccines are not a type of gene therapy; PolitiFact and others have reported that the claim is false. Gene therapy is a process of modifying genes to replace or fix mutations that lead to diseases, according to PolitiFact.

Thats different from mRNA vaccines, which send instructions to the bodys cells to make a piece of spike protein, which is also found on the surface of the virus that causes COVID-19, so that the immune system can respond to it.

Finally, the videos narrator says "several top scientists warn" that the COVID-19 vaccines "will kill you," and names Dr. Ryan Cole and Dr. Nathan Thompson. Cole, who is licensed to practice medicine in several states and is under investigation by the Washington Medical Commission, falsely claimed in the spring that mRNA vaccines cause cancer and autoimmune diseases. He was rebuked by the author of the medical paper he cited as evidence for the claim.

The other doctor identified, Thompson, has claimed that COVID-19 vaccines weaken the immune system, which PolitiFact rated False.

Our ruling

A TikTok video posted on Facebook says COVID-19 vaccines "failed miserably" in animal trials and are "a type of gene therapy that several top scientists warn will kill you." The video originated on InfoWars, known for spreading conspiracy theories.

The vaccines did not fail in animal trials or result in the death of the animals tested.

COVID-19 vaccines are not a type of gene therapy, which involves modifying genes to replace or fix mutations that lead to diseases. The mRNA vaccines do not change a persons genetic makeup and never enter the part of the cell that hosts DNA.

The scientists cited in the video have spread misinformation about the vaccines.

We rate this claim False.

See the rest here:
A video that originated on InfoWars is filled with falsehoods about COVID-19 vaccines - PolitiFact