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News Article | February 17, 2017
Site: www.eurekalert.org

(PHILADELPHIA) - Adult stem cells collected directly from human fat are more stable than other cells - such as fibroblasts from the skin - and have the potential for use in anti-aging treatments, according to researchers from the Perelman School of Medicine at the University of Pennsylvania. They made the discovery after developing a new model to study chronological aging of these cells. They published their findings this month in the journal Stem Cells. Chronological aging shows the natural life cycle of the cells - as opposed to cells that have been unnaturally replicated multiple times or otherwise manipulated in a lab. In order to preserve the cells in their natural state, Penn researchers developed a system to collect and store them without manipulating them, making them available for this study. They found stem cells collected directly from human fat - called adipose-derived stem cells (ASCs) - can make more proteins than originally thought. This gives them the ability to replicate and maintain their stability, a finding that held true in cells collected from patients of all ages. "Our study shows these cells are very robust, even when they are collected from older patients," said Ivona Percec, MD, director of Basic Science Research in the Center for Human Appearance and the study's lead author. "It also shows these cells can be potentially used safely in the future, because they require minimal manipulation and maintenance." Stem cells are currently used in a variety of anti-aging treatments and are commonly collected from a variety of tissues. But Percec's team specifically found ASCs to be more stable than other cells, a finding that can potentially open the door to new therapies for the prevention and treatment of aging-related diseases. "Unlike other adult human stem cells, the rate at which these ASCs multiply stays consistent with age," Percec said. "That means these cells could be far more stable and helpful as we continue to study natural aging." ASCs are not currently approved for direct use by the Food and Drug Administration, so more research is needed. Percec said the next step for her team is to study how chromatin is regulated in ASCs. Essentially, they want to know how tightly the DNA is wound around proteins inside these cells and how this affects aging. The more open the chromatin is, the more the traits affected by the genes inside will be expressed. Percec said she hopes to find out how ASCs can maintain an open profile with aging. Funding for this study was provided by the National Institutes of Health (K08 AG042496). Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


News Article | March 2, 2017
Site: www.eurekalert.org

PHILADELPHIA--Using antibodies to treat disease has been one of the great success stories of early 21st-century medicine. Already five of the ten top-selling pharmaceuticals in the United States are antibody products. But antibodies are large, complex proteins that can be expensive to manufacture. Now, a team led by scientists from the Perelman School of Medicine at the University of Pennsylvania demonstrates in an animal model a new way to deliver safer and more cost-effective therapeutic antibodies. The technique involves the injection of messenger RNAs (mRNAs), the "blueprint" molecules that cells use to manufacture proteins. The mRNA molecules are taken up by cells in the body, which then become factories for making the therapeutic proteins--in this case, antibody proteins--encoded by the mRNAs. These mRNAs are modified so they can easily enter cells and not activate inflammatory molecules that lead to adverse events. Researchers have previously shown that they can use this method to make hormones and other proteins in lab animals. In the new study, reported today in Nature Communications, the Penn-led team demonstrated that the mRNA method can be used to make antibody proteins--enough to confer vaccine-like protection against HIV with one, small dose--in mice. "We showed that you can give 1/40th the dose of mRNA compared to the antibody protein itself, and completely protect mice from HIV infection when they are exposed to the virus," said senior author Drew Weissman, MD, PhD, a professor of Infectious Diseases. "Clinical trials of this anti-HIV antibody are already underway, but we think our mRNA approach could in principle be a very effective alternative to this and other antibody therapies." The basic idea of injecting mRNA into patients to make therapeutic proteins in their cells has been around for a long time, but ordinary mRNA doesn't work well for this application. After standard mRNA is injected, enzymes and the immune system tend to treat it like an invading virus and make inflammatory proteins and responses that could make patients sick along with other adverse events. However, in a series of papers starting in 2005,Weissman, co-developer Katalin Karikó, PhD, now an adjunct associate professor of Neurosurgery and vice president of BioNTech RNA Pharmaceuticals, and colleagues reported that ordinary mRNAs could be modified in relatively straightforward ways so that they do not activate inflammatory pathways and can efficiently produce large amounts of protein for an extended amount of time. This team, along with lead author Norbert Pardi, PhD, a postdoctoral research associate in the Weissman lab, and Michael Hogan, a pre-doctoral student at Penn, recently published the use of nucleoside-modified mRNA complexed to lipid nanoparticles as a vaccine for Zika in the journal Nature. Production of therapeutic proteins via mRNAs within a patient's own cells may be safer, in many cases, than the production of the proteins in a biotech facility. "Biotech manufacturing requires a cell line and extensive purification that can aggregate or misfold the protein, resulting in an unwanted immune response against the protein or other adverse events," Weissman said. In the current study, the researchers demonstrated the therapeutic potential of modified mRNAs that code for the anti-HIV antibody VRC01. Most antibodies produced in response to HIV infection are ineffective at stopping the ever-changing virus. By contrast, VRC01--first isolated from a human HIV-positive volunteer--hits a well conserved target on multiple HIV strains and thus neutralizes about 90 percent of HIV strains. Other researchers are now developing VRC01 as a possible therapy for people who already have HIV infection or as a passive vaccine to protect uninfected people. However, the likely high cost of the VRC01 antibody therapy could present an obstacle to its widespread use. Weissman, Pardi, and colleagues showed that a single injection of the mRNAs that encode the VRC01 monoclonal antibody led to robust production of the resulting antibody protein in the livers of mice within 24 hours. A small weekly injection was enough to maintain high levels VRC01 antibody levels in the circulation. Most importantly, the scientists showed that a single 30- or 15-microgram injection of VRC01 mRNA was enough to protect mice, which had been engineered to be infectable by HIV--from intravenous exposure to two reference strains of HIV. For comparison, the team showed that when they directly injected VRC01 antibodies into the same mice, 600 micrograms was needed to provide the same level of protection against HIV. "This is the first proof-of-principal demonstration of mRNAs in a truly therapeutic role and as a replacement for antibodies," Weissman said. Other co-authors of the study are Anthony J. Secreto, Xiaochuan Shan, Fotini Debonera, Joshua Glover, Yanjie Yi, Hiromi Muramatsu, Houping Ni, Farida Shaheen, Ronald G. Collman, and Gwenn A. Danet-Desnoyers, all of Penn; and Barbara L. Mui, Ying K. Tam, Thomas D. Madden, and Michael J. Hope, of Acuitas Pharmaceuticals, Vancouver, BC. The study was made possible by grants from the National Institute of Health (R01-AI050484, R01-AI084860, P30-AI045008), and a Takeda Pharmaceuticals New Frontier Science award. Editor's Note: Karikó and Weissman are named inventors of Penn-owned patents and patent applications that describe the use of nucleoside-modified mRNA as a platform to deliver therapeutic proteins. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania(founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


News Article | February 17, 2017
Site: www.eurekalert.org

PHILADELPHIA - For most vaccines to work the body needs two cell types - B cells and T helper cells - to make antibodies. B cells are the antibody factories and the T helper cells refine the strength and accuracy of antibodies to home and attack their targets. A technique that identifies these helper immune cells could inform future vaccine design, especially for vulnerable populations. Flu vaccines work by priming the immune system with purified proteins from the outer layer of killed flu viruses. An antibody is a protein that recognizes a unique pathogen molecule called an antigen that is specific for a particular strain. Antibodies bind to their targets with precision in the best of circumstances. In doing so, the antibody blocks a harmful microbe from replicating or marks it to be killed by other immune cells. The level of antibodies in the blood tells immunologists how well a vaccine is working, specifically, how many antibodies are made and how strongly they disable microbes. The relatively scarce circulating T follicular helper cells, or cTfh for short, are key to antibody strength. Without Tfh, effective antibodies cannot be made, yet very little is known about cTfh cells in humans after vaccination. Now, a team led by researchers from the Perelman School of Medicine at the University of Pennsylvania has found a way to identify the small population of cTfh present in the blood after an annual flu vaccine to monitor their contribution to antibody strength. They published their findings in Science Immunology this week. The studies, led by Ramin Herati, MD, an instructor of Infectious Disease, used high dimensional immune-cell profiling and specific genomic tests to identify and track these rare cells over time. "The poor understanding of cTfh function is, in part, because these cells spend most of their time waiting in lymph nodes for the next infection, and not circulating in the blood," said senior author E. John Wherry, PhD, a professor of Microbiology and director of the Institute of Immunology at Penn. "To get a handle on how well these cells are doing their job following vaccination, we have needed a way to measure their responses without gaining direct access to lymph nodes. Because of the central role of circulating T follicular helper cells in antibody development, new vaccine development strategies will benefit from a better understanding of the properties of these essential cells in the immune response." Every T cell has a unique receptor on its outer surface. After receiving a vaccine, the result is one T cell with this unique bar code of sorts that replicates, making thousands of clones with identical copies of the same bar code. After vaccination this expansion of T cells dies down and a few clones remain behind. These memory cells wait it out in lymph nodes and other organs for the next time the infection or vaccine enters the body. These clones can then be called into action to protect the individual or help boost the vaccine immunity. In the current study, the team was able to track circulating helper T cells because the unique bar code they possessed is specific to the strains used in an annual flu vaccine. Wherry and colleagues traced antibody production in 12 healthy subjects, aged 20 to 45 for three years from 2013 to 2105. The circulating subset of helper follicular T cells expressed different transcription factors and cytokines -- Bcl-6, c-Maf, and IL-21 - compared to other T-cell subpopulations in the blood. The number of the cTfh cells sharply increased at seven days after a subject received a flu shot. Repeated vaccination of the study participants brought back genetically identical clones of cTfh cells in successive years, indicating robust cTfh memory to the flu vaccine. These responses are a proxy for specific antibodies to the flu vaccine each year. In addition, these results measure the dynamics of vaccine-induced cTfh memory and recall over time, allowing investigators to monitor the key human-vaccine-induced cTfh responses and gain insights into why responses to flu vaccines are suboptimal in many people. The ability to track these cTfh responses in the blood, instead of accessing lymph nodes in humans, allows for real-time monitoring of key cellular mechanisms involved in vaccination. Such knowledge should allow further optimization of vaccines for hard-to-treat diseases like the flu, but also HIV, and other infections in which inducing potent vaccines has been a challenge. "These cTfh are a missing piece of being able to truly monitor and predict their ability to induce the desired magnitude and quality of immune memory, and therefore protection by vaccines," Wherry said. The team next intends to look at elderly populations in which vaccines are not as effective and ask what role cTfh cell populations play in that part of the human population. This research was supported by the National Institutes of Health (AI114852, AG047773, AG028716, AI113047, AI108686, AI112521, AI117950, AI2010085), the Penn Center for AIDS Research (P30 AI045008), and the U.S. Broad Agency Announcement (HHSN272201100018C). E. John Wherry is a member of the Parker Institute for Cancer Immunotherapy, which supports the Penn Cancer Immunotherapy Program. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


News Article | February 21, 2017
Site: www.eurekalert.org

PHILADELPHIA--Cervical cancer is the leading cause of cancer deaths for women low- and middle-income countries, including Botswana, where 75 percent of cervical cancer patients suffer from advanced forms of the disease. These patients can face wait times as long as five months after diagnosis before receiving lifesaving treatment. A new, multidisciplinary model of cervical cancer care developed by a University of Pennsylvania team based in Botswana cut the delay between diagnosis and treatment by more than 50 percent, according to research published this month in the Journal of Global Oncology. Limited access to preventive screenings combined with the HIV epidemic are driving the high rate of cervical cancer in Botswana, which has the second highest HIV rate in the world. The risk of developing cervical cancer in women infected with HIV is three- to six-fold higher than those who are HIV-negative. In Botswana, more than two-thirds of all cervical cancer cases occur among women who are also living with HIV. However, radiation therapy is not available at in public clinics in Botswana, requiring patients to seek care at private hospitals, which can be a cumbersome process with wait times as long as five months. "With so many women suffering from advanced cervical cancer in Botswana, long delays between treatment and diagnosis can mean the difference between life and death," said Surbhi Grover, MD, MPH, director of Global Radiation Oncology in the Perelman School of Medicine at the University of Pennsylvania and head of Oncology at Princess Marina Hospital in Botswana. "We saw an urgent need to develop a care program that gives cervical cancer patients the treatment they need as quickly as possible." Grover and her fellow researchers at Princess Marina Hospital developed a multidisciplinary team (MDT) approach to streamline care and communication between providers and get patients to treatment facilities faster. Weekly care team meetings were established across providers, including radiation oncologists, clinical oncologists, gynecologists, nurse coordinators, and palliative care specialists to discuss patient cases and develop treatment plans. The teams also worked to together to submit paperwork and other documentation, further reducing delays in treatment and simplifying the overall process. "While this type of model might seem common in the United States or other developed countries, it's actually a quite complicated process that lacks a global standard of guidelines," Grover said. "We saw many different models across the world, but no published outcomes on how to successfully implement an MDT approach for cervical cancer care." Over a six-month period, the team saw 135 patients, 60 percent of whom were diagnosed with cervical cancer and 42 percent had locally advanced cancer the required chemo-radiation. However, thanks to the MDT model, 62 percent of those patients required only one clinic visit to coordinate care, reducing the time between diagnosis and treatment initiation by more than 50 percent, with the median delay from biopsy to treatment initiation cut to 39 days from an average of 108 days before the new care model. "With this model, we've shown that the MDT approach works in a resource-limited setting and actually helps address several challenges providers face," Grover said. "Many of our patients must travel long distances or face other barriers that prevent them from returning to the clinic for multiple visits. Offering patients a comprehensive treatment plan during one clinic visit is a game-changer." Similar MDT models are being developed for head and neck cancer, breast cancer, and palliative care in Botswana. A follow-up clinic is also being piloted where patients with gynecological cancer receive continued follow-up care after chemotherapy and radiation are complete. All patients seen in the Penn MDT clinic will be linked to this new clinic and will receive regular communication about follow-up care. "What this approach really shows is the importance of integrated care and treatment models," Grover said. "We hope our MDT model will be applied on a broad scale across many different illnesses and clinics in resource-limited settings worldwide." Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania(founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


News Article | February 15, 2017
Site: www.eurekalert.org

PHILADELPHIA - More than six decades after Castleman disease (CD) was first described, a group of experts from Penn Medicine and other institutions around the world has established the first set of diagnostic criteria for a life-threatening subtype of the condition, idiopathic multicentric CD (iMCD), which is often misdiagnosed as other illnesses. The report was published online ahead of print in the journal Blood. Accurate diagnosis of iMCD has been challenging, with no standard diagnostic criteria to guide physicians and significant overlap with cancer and autoimmune, or infectious disorders. About 1,200 patients are diagnosed with iMCD each year in the United States. It can occur in patients of any age, and about 35 percent of iMCD patients die within five years of diagnosis; 60 percent die within 10 years. "The new criteria will accelerate time to diagnosis and, more importantly, administration of life-saving treatments for iMCD patients," said first author David Fajgenbaum, MD, MBA, MSc, an assistant professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania and associate director of patient impact at the Penn Orphan Disease Center. Many iMCD patients endure months without appropriate treatment, including Fajgenbaum, who is also an iMCD patient. It took over 11 weeks for Fajgenbaum to be correctly diagnosed, during which time he experienced two life-threatening episodes of the disease. "Previously, patients had to hope their doctors were familiar with the Castleman disease medical literature in order for them to even consider an iMCD diagnosis," Fajgenbaum said. "Then, for the doctors considering the diagnosis, actually diagnosing it was very difficult. Now, with these criteria, doctors will know exactly what to look for and what to check off to feel confident about a diagnosis." To establish the criteria, the international working group - led by Fajgenbaum and consisting of 34 pediatric and adult hematopathology, hematology/oncology, rheumatology, immunology, and infectious diseases experts in iMCD and related disorders representing eight countries on five continents, including two physicians that are also iMCD patients - reviewed 244 iMCD cases and 88 lymph node tissue biopsies over 15 months. Other working group members from Penn include senior authors Kojo Elenitoba-Johnson, MD, a professor of Pathology and Laboratory Medicine and director of the Center for Personalized Diagnostics, and Megan Lim, MD, PhD, a professor of Pathology and Laboratory Medicine. The criteria require that for a diagnosis of iMCD to be made, two major criteria and at least two of 11 minor criteria be met, including at least one laboratory abnormality, such as anemia or elevated C-reactive protein in the blood. Additionally, several diseases with similar clinical presentation to iMCD must be excluded, such as another sub-type of CD called HHV-8-associated multicentric CD. Several therapies have been used off-label to treat iMCD patients with varying success, including corticosteroids, cytotoxic chemotherapy, and immunosuppressants. In 2014, siltuximab, an anti-IL6 monoclonal antibody used to treat cancer, became the first U.S. Food and Drug Administration-approved iMCD therapy based on results from an international, randomized controlled trial in which 34 percent of patients had a complete or partial response to the drug compared to zero percent on placebo. "However, the lack of a defined diagnostic criteria has likely impeded the timely administration of treatment for many patients," Fajgenbaum said. "Such delays could lead to organ dysfunction and even death." The working group retrospectively applied the diagnostic criteria to patients from the siltuximab clinical trial. They found that individuals presumed to have iMCD, but who did not meet the diagnostic criteria, had a significantly lower (0 percent) response rate to siltuximab compared to patients who met the diagnostic criteria (43 percent). The working group will continue to improve upon the new diagnostic criteria, in part by relying on the ACCELERATE patient registry. ACCELERATE is a CD natural history registry based at Penn. The data collected from the registry will help researchers validate and potentially tweak the criteria. "I feel so pleased and optimistic that we're finally turning the tide against this disease," Fajgenbaum said. "I've heard of too many patients diagnosed with the disease only after they died and underwent an autopsy, and hopefully this will help doctors to diagnose it before it is too late." Co-authors also include Elaine Jaffe, MD and Thomas S. Uldrick, MD, MS, from the National Cancer Institute's Center for Cancer Research. The study was supported in part by the Castleman Disease Collaborative Network, the Penn Orphan Disease Center, and the Intramural Research Program of the National Institutes of Health. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


News Article | February 27, 2017
Site: www.eurekalert.org

PHILADELPHIA - Since the introduction of the Affordable Care Act, which provided access to health insurance to millions of previously uninsured adults in the United States, the availability of appointments with primary care physicians has improved for patients with Medicaid and remains unchanged for patients with private coverage, according to new research led by the Perelman School of Medicine and the Leonard Davis Institute of Health Economics at the University of Pennsylvania. The study, which compared new patient appointment availability in 10 states between 2012/13 (before the Affordable Care Act came into effect) and 2016, is published today in JAMA Internal Medicine. The study found appointment availability for Medicaid enrollees jumped from 57.9 percent to 63.2 percent between 2012/2013 and 2016. "Results of our study should ease concerns that the Affordable Care Act would aggravate access to primary care," said lead author Daniel Polsky, PhD, a professor of Medicine at the Perelman School of Medicine and Health Care Management in the Wharton School at the University of Pennsylvania, and the executive director of Penn's Leonard Davis Institute of Health Economics. "The finding that more doctors are accepting patients with Medicaid, not fewer, is particularly timely given the active health care reform debate as offers evidence contradicting that the stated criticism of Medicaid that 'more and more doctors just won't take Medicaid." The study included two waves of data collection, from November 2012 to April 2013 and from February to June 2016. Simulated patients differing in age, sex, race, and ethnicity were randomized to an insurance type (Medicaid or private coverage) and clinical scenario (hypertension or check-up). Participants called in-network primary care practices in Arkansas, Georgia, Illinois, Iowa, Massachusetts, Montana, New Jersey, Oregon, Pennsylvania, and Texas, then requested the earliest available appointment with a randomly selected primary care provider. Researchers compared results of the two time periods to determine changes in appointment availability. They also estimated changes in the probability of short wait times (seven days or less) and long wait times (more than 30 days). In addition to an increase in appointment availability, patients with Medicaid and private coverage experienced somewhat longer wait times. Medicaid callers faced a 6.7 percentage point decrease in short wait times and, among privately insured callers, the share of short wait times decreased 4.1 percentage points and the share of long wait times increased 3.3 percentage points. The authors say the absorption of new patients may explain the increase in wait times, which was similarly observed in Massachusetts after it expanded Medicaid in 2006. Some initiatives to strengthen primary care delivery, such as raising Medicaid reimbursement rates to Medicare levels for some primary care providers in 2013 and 2014, increasing funds for federally qualified health centers, and expanding the penetration of Medicaid managed care, may explain the findings. Additionally, the authors suggest changes beyond Affordable Care Act initiatives, including team-based clinics, retail clinics, and data sharing, may have expanded capacity in some practices. Since this study focused solely on new patient appointment requests at in-network offices, further research is needed to determine how health system changes have affected established patients. Additionally, though the 10 states were selected specifically for their diversity along a number of dimensions, the results may not be generalizable to other settings. Additional authors on the study include Molly Candon from Penn's Leonard Davis Institute of Health Economics, Brendan Saloner from the Johns Hopkins Bloomberg School of Public Health, Katherine Hempstead from the Robert Wood Johnson Foundation, Douglas Wissoker and Genevieve M. Kenney from the Urban Institute, and Karin Rhodes from the Hofstra Northwell School of Medicine. The study was funded by the Robert Wood Johnson Foundation. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


News Article | March 1, 2017
Site: www.eurekalert.org

PHILADELPHIA - African Americans have a heightened risk of developing chronic and end-stage kidney disease. This association has been attributed to two common genetic variants - named G1 and G2 -- in APOL1, a gene that codes for a human-specific protein. However, direct evidence showing that these variants definitively cause kidney disease was lacking because APOL1 is widely expressed in different cell types but the gene is present in only some primates and humans. The challenge has been to create an animal model to prove this. Now, a team led by researchers from the Perelman School of Medicine at the University of Pennsylvania has engineered mice with these mutations that cause human-like kidney disease. "The key missing piece has been whether these variants are true disease culprits," said senior author Katalin Susztak, MD, PhD, an associate professor of Medicine and Genetics, of the study published online in Nature Medicine. "Our study established that these mutations are definitely disease causing." The G1 and G2 APOL1 gene variants, found almost exclusively in people of West African descent, have been shown to be associated with two-to-100-fold increased risk of kidney disease development, according to previous studies. Despite this highly significant risk, more than one third of African Americans carry the G1 and G2 variants. Biologists surmise that the reason these two mutations are so prevalent is that they emerged as a result of "positive selection" in people of African descent because the mutant proteins protect humans against the parasite that causes African sleeping sickness. Cells that express the G1 and G2 variants of the APOL1 protein are better able to kill these parasites. To prove that expression of APOL1 with the G1 and G2 mutations causes kidney disease, the team made mice in which they could induce the expression of the non-mutated APOL1 gene as well as the G1 or G2 mutated APOL1 genes in different cell types. The team found that when the G1 and G2 variants are expressed in the filtering cells of the kidney the disease in the mouse model strongly resembled features of human kidney disease at the functional, structural, and molecular level. "These mutant proteins caused the kidney filter to become leaky and scarred, resulting in defective kidney function" Susztak said. Kidney disease development was specific to the filtering cells of the kidney. The scientists found that G1 or G2 mutated APOL1 proteins interfere with the normal house-cleaning function of the cell, leading to an accumulation of jumbled proteins, inflammation, and eventually cell death. This trash removal system is especially important in kidney filtering cells, as these cells do not renew and losing them results in scarring of kidney tissue. "Now that we know that the G1 and G2 mutated APOL1 proteins cause human-like kidney disease, we can start to look for ways to target them to reduce kidney disease risk among millions of people of African descent," Susztak said. "The good news is that in mice the disease development was experimentally reversible when the G1 and G2 genes were turned off, and in a related finding, disease severity also correlated with the amount of expression of G1 and G2 APOL1 variant proteins in patient samples." This work was supported by the National Institutes of Health (DK105821, T32-DK007006). Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


News Article | February 15, 2017
Site: www.eurekalert.org

PHILADELPHIA - Casting one of the largest genomic nets to date for the rare tumors of the autonomic nervous system known as pheochromocytoma and paraganglioma (PCC/PGL) captured several new mutations driving the disease that could serve as potential drug targets, researchers from Penn Medicine and other institutions reported this week in Cancer Cell. Analyzing genetic data of 173 patients from The Cancer Genome Atlas, researchers, including senior author Katherine Nathanson, MD, a professor in the division of Translational Medicine and Human Genetics at the Perelman School of Medicine at the University of Pennsylvania and associate director for Population Science at Penn's Abramson Cancer Center, identified CSDE1 and fusion genes in MAML3 as drivers of the disease, both a first for any cancer type. The researchers also classified PCC/PGL into four distinct subtypes, each driven by mutations in distinct biological pathways, two of which are novel. "What's interesting about these tumors is that while they are astonishingly diverse genetically, with both inherited and somatic drivers influencing tumorigenesis, each has a single driver mutation, not multiple mutations," Nathanson said. "This characteristic makes these tumors ideal candidates for targeted therapy." Other cancer types typically contain anywhere from two to eight of these driver mutations. The discovery of these single drivers in PCC/PGL provides more opportunities for molecular diagnosis and prognosis in these patients, particularly those with more aggressive cancers, the authors said. PGLs are rare tumors of nerve ganglia in the body, whereas PCCs form in the center of the adrenal gland, which is responsible for producing adrenaline. The tumor causes the glands to overproduce adrenaline, leading to elevated blood pressure, severe headaches, and heart palpitations. Both are found in about two out of every million people each year. An even smaller percentage of those tumors become malignant - and become very aggressive. For that group, the five-year survival rate is about 50 percent. Matthew D. Wilkerson, MD, the Bioinformatics Director at the Collaborative Health Initiative Research Program at the Uniformed Services University, is the paper's co-senior author. To identify and characterize the genetic missteps, researchers analyzed tumor specimens using whole-exome sequencing, mRNA and microRNA sequencing, DNA-methylation arrays, and reverse-phase protein arrays. The four molecularly defined subgroups included: a kinase-signaling subtype, a pseudohypoxia subtype, a cortical admixture subtype, and a Wnt-altered subtype. The last two have been newly classified. The results also provided clinically actionable information by confirming and identifying several molecular markers associated with an increased risk of aggressive and metastatic disease, including germline mutations in SDBH, somatic mutations in ATRX (previously established in a Penn Medicine study), and new gene fusions - a genetic hybrid, of sorts - in MAML3. Because the MAML3 fusion gene activates the Wnt-altered subtype, the authors said, existing targeted therapies that inhibit the beta-catenin and STAT3 pathways may also prove effective in certain PCC/PGL tumors. Other mutations identified in the analysis may also serve as potential targets for drugs currently being investigated in other cancers. For example, glutaminase inhibitors are being tested in SDH-mutant tumors, including breast and lung, and ATR inhibitors are being investigated in blood cancers. Today, there are several U.S. Food and Drug Administration-approved targeted therapies for mutations, such as BRAF and FGFR1, among others, also found in PCC/PGL. "The study gives us the most comprehensive understanding of this disease to date - which we believe will help researchers design better trials and target mutations that will ultimately help improve treatment for these patients," Nathanson said. "The next step is to focus more on aggressive cancers that metastasize and the drivers behind those tumors." Lauren Fishbein, MD, PhD, MTR, a former instructor in the division of Endocrinology, Diabetes and Metabolism at Penn who is now at the University of Colorado Hospital, served as the study's first author. The study was supported with grants by the National Institutes of Health (U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, P30 CA016672). Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


News Article | February 21, 2017
Site: www.eurekalert.org

PHILADELPHIA -- It is commonly known that testosterone levels decrease as men age, but until last year, little was known about the effects of testosterone treatment in older men with low testosterone. Today, in a group of papers published in the Journal of the American Medical Association (JAMA) and JAMA Internal Medicine, researchers found that testosterone treatment improved bone density and anemia for men over 65 with unequivocally low testosterone. However, testosterone treatment did not improve cognitive function, and it increased the amount of plaque buildup in participants' coronary arteries. A team of researchers from the Perelman School of Medicine at the University of Pennsylvania, and twelve other medical centers in the United States, in partnership with the National Institute on Aging, conducted The Testosterone Trials (TTrials), a coordinated group of seven trials, which studied the effects of testosterone treatment for one year as compared to placebo for men 65 and older with low testosterone. The first paper, which reported that testosterone treatment improved sexual function and mood, was published in February 2016. Today's publications of the Bone, Anemia, Cognition and Cardiovascular Trials conclude the primary results of the study. Researchers found that testosterone treatment improved bone density and estimated bone strength, as determined by quantitative computed tomography (CT). The treatment also increased hemoglobin concentrations, corrected the anemia of men who had no other identifiable cause of anemia and corrected the anemia of men who had an identifiable cause, such as iron deficiency. While these conclusions proved testosterone to be beneficial to the participants, testosterone treatment did not improve memory or any other measure of cognitive function. "The paper reporting the results of the first three trials published last year was the first to show there were advantages to giving testosterone treatment to older men with low testosterone levels, and the bone and anemia trial results further support a benefit," said the principal investigator Peter J. Snyder, MD, a professor of Medicine in the Division of Endocrinology, Diabetes and Metabolism. "However, the increase of plaque buildup in the coronary artery shows that this treatment may also have some risk" In the cardiovascular trial, researchers assessed coronary artery plaque buildup by CT angiography. That assessment showed more plaque buildup in men treated with testosterone than in men treated with placebo. Nonetheless, in all 788 men in the TTrials, the number of major adverse cardiovascular events was similar in the men treated with testosterone as in the men treated with placebo. However, Snyder added, "treating 788 men for one year is far too few to draw conclusions about the clinical significance of the increase in coronary artery plaque volume and the cardiovascular risk of testosterone treatment." The TTrials are now the largest trials to examine the efficacy of testosterone treatment in men 65 and older whose testosterone levels are low due seemingly to age alone. TTrials researchers screened 51,085 men to find 790 who qualified with a sufficiently low testosterone level and who met other criteria. The men enrolled were randomized into two groups: one to take a daily testosterone gel and the other a daily placebo gel, for one year. Efficacy was then evaluated at months three, six, nine and 12. "Final decisions about testosterone treatment for older men will depend on balancing the results from these seven TTrials with the results from a much larger and longer term trial designed to assess cardiovascular and prostate risk in the future," said Snyder. The TTrials were conducted at 12 additional medical centers across the country including Albert Einstein College of Medicine, Baylor College of Medicine, Brigham and Women's Hospital, Harbor-UCLA Medical Center, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Puget Sound Health Care System, University of California at San Diego School of Medicine, University of Florida School of Medicine, University of Minnesota School of Medicine, University of Pittsburgh School of Public Health, and Yale School of Medicine. The Testosterone Trials were supported by a grant from the National Institute on Aging (NIA), National Institutes of Health (U01 AG030644). The TTrials were also supplemented by funds from the National Heart, Lung and Blood Institute, National Institute of Neurological Diseases and Stroke, and National Institute of Child Health and Human Development. AbbVie (formerly Solvay and Abbott Laboratories) also provided funding, AndroGel, and placebo gel. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the leading RNAi therapeutics company, today marked the 10th annual Rare Disease Day by underscoring its commitment to enabling diagnosis for people and caregivers impacted by specific rare diseases, such as hereditary ATTR amyloidosis (hATTR amyloidosis). As part of this effort, Alnylam sponsors free third-party genetic counseling and testing through Alnylam Act™ (previously known as Alnylam Assist), a program created to empower patients with the knowledge and tools to make informed decisions about their health and facilitate an early, accurate diagnosis, potentially leading to improved care. The services, currently available in the United States, are provided by independent third parties. hATTR amyloidosis is an inherited, rapidly progressive life-threatening disease impacting 50,0001 people worldwide. It is caused by a mutation in the transthyretin (TTR) gene that results in misfolded TTR proteins accumulating as amyloid fibrils in multiple tissues including the nerves, heart and gastrointestinal tract. The degree and severity of symptoms vary from person to person but can lead to morbidity, disability and mortality within two to 15 years of symptom onset.1,2 “hATTR amyloidosis is significantly under-diagnosed and often misdiagnosed because of its constellation of symptoms that may overlap with other diseases, leading many patients to experience inappropriate medical intervention, such as unnecessary medicine and surgery,” said Sami L. Khella, M.D., Chief, Department of Neurology, Penn Presbyterian Medical Center and Professor of Clinical Neurology, University of Pennsylvania School of Medicine. “For my patients who have symptoms consistent with hATTR amyloidosis, Alnylam Act helps to make an accurate diagnosis.” “As of January 2017 approximately one thousand people have been tested via Alnylam Act, and nearly 16 percent of these tests were positive for a pathogenic mutation in the TTR gene, demonstrating the need to increase awareness and improve diagnosis rates,” said Pritesh Gandhi, Vice President, Medical Affairs at Alnylam. “Alnylam Act is a reflection of our commitment to the hATTR amyloidosis community, and we are proud to make these complimentary third-party services available to the people at risk for, or impacted by, this progressive rare disease.” In addition to genetic testing that can be ordered by a healthcare professional, Alnylam Act allows patients and their families to connect with genetic counselors who provide education and support, serving as an advocate to help guide them through the diagnostic journey. “It can be beneficial to meet with a genetic counselor prior to undergoing testing to understand the benefits and risks involved, including life and health insurance implications and how to work through a diagnosis,” said Shawna Feely, MS, CGC, Genetic Counselor, University of Iowa. “It is our goal to help enable those at risk for hATTR amyloidosis to obtain the answers and support they need to make more informed decisions about their health and the health of their family.” For physicians interested in ordering free hATTR amyloidosis genetic testing for their patients, or for people interested in scheduling a genetic counseling session to discuss the benefits, risks and limitations of genetic testing, visit Alnylam Act. About hATTR Amyloidosis Hereditary ATTR amyloidosis (hATTR amyloidosis) is an inherited, rapidly progressive, life-threatening disease. hATTR amyloidosis is a multisystemic disease with a heterogeneous clinical presentation that includes sensory and motor, autonomic (e.g., diarrhea, erectile dysfunction, hypotension) and cardiac symptoms. hATTR amyloidosis can lead to significant morbidity, disability and mortality within two to 15 years. The disease continuum of hATTR amyloidosis includes patients who present with predominantly polyneuropathy symptoms, historically known as familial amyloidotic polyneuropathy (FAP), as well as patients who present with predominantly cardiomyopathy symptoms, historically known as familial amyloidotic cardiomyopathy (FAC). However, many patients suffer from both polyneuropathy and cardiomyopathy symptoms. hATTR amyloidosis represents a major unmet medical need, affecting approximately 50,000 people worldwide. The only approved treatment options for early stage disease are liver transplantation and tafamidis (approved in Europe, certain countries in Latin America and Japan, where it is approved for all stages of the disease). There is a significant need for novel therapeutics to treat patients with ATTR amyloidosis. About RNAi RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way. About Alnylam Pharmaceuticals Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines. Alnylam's pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs - including 4 in late stages of development - across its 3 STArs. The company's demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Ionis, Novartis, Roche, Takeda, Merck, Monsanto, The Medicines Company, and Sanofi Genzyme. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world's top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information about Alnylam's pipeline of investigational RNAi therapeutics, please visit www.alnylam.com. Alnylam Forward Looking Statements Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, Alnylam's views with respect to the potential for RNAi therapeutics, its expectations regarding its STAr pipeline growth strategy, and its “Alnylam 2020” guidance for the advancement and commercialization of RNAi therapeutics, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation, Alnylam's ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its product candidates, the pre-clinical and clinical results for its product candidates, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates for a specified indication or at all, actions or advice of regulatory agencies, which may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional pre-clinical and/or clinical testing, delays, interruptions or failures in the manufacture and supply of our product candidates, obtaining, maintaining and protecting intellectual property, Alnylam's ability to enforce its intellectual property rights against third parties and defend its patent portfolio against challenges from third parties, obtaining and maintaining regulatory approval, pricing and reimbursement for products, progress in establishing a commercial and ex-United States infrastructure, competition from others using technology similar to Alnylam's and others developing products for similar uses, Alnylam's ability to manage its growth and operating expenses, obtain additional funding to support its business activities, and establish and maintain strategic business alliances and new business initiatives, Alnylam's dependence on third parties for development, manufacture and distribution of products, the outcome of litigation, the risk of government investigations, and unexpected expenditures, as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

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