Would you like to contribute your creativity to an international team of scientists from various disciplines focusing on basic research in the area of molecular life sciences?

The European Molecular Biology Laboratory (EMBL) invites you to apply for PhD positions in Heidelberg, Barcelona, Grenoble, Hamburg, Hinxton (near Cambridge) and Rome. We welcome candidates with diverse backgrounds, such as in Biology, Chemistry, Physics, Mathematics, Computer Science, Engineering and Molecular Medicine.

EMBL provides PhD students with a starting platform for a successful career in science by fostering early independence and interdisciplinary research. The enriching encounter of different nationalities, the friendly and collaborative atmosphere, and the passion for science is what unites EMBL s diverse staff and provides an ideal setting to forge long-lasting connections and make studying at EMBL a formative experience. Our PhD positions are fully funded and offer broad health care and pension benefits.

Full details on how to submit your online application are available here: https://www.embl.org/about/info/embl-international-phd-programme/applica...

The deadline for submitting the application is 19 April 2022.

Recruited candidates would start their work at EMBL latest by mid of October 2022.

For further information, please visit our web page or contact the EMBL Graduate Office (graduate-office@embl.org).

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Exciting PhD positions at the European Molecular Biology Laboratory (EMBL) job with EUROPEAN MOLECULAR BIOLOGY LABORATORY (EMBL) | 288637 - Times...

Basel, April 6, 2022 Novartis today announced that the U.S. Food and Drug Administration (FDA) granted accelerated approval to Vijoice (alpelisib) for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy.1 Vijoice is the first FDA-approved treatment for PROS, a spectrum of rare conditions characterized by overgrowths and blood vessel anomalies impacting an estimated 14 people per million.2,3 In accordance with the Accelerated Approval Program, continued approval may be contingent upon verification and description of clinical benefit from confirmatory evidence.

Todays approval of the first treatment for PROS offers hope for a better quality of life to patients and families affected by these rare conditions, said Kristen Davis, Executive Director of CLOVES Syndrome Community. PROS conditions can be debilitating and disabling and can result in disruptions to everyday activities. Until today, often the only treatment options for patients were surgical or interventional radiology procedures.

PROS conditions can affect quality of life and pose a range of physical, emotional and social challenges for patients and their families, ranging from functional impacts and developmental delays to chronic pain, mobility issues, and feelings of isolation.3-6 PROS management can be challenging, requiring collaboration from a multidisciplinary team, and patients and physicians have only had access to interventions focused on symptom management.6,7

I am proud of this outstanding achievement for the PROS community. The EPIK-P1 study results build on our earlier pre-clinical findings and demonstrate the efficacy of Vijoice for select PROS conditions, effectively reducing PROS growths, said Guillaume Canaud, MD, PhD, Necker-Enfants Malades Hospital AP-HP, the Paris Descartes University, Inserm (INEM Institute Necker Enfants Malades Centre for Molecular Medicine). This is a significant advancement in therapy for PROS with the potential to positively change the treatment trajectory and outcomes for patients.

FDA approval was based on real-world evidence from EPIK-P1, a retrospective chart review study that showed patients treated with Vijoice experienced reduced target lesion volume and improvement in PROS-related symptoms and manifestations. The primary endpoint analysis conducted at week 24 showed 27% of patients (10/37) achieved a confirmed response to treatment, defined as 20% or greater reduction in the sum of PROS target lesion volume. Nearly three in four patients with imaging at baseline and week 24 (74%, 23/31) showed some reduction in target lesion volume, with a mean reduction of 13.7%, and no patients experienced disease progression at time of primary analysis. Additionally, at week 24, investigators observed patient improvements in pain (90%, 20/22), fatigue (76%, 32/42), vascular malformation (79%, 30/38), limb asymmetry (69%, 20/29), and disseminated intravascular coagulation (55%, 16/29). These improvements were observed in subsets of patients across the study population (n=57) who reported symptoms at baseline and at week 24.1,2

The approval of Vijoice marks a turning point for patients who, until now, have not had an approved therapy to specifically address their disease, said Victor Bulto, President, Novartis Innovative Medicines US. We are grateful to the physicians, patients and families who participated in the EPIK-P1 trial. We are continuing to invest in studies to advance the scientific understanding of PROS conditions and to understand the full potential of Vijoice.

In EPIK-P1, the most common adverse events (AEs) of any grade were diarrhea (16%), stomatitis (16%), and hyperglycemia (12%). The most common grade 3/4 AE was cellulitis (4%); one adult case was considered treatment-related.1

Novartis is committed to providing patients with access to medicines, as well as resources and support to address a range of needs. The Novartis Oncology Patient Support Program is available to help guide eligible patients through the various aspects of getting started on treatment, from providing educational information to helping them understand their insurance coverage and identify potential financial assistance options. Patients or providers can call 800-282-7630 or visit Patient.NovartisOncology.com or HCP.Novartis.com/Access to learn more about eligibility and to enroll.

About PIK3CA-Related Overgrowth Spectrum (PROS)The PROS classification was proposed by researchers and parent representatives of patient-family support and advocacy organizations at a National Institutes of Health workshop in 2013 to unite a group of rare overgrowth conditions caused by PIK3CA mutations.4,6Specific conditions associated with PROS include KTS, CLOVES syndrome, ILM, MCAP/MCM, HME, HHML, FIL, FAVA, macrodactyly, muscular HH, FAO, CLAPO syndrome and epidermal nevus, benign lichenoid keratosis, or seborrheic keratosis.4,6The estimated prevalence of PROS conditions is approximately 14 people per million.3

About VijoiceVijoice (alpelisib) is a kinase inhibitor that treats rare overgrowth conditions caused by the effects of PIK3CA mutations in adults and children with PIK3CA-Related Overgrowth Spectrum (PROS). Vijoice works by inhibiting the PI3K pathway, predominantly the PI3K-alpha isoform.1 Vijoice is the first FDA-approved treatment for PROS conditions. Vijoice is not approved for use outside the United States.

FDA approval of Vijoice is based primarily on real-world evidence from the EPIK-P1 study. To further understand the long-term efficacy and safety of alpelisib in PROS, Novartis is conducting additional clinical trials. EPIK-P2 is a prospective Phase II multi-center study with a randomized, double-blind, upfront 16-week placebo-controlled period, and extension period to evaluate the safety, the efficacy and pharmacokinetics of alpelisib to treat pediatrics and adults with PROS. EPIK-P3 is a Phase II study to assess long-term safety and efficacy of alpelisib in people with PROS who participated in EPIK-P1.

DisclaimerThis press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as potential, can, will, plan, may, could, would, expect, anticipate, seek, look forward, believe, committed, investigational, pipeline, launch, or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AGs current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About NovartisNovartis is reimagining medicine to improve and extend peoples lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the worlds top companies investing in research and development. Novartis products reach nearly 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 108,000 people of more than 140 nationalities work at Novartis around the world. Find out more at https://www.novartis.com.

Novartis is on Twitter. Sign up to follow @Novartis at https://twitter.com/novartisnewsFor Novartis multimedia content, please visit https://www.novartis.com/news/media-libraryFor questions about the site or required registration, please contact media.relations@novartis.com

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FDA approves Novartis Vijoice (alpelisib) as first and only treatment for select patients with PIK3CA-Related Overgrowth Spectrum (PROS) -...

SAN ANTONIO (April 5, 2022) In a breakthrough discovery, scientists from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) today reported that inhibiting a liver enzyme in obese mice decreased the rodents appetite, increased energy expenditure in adipose (fat) tissues and resulted in weight loss.

The finding, published in Cell Metabolism, provides a potentially desirable drug target to treat metabolic issues such as obesity and diabetes, the authors said.

We first needed to discover this mechanism and, now that we have, we can develop drugs to improve metabolic syndrome, said senior author Masahiro Morita, PhD, assistant professor of molecular medicine in UT Health San Antonios Sam and Ann Barshop Institute for Longevity and Aging Studies.

We have an enzyme inhibitor that we want to make more specific to increase its effects, said first author Sakie Katsumura, DDS, PhD, postdoctoral fellow in the Morita laboratory.

The liver enzyme, called CNOT6L deadenylase, turns off messenger ribonucleic acids (mRNAs) that ordinarily carry genetic instructions from the nucleus to sites in the cell where two liver proteins are made.

One of the proteins, growth differentiation factor 15 (GDF15), sends signals to two regions of the hindbrain to control food intake. The other, fibroblast growth factor 21(FGF21), sends signals to brown and white adipose tissues to increase energy expenditure. CNOT6L deadenylase impedes mRNA code-carrying for both GDF15 and FGF21, which reduces these benefits.

The researchers first-in-class CNOT6L inhibitor, dubbed iD1, stabilized liver GDF15 and FGF21 mRNAs in obese mice, increasing levels of the two proteins in the blood. After 12 weeks, treated rodents ate 30% less food and exhibited 30% reduced body weight. Energy expenditures in the adipose tissues increased by about 15%. Liver fat decreased 30%.

Mice treated with iD1 showed improved insulin sensitivity and lower blood glucose levels.

In the treatment of metabolic disease, targeting mRNA is a fairly novel concept, said coauthor Nicolas Musi, MD, professor of medicine at UT Health San Antonio and director of the Sam and Ann Barshop Institute. It is a new platform for thinking about how to treat this group of diseases.

In Texas and the U.S., obesity, type 2 diabetes, fatty liver disease and related metabolic disorders are at epidemic proportions.

According to the U.S. Centers for Disease Control and Prevention (CDC), more than 37 million Americans have diabetes. Type 2 diabetes represents at least 90% of the cases. In Texas, approximately 2.7 million people have diagnosed diabetes, and an additional 600,000 people in Texas have diabetes but dont know it. Another 7 million people in Texas have prediabetes.

Obesity prevalence in the U.S. is more than 40% and is climbing, according to the CDC. Obesity-related diseases include heart attack, stroke, type 2 diabetes and some cancers.

These are very serious problems, and any intervention, including drugs, that can treat them are necessary, Dr. Musi said. Dr. Morita and Dr. Katsumura have made a groundbreaking discovery by delineating this mechanism and the proof of concept that a drug that targets this pathway improves all these parameters including glucose levels, glucose tolerance and insulin resistance caused by a high-fat diet and fatty liver.

Their next step, Dr. Katsumura reiterated, is to refine this mechanism and identify new drugs that may be more specific and more potent.

I want to congratulate Dr. Morita and Dr. Katsumura for this fantastic work, Dr. Musi said. It is comprehensive, thorough and paradigm-changing.

The Sam and Ann Barshop Institute, one of the worlds premier centers of aging research, is among more than a dozen institutes, schools and departments that collectively make The University of Texas Health Science Center at San Antonio the preeminent research institution and primary engine of innovation in South Texas.

Dr. Masahiro Moritas work was supported by The University of Texas System Rising STARs Award, Cancer Prevention and Research Institute of Texas (CPRIT) Award (RP220267), Helen F. Kerr Foundation Grant, Shelby Tengg Foundation Grant, Cancer Center Support Grant (P30 CA054174), Grant-in-Aid for Scientific Research (18K07237 and 21K07102), and JST FOREST Program (JPMJFR216D). Dr. Sakie Katsumura was supported by the American Heart Association Postdoctoral Fellowship, JSPS Overseas Research Fellowship and Uehara Memorial Foundation Postdoctoral Fellowship. Dr. Nicolas Musi was supported by the San Antonio Claude D. Pepper Older Americans Independence Center (P30 AG044271) and the San Antonio Nathan Shock Center of Excellence on the Biology of Aging (P30 AG021890), and by grants from the National Institute on Aging (R01-DK80157 and R01-DK089229) and the American Diabetes Association.

Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure

Sakie Katsumura, Nadeem Siddiqui, Michael Rock Goldsmith, Jaime H. Cheah, Teppei Fujikawa, Genki Minegishi, Atsushi Yamagata, Yukako Yabuki, Kaoru Kobayashi, Mikako Shirouzu, Takeshi Inagaki, Tim H.-M. Huang, Nicolas Musi, Ivan Topisirovic, Ola Larsson, Masahiro Morita

First published: April 5, 2022, Cell Metabolism

https://doi.org/10.1016/j.cmet.2022.03.005

The University of Texas Health Science Center at San Antonio(UT Health San Antonio)is the chief catalyst of San Antonios $42.4 billion health care and biosciences sector, the citys largest economic generator. UT Health San Antonio is the largest research university in South Texaswith a research portfolio of approximately $350 million. With its five professional schools, a diverse workforce of 7,200, an annual operating budget of $1 billion and a clinical practice with annual revenues of more than $540 million, UT Health San Antonio is poised to add 1,000 well-paying jobs over the next five years.

Stay connected with The University of Texas Health Science Center at San Antonio onFacebook,Twitter,LinkedIn,InstagramandYouTube.

Experimental study

Animals

Boosting liver mRNAs curbs appetite, body weight in obese mice

5-Apr-2022

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Boosting liver mRNAs curbs appetite, body weight in obese mice - EurekAlert

The festival commemorated the 30 year anniversary of the UC Davis Center for Neuroscience

By ISABELLA KRZESNIAK campus@theaggie.org

On March 12, the UC Davis Center for Neuroscience hosted NeuroFest 2022, a free event where faculty and graduate students shared neuroscience research with the public. The event took place at the UC Davis Conference Center and marked the centers 30-year anniversary. It also coincided with Brain Awareness week, a campaign organized by the Dana Foundation to bring attention to neurological research.

The festival featured four keynote speakers whose respective fields, according to Center for Neuroscience Director Kimberley McCallister, highlighted the strengths of neurological research at UC Davis. The presentations covered neurodevelopmental disorders, mental health issues, memory and brain-computer interfaces.

The event was this really nice community-centered learning opportunity, said Christina Kim, a keynote speaker and an associate professor for neurology. Neuroscience-related faculty gave a really broad overview of their respective fields and what advances weve made in understanding over the past 30 years, how their research is trying to fill in existing gaps and envisioning what the next 30 years are going to look like.

Kims research is centered on imbalances in neurochemicals and neural activity and how these can contribute to mood changes. She prefaced a discussion of her current research with a history of discoveries in pharmacology, as they relate to neuropsychiatric disorders. Kim said she enjoyed presenting to both community members and scientists.

Typically, when you are training to be a scientist, you dont get much practice in giving these kinds of talks where youre speaking to the public and figuring out the best way to distill your research in a way thats understandable and interesting, Kim said. The majority of presentations that we normally give are geared more toward purely scientific audiences, so its a big change to give a public talk.

David Segal, a keynote speaker and a professor of biochemistry and molecular medicine, spoke about his work with gene therapy and treating rare neurological diseases such as Angelman Syndrome, which results in a host of cognitive impairments and communication issues. Despite the relative infrequency of a given rare disease, these diseases as a whole affect more people than cancer and AIDS combined, according to Segal.

The government cant fund research for these rare diseases and companies arent as interested in trying to develop therapies for this, so I think theres an important role for an academic center for interventional genetics that we put together here at UC Davis, Segal said.

The festival also offered interactive booths organized by graduate students for attendees to learn about neurobiology. The booths, which were available throughout the event, featured activities that ranged from monitoring ones brain activity to observing neurons on a microscopic level.

The event also featured NeuroBlitz, a competition where graduate students presented their research and audience members voted for the best presentation.

NeuroBlitz challenges our graduate students to sum up their research in a succinct talk, similar to an elevator pitch, that is geared toward a general audience, Kostas Zarbalis, an associate professor of pathology and laboratory medicine who worked with the contestants, said.

Neuroscientists were also invited to submit art that represents their research. The NeuroFest Committee selected the eight best submissions, displayed them at the event and invited attendees to vote for their three favorites.

The NeuroFest concept is really unique, and its not something that I had an opportunity to participate in at any other institution Ive been at, Kim said. Other universities dont really have this kind of openness, and I appreciate this blend between Davis community members and Davis researchers.

Written by: Isabella Krzesniak campus@theaggie.org

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NeuroFest celebrates 30 years of neurological research at UC Davis - The Aggie - The Aggie

4D Molecular Therapeutics, Inc.

EMERYVILLE, Calif., April 04, 2022 (GLOBE NEWSWIRE) -- 4D Molecular Therapeutics, Inc. (4DMT) (Nasdaq: FDMT), a clinical-stage biotherapeutics company harnessing the power of directed evolution for targeted genetic medicines, announced that the first patient has been dosed in its Phase 1/2 clinical trial of 4D-710 in patients with cystic fibrosis.

The dosing of the first patient in the 4D-710 Phase 1/2 clinical trial in cystic fibrosis marks an important milestone for our company and for the patients we aim to benefit, said Robert Fishman, M.D., Chief Medical Officer and Pulmonology Therapeutic Area Head of 4DMT. 4D-710 utilizes the aerosol-delivered A101 vector developed at 4DMT through our proprietary Therapeutic Vector Evolution platform. To date, our platform has produced five clinical-stage product candidates that incorporate three different proprietary and novel capsids. We are seeking to unlock the full potential of genetic medicines through our platform and to fulfill the promise of transformative biotherapeutics to benefit patients.

4D-710 is designed for aerosol delivery to achieve CFTR expression within lung airway epithelial cells, said Jennifer L. Taylor-Cousar, M.D., M.S.C.S, Professor of Medicine and Pediatrics at National Jewish Health and lead principal investigator for the Phase 1/2 clinical trial. This therapy has the potential to treat a broad range of people with cystic fibrosis independent of their specific CFTR mutations. It could benefit both people with cystic fibrosis who arent able to take CFTR modulators as well as those who have a substantial residual deficit in lung function in spite of modulator therapy.

The Phase 1/2 clinical trial is a multicenter, open-label, dose-escalation and dose-expansion trial of 4D-710 in patients (n=~18) with cystic fibrosis who are ineligible for CFTR modulator therapy or who have discontinued therapy due to adverse effects. In the dose-escalation phase, two dose levels of 4D-710 will be examined in a 3+3 design. The primary endpoint of the study is safety and tolerability. Secondary endpoints include assessments of clinical activity including lung function, plus exploratory endpoints on the feasibility of detecting transgene transfer and microCFTR expression as measured in bronchoscopic biopsies and brushings.

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About 4D-710 and Cystic Fibrosis

4D-710 is comprised of our targeted and evolved vector, A101, and a codon-optimized microCFTR transgene. 4D-710 has the potential to treat a broad range of patients with cystic fibrosis, independent of the specific CFTR mutation, and is designed for aerosol delivery to achieve CFTR expression within lung airway epithelial cells. 4D-710 is being initially developed in the approximately 10-15% of patients whose disease is not amenable to existing medicines targeting the CFTR protein. In patients with CFTR mutations whose disease is amenable to modulator medicines, the improvement in lung function is variable. We therefore expect to potentially develop 4D-710 in this broader patient population, as a single agent and/or in combination with these CFTR modulator small molecule medicines.

Cystic fibrosis is a major inherited disease caused by mutations in the CFTR gene. According to the CF Foundation, more than 30,000 people in the United States and more than 70,000 people worldwide are living with cystic fibrosis, with approximately 1,000 new cases of cystic fibrosis diagnosed in the United States each year. Cystic fibrosis is a multisystem disorder affecting the lungs, digestive system and reproductive tract. Lung disease is the leading cause of morbidity and mortality. Cystic fibrosis causes impaired lung function, inflammation and bronchiectasis and is commonly associated with persistent lung infections and repeated exacerbations due to the inability to clear thickened mucus from the lungs. Patients with cystic fibrosis require lifelong treatment with multiple daily medications. These complications result in progressive loss of lung function and hospitalizations, and ultimately lead to end-stage respiratory failure.

About 4DMT

4DMT is a clinical-stage company harnessing the power of directed evolution for targeted genetic medicines. 4DMT seeks to unlock the full potential of gene therapy using its platform, Therapeutic Vector Evolution, which combines the power of directed evolution with approximately one billion synthetic capsid sequences to invent evolved vectors for use in targeted genetic medicine products. The company is initially focused on five clinical-stage products in three therapeutic areas: ophthalmology, cardiology (including Fabry disease) and pulmonology. The 4DMT targeted and evolved vectors are invented with the goal of being delivered through clinically routine, well-tolerated and minimally invasive routes of administration, transducing diseased cells in target tissues efficiently, having reduced immunogenicity and, where relevant, having resistance to pre-existing antibodies. The five 4DMT product candidates in clinical development are: 4D-310 for Fabry disease, 4D-150 for wet AMD, 4D-125 for XLRP, 4D-110 for choroideremia and 4D-710 for cystic fibrosis.

4D-310, 4D-150, 4D-125, 4D-110 and 4D-710 are in clinical trials and have not yet been approved for marketing by the US FDA or any other regulatory authority. No representation is made as to the safety or effectiveness of 4D-310, 4D-150, 4D-125, 4D-110 or 4D-710 for the therapeutic use for which they are being studied. 4D Molecular Therapeutics, 4DMT, Therapeutic Vector Evolution, and the 4DMT logo are trademarks of 4DMT.

Cautionary Note Regarding Forward Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended (Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended. In some cases, you can identify forward-looking statements by terminology such as aim, anticipate, assume, believe, contemplate, continue, could, design, due, estimate, expect, goal, intend, may, objective, plan, positioned, potential, predict, seek, should, target, will, would and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. All statements other than statements of historical facts contained in this press release are forward-looking statements. These forward-looking statements include, but are not limited to, statements about 4D-710s potential as a therapeutic product, including its potential to effectively treat a broad range of patients with cystic fibrosis independent of their specific CFTR mutations and the companys plans for developing 4D-710. Forward-looking statements are not guarantees of future performance and are subject to risks and uncertainties that could cause actual results and events to differ materially from those anticipated, including, but not limited to, risks and uncertainties related to: the companys history of net operating losses and limited operating history; the companys ability to obtain necessary capital to fund its clinical programs; the risk and uncertainties inherent in the clinical drug development process; the early stages of clinical development of the companys product candidates and the limited regulatory and clinical experience to date for novel AAV gene therapy product candidates; the effects of COVID-19 or other public health crises on the companys clinical programs and business operations; the companys ability to obtain regulatory approval of and successfully commercialize its product candidates; any undesirable side effects or other properties of the companys product candidates; the companys reliance on third-party suppliers and other service providers; the outcomes of any current or future collaboration and license agreements; and the companys ability to adequately maintain intellectual property rights for its product candidates. These and other risks are described in greater detail under the section titled Risk Factors contained in the companys most recent Annual Report on Form 10-K filed as of March 28, 2022, as well as any subsequent filings with the Securities and Exchange Commission . Any forward-looking statements that the company makes in this press release are made pursuant to the Private Securities Litigation Reform Act of 1995, as amended, and speak only as of the date of this press release. Except as required by law, the company undertakes no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise.

Contacts:

Media:

Ingrid MezoCanale Communicationsingrid.mezo@canalecomm.com

Investors:

Mike ZanoniVP, Investor Relationsmzanoni@4dmt.com

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4D Molecular Therapeutics Announces First Patient Dosed in Phase 1/2 Clinical Trial of 4D-710, an A101 AAV Vector-based, Aerosol-delivered Genetic...

In the presence of pancreatic tumors, certain immune cells break down structural proteins into molecules that trigger the building of dense tissue, a known barrier to therapy, a new study finds.

Led by researchers from NYU Grossman School of Medicine, the study revolves around the dense protein meshwork that supports organs and helps to rebuild damaged tissue. Collagen protein fibers, the major component of the mesh, are continually broken down and replaced to maintain tensile strength, and as part of the wound-healing process.

Past studies had shown that immune cells called macrophages contribute to a process called desmoplasia, which is caused by the abnormal turnover and excessive deposition of collagen that insulates pancreatic cancer. In this environment, macrophages are also known to engulf and break down collagen through the action of a protein called the mannose receptor (MRC1).

Published online April 4 in the Proceedings of the National Academies of Sciences, the current study found that the degraded collagen increased the amount of arginine, an amino acid that is used by the enzyme nitric oxide synthase (iNOS) to produce compounds called reactive nitrogen species (RNS). This, in turn, caused neighboring, supportive stellate cells to build collagen-based meshes around tumors, say the study authors.

Our results revealed how pancreatic tumors program macrophages to contribute to the construction of fibrotic barriers, says first study author Madeleine LaRue, PhD. At the time of the study, Dr. LaRue was a graduate student in the lab of senior study author Dafna Bar-Sagi, PhD, the Saul J. Farber Professor of Biochemistry and Molecular Pharmacology and vice dean for science at NYU Langone Health. This molecular framework could be harnessed to counter pro-cancer changes in structural tissues surrounding tumors, adds Dr. LaRue.

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States, with a 5-year survival rate of 10 percent. Pancreatic cancer remains difficult to treat in large part due to the extensive network of fibrotic tissue around tumors. This network not only blocks access by therapies, but also promotes aggressive growth.

For the current study, experiments showed that macrophages grown in dishes of nutrients (cultures), and converted into their cancer-tolerant setting (M2), broke down far more collagen than macrophages that attack cancer cells (M1). Further, the team confirmed with a series of tests that M2 macrophages have higher levels of enzymes that generate RNS, such as iNOS.

To confirm these findings in live mice, the team implanted stellate cells that were either pre-fed with collagen, or maintained in an unfed state, into the flanks of the study animals along with pancreatic cancer cells. The team observed a 100 percent increase in the density of intra-tumoral collagen fibers in tumors derived from cancer cells co-implanted with stellate cells pretreated with collagen.

Importantly, the study showed for the first time that macrophages near pancreatic cancer cells, not only take in and break down more collagen as part of scavenging for proteins that feed abnormal growth, but also are changed by the scavenging, such that their energy processing system (metabolism) is rewired and signals for fibrotic buildup.

Our team uncovered a mechanism that connects collagen turnover to the building of a treatment-resistant environment around pancreatic tumors, says Dr. Bar-Sagi. As this dense environment is a major reason why pancreatic cancer is so deadly, a better understanding of links between protein scavenging and the building of protective barriers will be needed to improve the treatment of this devastating malignancy.

Along with Dr. Bar-Sagi and Dr. LaRue, study authors from the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health were Seth Parker and Joseph Puccini. Other authors were Alec Kimmelman, MD, PhD, chair of the Department of Radiation Oncology and a clinician and researcher at NYU Langones Perlmutter Cancer Center, and Michael Cammer of the Microscopy Laboratory, Division of Advanced Research Technologies, at NYU Grossman School of Medicine. The study was funded by National Institutes of Health grants T32GM066704, CA210263, P01CA117969, and CA232124, as well as by the Lustgarten Foundation and Stand Up To Cancer (SU2C).

Dr. Kimmelman has financial interests in Vescor Therapeutics, and is listed on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach, and the autophagy control of iron metabolism. Dr. Kimmelman is on the scientific advisory board for Rafael/Cornerstone Pharmaceuticals, and consults for Deciphera and AbbVie. Dr. Bar-Sagi is on the Scientific Advisory Board of Rafael/Cornerstone Pharmaceuticals and Samumed LLC, and is also on the board of the Pancreatic Cancer Action Network. These relationships are being managed in keeping with the policies of NYU Langone Health.

Greg WilliamsPhone: 212-404-3500gregory.williams@nyulangone.org

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Pancreatic Cancer Cells Harness Tissue Turnover to Build Protective Barriers - NYU Langone Health

If the blood supply to your brain decreases, it can trigger Alzheimers disease. Scientists at UiO wanted to find out whether this leads to more or fewer blood vessels and what role one particular protein plays in such a process.

About 100,000 Norwegians suffer from dementia. Many of them have Alzheimers. The blood flow in the brain changes with Alzheimers disease.

"Nerve cells are destroyed and this must have something to do with the blood supply. Blood carries both oxygen and nutrients to the cells. The disease begins to develop long before patients get any symptoms - changes occur over 10 to 12 years before you notice that anything is wrong," explains researcher and Associate Professor Reidun Torp at the Institute of Basic Medical Sciences.

She is interested in what is called senile plaques in the brain and how the brain rids itself of them. Plaque is a form of waste matter that comes from incorrectly produced proteins that build up as deposits in the brain.

"The essential key to discovering how to prevent Alzheimers disease is to find out how the brain handles this plaque before it is too late," she says.

Torp and other researchers at the Department of Molecular Medicine have tried for many years to solve the puzzle of the various changes that occur in the brain. Their research represents stepping-stones on the way towards treating Alzheimers or preventing the disease.

One of the things Torp has studied is how particular proteinaceous fibres twist around each other in tangles and destroy brain cells.

"With Alzheimers, there is a connection between these two processes: the fibres that twist around each other and the senile plaque, which together result in the destruction of nerve tissue in the brain. They block the communication between nerve cells and disrupt the processes that nerve cells need to survive. We know a good deal about these two processes but this isnt much help if we cant stop it happening in the brain," she says.

Earlier research has shown that several of the same risk factors behind the development of cardiovascular disease also can lead to Alzheimers. In order to see the connection between the disease and the blood supply to the brain, the researchers wanted to find out whether the density of small blood vessels in the brain decreases, increases or remains unchanged in a patient with Alzheimers.

Her research team recentlypublished an article in the Journal of Alzheimers Disease.

Two of the methods used by the researchers were various microscopy techniques and biochemical analyses. Research fellow Gry Syverstad Skaaraas is the lead author of the study.

"We found that the density of blood vessels was unchanged in mice that had a lot of senile plaque, compared to mice without plaque," she says.

"What we found instead was that the protein deposits from the plaque affected the walls of the blood vessels and changed their growth factors, which would indicate that the vessels no longer function as they should.

Growth factors are proteins that break down and form new blood vessels in the brain. We believe that it is this process that is disrupted in Alzheimers disease," says Torp.

According to the researchers, the study led to several new discoveries. One was that a type of cells called pericytes are destroyed by senile plaques in the blood vessels. Pericytes lie partly round the smallest blood vessels, allowing these to contract and regulate the blood stream in the brain.

Torp points out that a great deal of research is being carried out into Alzheimers and she can see a lot of positive signs.

"I think we are at a turning point towards finding a better treatment," she says.

Reference: Skaaraas GHES, Melbye C, Puchades MA, et al. Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimers Disease Associates with Upregulated Angiopoietin and Downregulated Hypoxia-Inducible Factor. Journal of Alzheimers Disease. 2021;83(4):1651-1663. doi:10.3233/JAD-210571

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How Alzheimer's Disease Changes Small Blood Vessels in the Brain - Technology Networks

This story has been updated to include additional comments from Robert Green.

NEW YORK BabySeq, the next-generation sequencing-based universal screening program for newborns, is gearing up for a second, expanded study. The lead researchers said they want the four-year, $5.1 million grant to help address a lack of diversity in the first cohort.

The originalBabySeq cohort was not diverse and thus the findings are not generalizable, according to the project's co-principal investigators Robert Green of Brigham and Women's Hospital and Ingrid Holm of Boston Children's Hospital.

"They were pretty overwhelmingly wealthier people and of European ancestries," Green said. Holm added that in phase two, they're hoping to recruit more than half of the participants from African American or Hispanic families.

The grant, funded mostly by the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health, will help sequence 500 babies and their families at three clinics in the Eastern US. Whereas the first phase of BabySeq was conducted in a hospital setting, phase two will move to enroll participants in community clinics in Boston, New York, and Birmingham, Alabama. The program has partnered with Mount Sinai and the University of Alabama-Birmingham to enroll participants and will work with researchers at Baylor University on surveys and outcomes analysis. The Laboratory for Molecular Medicine will perform sequencing.

The new project will feature two other changes. The children will be a little older, up to 6 months in age, and they will receive whole-genome sequencing, rather than whole-exome sequencing.

"Primarily, [WGS] means that we can look for copy number variants," Holm said.

While some bioethicists have been skeptical of universal newborn screening with NGS, Green and Holm suggested that the case for it isgaining strength.

"There is a whole revolution occurring in terms of gene targeted therapies," Green said, with a handful already and a hundred more in development. "These are rare diseases, most of which the risk can be detected with early sequencing."

"It's a really strong team," said Josephine Johnston, a bioethicist and director of research at the Hastings Center who was first author on a 2018 report critical of universalnewborn sequencing. "If there is benefit to be had, if this project could be helpful to primary pediatric care, these people will find it because they are really enthusiastic about it and they're good researchers."

"My overall take on the first study was they had low enrollment and quite modest findings," she said. "But they still got another big grant, so they're going to try it in a different context."

Launched in 2013, BabySeq phase one wrapped up in 2019. The project produced more than 20 peer-reviewed papers and the researchers felt that their randomized controlled trial helped ease fears that newborn screening would have deleterious psychological effects on parents. In a paper published in September in JAMA Pediatrics, the BabySeq team suggested that there was no signal of increased anxiety or distress and no disruption in parent-child bonding, between the two arms of the study (the control group received a standard heel prick newborn screening test).

In other publicationsthey revealed that 18 infants, or 11 percent of the sequenced newborns, harbored a variant associated with risk of a childhood-onset disorder. In some cases, these variants helped explain phenotypic observations already made. The original BabySeq study curated a list of approximately 1,000 disease-associated genes to return results for.

"Based on these exciting data, we wrote several follow-up grants that were not funded," Holm said. One was an application for a follow-up study, submitted to the Eunice Kennedy Shriver National Institute of Child Health and Human Development as part of an RFA. "It just wasn't innovative enough, for whatever reason," she said.

With their new funding, researchers are seeking to correct their earlier lapse by emphasizing community pediatric clinics. "This is a big issue in genomics, across every research domain and all over precision medicine," Green said. "It's partly access to care, which is exacerbated for all the reasons we're aware of: historical injustice, distrust, and failures of many research projects to make themselves culturally relevant. We are just trying our best to make sure BabySeq 2 does a better job of that."

They have also established a stakeholder board "that really represent perspectives from diverse sources that are helping with protocol design, education, and so forth," Holm said.

Moving to a community-based clinic may also help increase the participation rate, Johnston said. "BabySeq 1 did not get anything like the level of uptake that they were expecting," she said. "One of the possible explanations was because they were asking people who had just given birth. My thought is that they're hoping they'll get much higher enrollment if they do it in a primary care context."

Using whole-genome sequencing could lead to finding more newborns with risk-associated genetic variants. "My guess is that we'll find some, but I don't think it's going to increase to 20 percent [from 11 percent]," Holm said. Many variants could be of unknown significance, which the study will not return to patients.

Another rationale for expanding BabySeq relates to newly available treatments for rare diseases. The recommended uniform screening panel (RUSP) the list of conditions that the US Department of Health and Human Services recommends for states to screen for is "not keeping up with treatable genetic conditions," Green said. According to him, there are more than 800 treatablechildhood genetic conditions,while the RUSP currently has 35 (some states test for more conditions.)

Green said he believes that earlier critiques of the study's premise, including Johnston's were "written without appreciation of the flood of new treatments being developed, which completely changes the medical and ethical equation."

"There's just so much more going on now in ability to do genetic treatments that to put them all on the RUSP, you've got to have the exome. That's a big motivation, and thats why studies like this are timely," he said.

The researchers have not started recruiting yet but received conditional approval from their institutional review board late last month. "It's a big step," Green said. "It took us much, much longer the first time."

They're even looking toward bringing in partners with their own funding to increase the cohort size beyond what the new grant will support. "It would be nice to have several thousand [participants]," Holm said.

"The ultimate goal is to have a much larger group because we have a better chance of finding those n-of-ones," she said.

Link:
BabySeq Newborn Screening Project Aims For Increased Diversity in Second Phase - GenomeWeb