Category Archives: Genetic medicine

Copenhagen, Denmark 4 April 2022: When should patients and family members undergo genetic assessment for a heart condition? Find out in an international consensus document published in EP Europace,1 a journal of the European Society of Cardiology (ESC) and presented at EHRA 2022,2 a scientific congress of the ESC.

This is now the reference document that all clinicians should use to decide whether genetic testing is indicated for patients with inherited cardiac diseases and their relatives, said lead author Professor Arthur Wilde of the Academic Medical Centre, Amsterdam University Medical Centres, the Netherlands. We provide strict criteria on who should be assessed and recommend which genes should beexamined.

The aim of genetic testing in patients with an inherited cardiac disease is to determine the cause. In some conditions this helps clinicians make a precise diagnosis, provides information about prognosis, and determines the treatment. For example in long QT syndrome, which is potentially lethal but treatable, a normal electrocardiogram (ECG) does not exclude the condition and genetic testing is required to clarify the diagnosis. The specific genetic variant impacts both prognosis and therapeutic choices.

Once a genetic cause is identified in the patient, family members, including children, can be screened. The document outlines in which conditions relatives should receiving genetic testing. In long QT syndrome, for example, family members should be tested. Many of these conditions start with a cardiac arrest in a young individual who dies or almost dies, said Professor Wilde. The way to avoid that happening in a family members is by genetic testing in conjunction with clinical screening. Those who are affected can be treated, for example with medications or with a defibrillator to correct a fatal heart rhythm, and those who are unaffected can be reassured.

Genetic counselling is essential and should start even before clinical and genetic testing are performed. A diagnosis can be life-changing as it may provoke significant anxiety or aggressive treatment, states the document. Professor Wilde said that the consequences of a positive diagnosis should be explained before any examinations. For instance, if an individual has no symptoms but his or her sibling has a serious inherited cardiac disease, the first question should be do you want to know whether you have this condition, yes or no?, he said. A diagnosis may trigger difficulties with insurance, getting a mortgage, and so on. He or she needs to be informed before making any decisions.

The paper provides recommendations on genetic testing for four groups of heart conditions caused by genetic defects: inherited arrhythmia syndromes, cardiomyopathies, sudden cardiac death or survivors of unexplained cardiac arrest, and congenital heart disease. The most common of these is hypertrophic cardiomyopathy, which affects at least one in 500 individuals.

The chapter on congenital heart disease also provides detailed advice on genetic testing in pregnant women and offspring. Professor Wilde said: This is a rapidly moving field and genetic testing is recommended for conditions in which there is a high likelihood of identifying the cause. As for all genetic cardiac conditions, testing for congenital heart defects should be coordinated by cardiologists and clinical genetics specialists with support from genetic counsellors.

In addition to conditions caused by single genetic defects, the authors describe how genetics can play a role in the manifestation of more common heart conditions such as coronary artery disease and heart failure. Professor Wilde explained: These conditions are not caused by one genetic variant but in some patients there is a genetic component. Researchers are investigating how the combination of frequently occurring genetic variants may cause or influence susceptibility to disease. This is an emerging field and it is too early to make recommendations.

The international consensus statement on genetic testing for cardiac diseases was developed by the European Heart Rhythm Association (EHRA), a branch of the ESC; the Heart Rhythm Society (HRS); the Asia Pacific Heart Rhythm Society (APHRS); and the Latin American Heart Rhythm Society (LAHRS).3 It is also published in Heart Rhythm, the official journal of the HRS, Journal of Arrhythmia, the official journal of the APHRS, and Journal of Interventional Cardiac Electrophysiology, the official journal of the LAHRS.

ENDS

Authors: ESC Press Office

Mobile: +33 (0)7 8531 2036Email: press@escardio.org

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Notes to editor

Funding: None.

Disclosures: Please see the supplementary material online.

References and notes

1Wilde A, Semsarian C, Mrquez MF, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus statement on state of genetic testing for cardiac diseases. EP Europace. 2022. doi:10.1093/europace/euac030.

2The paper will be presented during the session Expert consensus statement on state of genetic testing for cardiac diseases on 4 April at 14:05 to 15:05 CEST in Room 1.

3Preparation of the document was led by: Arthur Wilde (EHRA Chair), Elizabeth Kaufman (HRS Co-Chair), Christopher Semsarian (APHRS Co-Chair) and Manlio F Mrquez (LAHRS Co-Chair).

About the European Heart Rhythm Association

The European Heart Rhythm Association (EHRA) is a branch of the European Society of Cardiology (ESC). Its aim is to improve patients quality of life and reduce sudden cardiac death by limiting the impact of heart rhythm disturbances.

About the EHRA Congress #EHRA2022

EHRA 2022 is the annual congress of the European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC).

About the European Society of Cardiology

The European Society of Cardiology brings together health care professionals from more than 150 countries, working to advance cardiovascular medicine and help people lead longer, healthier lives.

About the Heart Rhythm Society

The Heart Rhythm Society (HRS) is the international leader in science, education, and advocacy for cardiac arrhythmia professionals and patients, and the primary information resource on heart rhythm disorders. Its mission is to improve the care of patients by promoting research, education, and optimal health care policies and standards. Incorporated in 1979 and based in Washington, DC, it has a membership of more than 7,000 heart rhythm professionals in more than 90 countries around the world. For more information, visitwww.HRSonline.org.

About the Asia Pacific Heart Rhythm Society

The Asia Pacific Heart Rhythm Society (APHRS) is the international organisation specialising in science and education for cardiac arrhythmia professionals. For members, the society regularly offers various educational programmes at the state-of-the-art laboratories with excellent lectures. For more information, visit http://www.aphrs.org.

About the Latin American Heart RhythmSociety

TheLatin American Heart RhythmSociety (LAHRS) was founded in 2017 with the aim of continuing the mission started by Sociedad Latinoamericana de Estimulacin Cardaca y Electrofisiologa (SOLAECE) morethan twenty years ago, promoting the improvement of the quality of life and reducing mortality related to cardiac arrhythmias in the Latin American population. For more information, visithttp://www.lahrs.org.

Information for journalists about registration for EHRA 2022

EHRA 2022 takes 3 to 5 April at the Bella Center in Copenhagen, Denmark and online. Explore the scientific programme.

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Recommendations on genetic testing for inherited cardiac diseases published today - EurekAlert

INDIANAPOLIS, April 1, 2022 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced updated data from the Phase 1/2 LIBRETTO-001 trial of Retevmo (selpercatinib 40 mg & 80 mg capsules) in patients with RET fusion-positive non-small cell lung cancer (NSCLC). Retevmo (marketed as Retsevmo outside of the U.S.) is a selective and potent RET kinase inhibitor that is approved in multiple countries including the United States for treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive NSCLC, and the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, or advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). These data were presented at the European Lung Cancer (ELCC) 2022 (poster 27p).

"The LIBRETTO trial provides the largest set of clinical data for a RET inhibitor and these results continue to demonstrate evidence of meaningful clinical outcomes for patients with metastatic RET fusion-positive NSCLC treated with Retevmo, including those with difficult-to-treat brain metastases," said David Hyman, M.D. chief medical officer, oncology at Lilly. "We are continuing to build on the robust body of evidence supporting Retevmo, including through an ongoing randomized Phase 3 confirmatory study, with a planned readout in 2023."

The updated analysis utilized a June 15, 2021, data cut-off and included 355 patients who were eligible for efficacy analysis, 247 of which were previously treated with at least one line of platinum chemotherapy and 69 of which were treatment-nave. Patients who were previously treated with at least one line of platinum chemotherapy received a median of two prior treatment regimens (range: 1-15), with 58% having received anti-PD-1 or anti-PD-L1 therapy. Responses are based on independent review committee (IRC) assessment.

Among 247 patients previously treated with platinum chemotherapy, the confirmed objective response rate (ORR) was 61.1% (95% CI: 54.7-67.2%) and among 69 treatment-nave patients, the confirmed ORR was 84.1% (95% CI: 73.3-91.8%). Twenty-six patients had measurable central nervous system (CNS) metastases at baseline and treatment with Retevmo resulted in a CNS ORR of 84.6%, with 22 patients having a confirmed best response of complete response or partial response.

At a median follow-up of approximately two years in both the treatment-nave and platinum-chemotherapy pretreated populations, median duration of response (DoR) is estimated at 20.2 (55.2% censoring rate; 20.3 months median duration of follow-up) and 28.6 (60.9% censoring rate; 21.2 months median duration of follow-up) months, respectively and median progression free survival (PFS) is estimated at 22.0 (53.6% censoring rate; 21.9 months median duration of follow-up) and 24.9 (55.9% censoring rate; 24.7 months median duration of follow-up) months, respectively. Of the 26 patients with measurable CNS disease, Retevmo treatment resulted in a median intracranial PFS of 19.4 months. These median estimates remain immature.

Safety among patients in this cohort was consistent with the known safety profile of Retevmo. In the safety population (all NSCLC patients that received at least one dose of Retevmo, N=356), the most common adverse events (AEs in 25% of patients) were dry mouth, diarrhea, hypertension, increased ALT/AST, peripheral edema, constipation, rash, headache, and fatigue. Thirty-four patients discontinued due to an adverse event (10%), eleven (3%) of which were deemed related to Retevmo.

A global, randomized, Phase 3 trial is currently recruiting and will compare treatment with Retevmo to the current standard of care in the first-line treatment of advanced or metastatic RET fusion-positive NSCLC.

Retevmo was the first RET inhibitor to receive Accelerated Approval from the U.S. Food and Drug Administration (FDA) in May 2020 and was the first approved by the European Commission in February 2021. Retevmo was approved under the FDA's Accelerated Approval regulations based on the LIBRETTO-001 Phase 1/2 trial's endpoints of objective response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

About LIBRETTO-001

The Phase 1/2 LIBRETTO-001 trial is the largest clinical trial of patients with RET-driven cancers treated with a RET inhibitor. The trial, which spans 16 countries and 89 sites,included a dose escalation phase (Phase 1) and a dose expansion phase (Phase 2). The primary objective was to determine ORR by independent review committee (IRC) and key secondary objectives included DoR, CNS ORR & DOR, safety and PFS.

LIBRETTO-001 continues to enroll patients with RET-altered tumors beyond lung cancer.

AboutRetevmo(selpercatinib)

Retevmo (selpercatinib, formerly known as LOXO-292) (pronounced ret- tv-mo) is a selective and potent RET kinase inhibitor. Retevmo may affect both tumor cells and healthy cells, which can result in side effects. RET-driver alterations are predominantly mutually exclusive from other oncogenic drivers. Retevmo is an U.S. FDA-approved oral prescription medicine, 120 mg or 160 mg dependent on weight (<50 kg or 50 kg, respectively), taken twice daily until disease progression or unacceptable toxicity. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION FOR RETEVMO(selpercatinib)

Hepatotoxicity: Serious hepatic adverse reactions occurred in 2.6% of patients treated with Retevmo. Increased aspartate aminotransferase (AST) occurred in 51% of patients, including Grade 3 or 4 events in 8% and increased alanine aminotransferase (ALT) occurred in 45% of patients, including Grade 3 or 4 events in 9%. The median time to first onset for increased AST was 4.1 weeks (range: 5 days to 2 years) and increased ALT was 4.1 weeks (range: 6 days to 1.5 years). Monitor ALT and AST prior to initiating Retevmo, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Retevmo based on the severity.

Hypertensionoccurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate Retevmo in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Retevmo. Monitor blood pressure after 1 week, at least monthly thereafter, and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Retevmo based on the severity.

Retevmo can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients. Retevmo has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia and hypocalcemia prior to initiating Retevmo and during treatment. Monitor the QT interval more frequently when Retevmo is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue Retevmo based on the severity.

Serious, including fatal, hemorrhagic events can occur with Retevmo. Grade 3 hemorrhagic events occurred in 2.3% of patients treated with Retevmo including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis. Permanently discontinue Retevmo in patients with severe or life-threatening hemorrhage.

Hypersensitivityoccurred in 4.3% of patients receiving Retevmo, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range 6 days to 1.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. If hypersensitivity occurs, withhold Retevmo and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume Retevmo at a reduced dose and increase the dose of Retevmo by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. Permanently discontinue Retevmo for recurrent hypersensitivity.

Tumor lysis syndrome (TLS)occurred in 1% of patients with medullary thyroid carcinoma receiving Retevmo. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

Impaired wound healingcan occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Retevmo has the potential to adversely affect wound healing. Withhold Retevmo for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Retevmo after resolution of wound healing complications has not been established.

Based on data from animal reproduction studies and its mechanism of action, Retevmo can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for at least 1 week after the final dose. There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Retevmo and for 1 week after the final dose.

Severe adverse reactions (Grade 3-4) occurring in 15% of patients who received Retevmo in LIBRETTO-001, were hypertension (18%), prolonged QT interval (4%), diarrhea (3.4%), dyspnea (2.3%), fatigue (2%), abdominal pain (1.9%), hemorrhage (1.9%), headache (1.4%), rash (0.7%), constipation (0.6%), nausea (0.6%), vomiting (0.3%), and edema (0.3%).

Serious adverse reactionsoccurred in 33% of patients who received Retevmo. The most frequently reported serious adverse reaction (in 2% of patients) was pneumonia.

Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in >1 patient included sepsis (n=3), cardiac arrest (n=3) and respiratory failure (n=3).

Common adverse reactions (all grades) occurring in 15% of patients who received Retevmo in LIBRETTO-001, were dry mouth (39%), diarrhea (37%), hypertension (35%), fatigue (35%), edema (35%), rash (27%), constipation (25%), nausea (23%), abdominal pain (23%), headache (23%), cough (18%), prolonged QT interval (17%), dyspnea (16%), vomiting (15%), and hemorrhage (15%).

Laboratory abnormalities (all grades; Grade 3-4) 20% worsening from baseline in patients who received Retevmo in LIBRETTO-001, were AST increased (51%; 8%), ALT increased (45%; 9%), increased glucose (44%; 2.2%), decreased leukocytes (43%; 1.6%), decreased albumin (42%; 0.7%), decreased calcium (41%; 3.8%), increased creatinine (37%; 1.0%), increased alkaline phosphatase (36%; 2.3%), decreased platelets (33%; 2.7%), increased total cholesterol (31%; 0.1%), decreased sodium (27%; 7%), decreased magnesium (24%; 0.6%), increased potassium (24%; 1.2%), increased bilirubin (23%; 2.0%), and decreased glucose (22%; 0.7%).

Concomitant use of acid-reducing agents decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid concomitant use of proton-pump inhibitors (PPIs), histamine-2 (H2) receptor antagonists, and locally-acting antacids with Retevmo. If coadministration cannot be avoided, take Retevmo with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid).

Concomitant use ofstrong and moderate CYP3A inhibitorsincreases selpercatinib plasma concentrations which may increase the risk of Retevmo adverse reactions including QTc interval prolongation.Avoid concomitant use of strong and moderate CYP3A inhibitors with Retevmo. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the Retevmo dosage as recommended and monitor the QT interval with ECGs more frequently.

Concomitant use ofstrong and moderate CYP3A inducers decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity. Avoid coadministration of Retevmo with strong and moderate CYP3A inducers.

Concomitant use of Retevmo with CYP2C8 and CYP3A substrates increases theirplasma concentrations which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of Retevmo with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

The safety and effectiveness of Retevmo have not been established in pediatric patientsless than 12 years of age. The safety and effectiveness of Retevmo have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of Retevmo for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing Retevmo if abnormalities occur.

No dosage modification is recommended for patients with mild to severe renal impairment (estimated Glomerular Filtration Rate [eGFR] 15 to 89 mL/min, estimated by Modification of Diet in Renal Disease [MDRD] equation). A recommended dosage has not been established for patients with end-stage renal disease.

Reduce the dose when administering Retevmo to patients with severe hepatic impairment (total bilirubin greater than 3 to 10 times upper limit of normal [ULN] and any AST). No dosage modification is recommended for patients with mild or moderate hepatic impairment. Monitor for Retevmo-related adverse reactions in patients with hepatic impairment.

Please see full Prescribing Informationfor Retevmo.

SE HCP ISI All_25MAR2021

About Lilly

Lilly unites caring with discovery to create medicines that make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer's disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visitLilly.comandLilly.com/newsroomor follow us onFacebook, Instagram, Twitterand LinkedIn. P-LLY

Lilly USA, LLC 2022. ALL RIGHTS RESERVED.

Retevmo and Retsevmo are trademarks owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Retevmo (selpercatinib) for the treatment of metastatic RET fusion-positive NSCLC, advanced or metastatic RET mutation-positive MTC, and advanced or metastatic RET fusion-positive thyroid cancer, and as a potential treatment for other indications, and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. Among other things, there is no guarantee that future study results will be consistent with study findings to date or that Retevmo will receive additional regulatory approvals. For further discussion of these and other risks and uncertainties, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

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SOURCE Eli Lilly and Company

Excerpt from:
Lilly Presents Updated Data on Retevmo (selpercatinib) in Advanced RET Fusion-Positive Non-Small-Cell Lung Cancer (NSCLC) at the 2022 European Lung...

Early data from landmark studyshows rapid whole genome sequencing (rWGS) provided diagnostic insights for more than half of newborns who received testing; one-third had no previously documented clinical suspicion of a genetic condition

GAITHERSBURG, Md., March 24, 2022 /PRNewswire/ -- GeneDx, LLC, a leader in genomic analysis, today announced new research in collaboration with the University of Washington, Seattle Children's and the Brotman-Baty Institute during the American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting which demonstrates the utility of rapid whole genome sequencing (rWGS) to diagnose critically ill infants in the neonatal intensive care unit.

The data is part of SeqFirst, a study at the University of Washington examining the impact on care of broad access to routine whole genome sequencing in critically ill infants at Seattle Children's Hospital. Results showed that rapid whole genome sequencing provided a potential, partial or full diagnosis for 53% of newborns tested. Moreover, of those infants who received a diagnosis through whole genome sequencing, 30% had no previously-documented suspicion of a genetic condition, highlighting the limitations of strategies that rely on family history or clinical indicators to qualify for genetic testing. The impact of the genetic information was profound, leading to a change of management for 93% of these patients.

In addition to improving diagnosis, the SeqFirst data also suggested that making whole genome sequencing routine for critically ill patients in the NICU could help overcomes disparities in access to testing. Notably, 67% of patients in whom a genetic condition was not considered prior to testing identified as non-White.

"Our study shows how impactful routine use of whole genome sequencing can be in the neonatal ICU," said Mike Bamshad, M.D., SeqFirst principal investigator and professor and chief of genetic medicine in the department of pediatrics at the University of Washington and Seattle Children's Hospital. "Whole genome sequencing is the most advanced type of genetic testing and our study offers clear insight on the benefit of using it early in the diagnostic process to help families of children with health conditions find a precise genetic diagnosis, better anticipate their child's needs and take advantage of new treatments."

The SeqFirst study was established at the University of Washington with the goal of making whole genome sequencing more accessible. SeqFirst is one of several projects focused on access to testing in the NICU and for use in diagnosing developmental delays in outpatient settings.

"The data is clear rapid whole genome sequencing can provide critical diagnostic insights and much-needed answers for infants in the NICU," said Paul Kruszka, M.D., chief medical officer at GeneDx. "Whole genome sequencing is vastly underutilized in the NICU, despite the clear support for its utility in getting to a diagnosis quickly. Genetic disorders are a leading cause of morbidity and mortality in infants and very often every minute counts. Our hope is that by understanding the benefits of sequencing, we may be able to intervene earlier and pursue clinical approaches that improve outcomes."

GeneDx performs exome sequencing for infants enrolled in the SeqFirst study. GeneDx has played a pivotal role in pediatric disease diagnosis for hundreds of thousands of patients. With a database of more than 300,000 clinical exomes and corresponding clinical information, GeneDx is a key driver in understanding gene-disease relationships.

About GeneDx

GeneDx, LLC, is a global leader in genomics, providing testing to patients and their families worldwide. Originally founded by scientists from the National Institutes of Health, GeneDx offers a world-renowned clinical genomics program with particular expertise in rare and ultra-rare genetic disorders. In addition to its market-leading exome sequencing service, GeneDx offers a suite of additional genetic testing services, including diagnostic testing for hereditary cancers, cardiac, mitochondrial, neurological disorders, prenatal diagnostics, and targeted variant testing. To learn more, please visit http://www.genedx.com.

CONTACT:Julie McKeough,JMcKeough@genedx.com

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New Research Illustrates the Benefits of Rapid Whole Genome Sequencing for Critically Ill Infants - Longview News-Journal

LEXINGTON, Mass., March 23, 2022 /PRNewswire/ -- LogicBioTherapeutics, Inc.(Nasdaq: LOGC), a clinical-stage genetic medicine company, today announced that president and chief executive officer, Frederic Chereau, will present a company overview at the H.C. Wainwright Gene Therapy and Gene Editing Conference. The presentation will be available on demand beginning at 7:00 a.m. ET on March 30, 2022.

A webcast of the presentation will be made available on the Investors section of the Company's website at https://investor.logicbio.com. The webcast replay will be available for approximately 30 days.

AboutLogicBio Therapeutics

LogicBio Therapeutics is a clinical-stage genetic medicine company pioneering genome editing and gene delivery platforms to address rare and serious diseases from infancy through adulthood. The company's genome editing platform, GeneRide, is a new approach to precise gene insertion harnessing a cell's natural DNA repair process potentially leading to durable therapeutic protein expression levels. The company's gene delivery platform, sAAVy, is an adeno-associated virus (AAV) capsid engineering platform designed to optimize gene delivery for treatments in a broad range of indications and tissues. The company is based in Lexington, MA. For more information, visit http://www.logicbio.com, which does not form a part of this release.

Investor Contacts:

Stephen Jasper

Gilmartin Group

858-525-2047

stephen@gilmartinir.com

Media Contacts:

Adam Daley

Berry & Company Public Relations

W:212-253-8881

C: 614-580-2048

adaley@berrypr.com

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SOURCE LogicBio Therapeutics

Read more here:
LogicBio Therapeutics to Present at H.C. Wainwright Gene Therapy and Gene Editing Conference - 69News WFMZ-TV

NEW YORK GeneMatcher has become instrumental in the discovery of new genes underlying hereditary diseases. Since its inception in 2015, the "matchmaking" service, which connects researchers, clinicians, and patients interested in the same genes, has been used to help identify at least 416 novel disease-related genes and has been cited in 562 publications.

As the service continues to grow, its developers at the Baylor-Hopkins Center for Mendelian Genomicsplan to make it easier for researchers to find information related to animal models and to add tools for patients as more of them start using the service to research their own conditions.

The growth in users is reflected in a huge uptick in publications referencing GeneMatcher, which increased from 20 publications in 2015 to 143 in 2021, with 58 already having been published this year.

"It's like 'Field of Dreams'," said Ada Hamosh, one of GeneMatcher's original developers and a professor of genetic medicine at Johns Hopkins University. "If you build it, they will come."

That said, both Hamosh and Nara Sobreira, the first author of the original GeneMatcher publication and an assistant professor of genetic medicine at Johns Hopkins, are quick to point out that initially building the service was no walk in the park.

"It took us years talking about GeneMatcher and convincing people to use it," Sobreira said. "Now it's all good and beautiful but at the beginning, we got a lot of pushback, with a lot of people thinking that it was not going to work."

GeneMatcher is part of the Matchmaker Exchange project, which also allows GeneMatcher submitters to query other connected databases through the Exchange's API. These include PhenomeCentral, Decipher, IRUD, MyGene2, and the newer ModelMatcher, which is geared toward researchers using animal models.

GeneMatcher allows individuals to submit genes of interest and automatically matches them with others submitting the same genes. Submitters may include other information along with the gene or genes, such as variants by base pair position, diagnoses from the OMIM database, and clinical/phenotypic features.

Submitters are currently limited to posting 10 candidate genes per submission, as a way to avoid unnecessary data dumping.

Most recently, GeneDx cited the service in a publication in Human Genetics, accrediting it with having helped the company and its collaborators discover over 200 new and expanded genetic conditions.

In its report, the company estimated that it accounts for some 20 percent of GeneMatcher submissions, an impressive quantity given the 11,883 total submitters from 98 countries that were recorded on the platform as of March 22.

GeneDx's GeneMatcher-mediated collaborations that have led to discoveries include a yet-unnamed neurological disorder caused by an autosomal dominant FAR1 variant, resulting in spastic paraparesis and bilateral cataracts.

Similarly, HudsonAlpha has cited GeneMatcher in having facilitated the research needed to identify a previously unknown rare variant of the EBF3 gene that causes intellectual disability, ataxia, and facial dysmorphism.

"This gene encodes an early B-cell factor, is a known developmental transcription factor, suspected to function in neuronal differentiation and maturation, and was a target ofARX, a known NDD gene," Michelle Thompson, a variant analyst with HudsonAlpha, said via email.

After submitting to GeneMatcher, the HudsonAlpha researchers were able to find a second patient within their own cohort and to connect with several other labs investigating EBF3 around the world.

Graduate students at HudsonAlpha performed functional analysis on the variants and helped establishEBF3as a new neurodevelopmental disease gene.

"We were able to provide two diagnoses within our own study, and eight other patients were provided an answer, many of which had been on a diagnostic odyssey,"Thompson added.

Thompson said that GeneMatcher has led to 23 publications from HudsonAlpha, with additional manuscripts in preparation.

More recently, a team of researchers from across the globe published the discovery of RECON (RECql ONe) syndrome, a rare disorder caused by mutations in the RECQL1 helicase gene, after researchers and clinicians studying that gene connected with each other through GeneMatcher and were able to share their findings.

In addition to genetics professionals, patients also increasingly turn to GeneMatcher as a means of seeking information on their own conditions.

"I get a lot of emails from patients asking me how to use it, what's the best way to use it, if GeneMatcher is the best tool to use," Sobreira said. While she thinks that the best tool for patients right now is probably MyGene2, "I completely support them using GeneMatcher," and the site includes a way for patients to identify themselves as such and say whether they're looking to connect with clinicians or researchers.

As of March 1, approximately 688 patients had submitted requests for information from GeneMatcher, according to Hamosh.

Thanks to patients and researchers, use of GeneMatcher has grown steadily since its launch, and Sobreira now employs one lab technician whose job is to field emails concerning the platform, mainly from submitters, while she finds herself sometimes responding to emails from patients.

GeneDx also noted a rise in queries and matches made through GeneMatcher, particularly over the course of the pandemic.

"With stayathome orders," the company wrote in its recent article, "perhaps many clinicians and researchers suddenly had time they had lacked previously and decided to work on research projects."

As a result, the firm's response time to requests through GeneMatcher has increased, and it has found itself unable to respond to them in real time.

"We have a triage process to prioritize inquiries and work to respond to the most urgentwithin a week or so, while other inquiries can take longer," Julie McKeough, GeneDx's chief communications officer, explained via email.

Sobreira and Hamosh mentioned that as GeneMatcher's user base keeps growing, they plan to make improvements and add features to ensure that it remains useful for all stakeholders.

ModelMatcher, the most recent addition to the Matchmaker Exchange, has brought more queries from animal model researchers into GeneMatcher, as these scientists seek to link genes found in animals to their human counterparts.

Because of this, Sobreira and her team recently added model organism statistics to the platform and are planning to add a feature allowing users to identify themselves as model organism researchers, along with an option to connect with other animal model researchers.

She also plans to add a link for Publication and Researchers - Rare Disease Gene Mechanisms (PaR-RaDiGM), a feature aimed at connecting rare disease researchers to relevant publications, to the match email notification system.

More changes may yet come from further user feedback.

"It would be useful to be able to search for genes that have already been submitted to GeneMatcher," Thompson commented. "Currently, you submit a gene of interest and get a 'match report,'ranging from 'no matches'to a list of other researchers/clinicians with the same gene of interest. However, one potential downside would be that it may discourage submitters to continue submitting that gene through the portal, as it may later develop as a gene of interest."

As with any public database, the more people use it, the more useful it becomes, increasing the chances of finding clinically relevant rare variants in particular candidate genes.

It has already proven a valuable resource to GeneDx in the company's numerous collaborations.

"We hope that [our] article inspires others to participate in GeneMatcher so that, together, we can advance our understanding of human genetic disease and ultimately help more patients," McKeough said.

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GeneMatcher Team Plans Improvements for Researchers, Patients to Build on Recent Successes - GenomeWeb

Tennis legend Chris Evert known for her 18-time grand slam success in the sport has made recent headlines after revealing an early-stage ovarian cancer diagnosis and speaking out to help others by sharing her personal experience.

According to the American Cancer Society ovarian cancer is the fifth leading cause of cancer in women, accounting for more deaths than any other cancer of the female reproductive system. Impacting as many as 250,000 women each year, ovarian cancer is referred to as a silent disease because most women do not experience symptoms until its later stages. But when caught early and before the disease spreads, 90 percent of women can be cured. Late stage ovarian cancer, where the disease has spread beyond the ovaries, is more difficult to treat, and survival rates are low for patients.

Early detection of breast cancer is possible due in large part to screening methods including mammograms, self-breast exams, and annual visits with a doctor. The same holds true for colonoscopies for the prevention of colon cancer. While ovarian cancer is not as common as other womens cancers, a lack of early detection or prevention strategies is a major cause of poor outcomes for patients. For some, knowing family history and seeking out genetic testing to identify mutations in genes such as BRCA1 and BRCA2 is one way to detect risk for this cancer early. But most people with ovarian cancer do not have a family history or inherited genetic risk, so there is a pressing need for the development of earlier detection methods.

Catching cancer early often allows for more treatment options and provides patients the best chance for good outcomes. Some cancers have early signs and symptoms, but ovarian cancer does not. While patients undergo regular pelvic exams they may also get transvaginal ultrasounds and a specific blood test (which, while not accurate enough alone, measures the amount of the cancer antigen 125 protein in the blood).

However, there is no formal screening method for ovarian cancer that is equivalent to the pap smear for cervical cancer, which can detect early-stage cancer or even precancerous cells.

Those who know they have an elevated genetic risk due to family history are a step ahead, and can take action to learn about possible mutations or gene errors they may have, along with getting regular screenings. This knowledge can help inform a game plan towards earlier detection that offers an alternative to invasive and disruptive prevention surgery, or waiting for possible symptoms of late-stage disease.

Additional screening methods can help, and ongoing research here at Penn Medicine is looking to catch this cancer early by looking beyond the ovaries.

Penn Medicines Ovarian Cancer Research Center (OCRC) serves as a catalyst to promote comprehensive and interdisciplinary research on ovarian cancer. The center is focused on understanding how ovarian cancers begin, and translating those insights into potential approaches for early detection and ovarian cancer therapies. Whats more, the OCRC recently received a new $2.8 million grant from the Department of Defense (DoD) to further these efforts.

In the past, most doctors and scientists naturally assumed that ovarian cancer develops in the ovaries. However, about fifteen years ago, Penn researchers helped make an exciting discovery and found that the most common and deadly form of ovarian cancer, called high grade serous carcinoma (HGSC), actually often begins as tiny groups of abnormal cells in the fallopian tube. These precursor lesions, called serous tubal intraepithelial carcinomas (STICs), are so tiny that they can only be found by careful, microscopic examination of the fallopian tubes. Ever since this discovery, Penn has been dedicated to studying STICs and how these cells eventually spread to the ovaries where they can quickly form tumors that further spread to the rest of the body.

Learning about STICs lesions themselves is the beginning. Now, with support from the DoD grant, Penn experts are studying how STICs interact with surrounding tissues, and why they form in the first place. This includes building a shared, centralized bank of high-quality STIC specimens to perform studies of STICs and their surrounding tissues; leveraging tissue characterization technologies to examine DNA, RNA, and proteins of all cells located within and surrounding the STIC lesions; and identifying specific chemical changes (biomarkers) that occur that might be used to detect the lesions before they have a chance to progress. Collectively, this will help inform the creation of a test or tests to detect STICs using blood or Pap specimens from patients with lesions as a tool for physicians to help with early diagnosis of ovarian cancer.

For a long time experts studied the ovaries in the hopes of finding answers to assist with earlier diagnosis and detection of ovarian cancer, so knowing that these tumors start in the fallopian tubes opens up so many possibilities for prevention and detection, which can have a tremendous impact on standard of care for these patients, said Ronny Drapkin, MD, PhD, director of the OCRC, an associate professor of Pathology in Obstetrics and Gynecology, and a gynecologic cancer researcher with the Basser Center at Penn. Were even seeing this in the news today, with Chris Everts early ovarian cancer diagnosis, which was found in the fallopian tube after she was tested for a BRCA mutation.

Evert has shared that her family history of ovarian cancer is what led her to seek out genetic testing. Through the testing process, she was confirmed to have a BRCA genetic mutation, which led her to her preventive surgery where the cancer was found in her fallopian tube.

Both men and women have BRCA1 and BRCA2 genes, which play a role in controlling and preventing cancer. When there is an error, or mutation, in a BRCA1 or BRCA2 gene, an individual has increased risks for breast, ovarian, prostate, and pancreatic cancers. They can also pass the mutation on to their children who will then have increased cancer risks in adulthood.

Its important for individuals with a family history of cancer to get tested. While those who have mutations are considered high risk for developing breast cancer and ovarian cancer, not everyone who inherits these genes will get cancer. Furthermore, once they have this knowledge, patients can make plans to help lower their risk, saidSusan Domchek, MD, executive director the Basser Center for BRCA at Penn. Knowing that there is risk means you can choose different types of surveillance or prevention options to decrease your chances of developing and dying of cancer.

While these genetic mutations can increase risk, anyone with ovaries is at risk of ovarian cancer. However, some factors, such as afamily history, genetic predisposition, increasing age and use of hormone replacement therapycan put one at a higher risk. If you are concerned, learn more about your symptoms and talk to your doctor aboutovarian cancer prevention and screening.

And for those with a family history, like in Everts scenario, you can reach out to a genetic counselor who can help assess your history and criteria for testing.

No one can exactly predict whether or not a person will develop cancer. But, knowing the factors that increase risk may create an opportunity for prevention or more effective treatment.

For questions and assistance in finding a genetic counselor in your area, or general information about BRCA and risk assessment, contact the Basser Center at 215-662-2748 or visit basser.org.

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Key to Detecting Ovarian Cancer Early May Be in the Fallopian Tubes - Penn Medicine

BETHESDA, Md., March 24, 2022 /PRNewswire/ -- The unprecedented, rapid advances in genetic and genomic knowledge and technologies have made it challenging for primary care and other nongenetics healthcare providers to stay current on recommendations and practices in clinical genetics. To address this education gap for nongenetics providers and to foster the effective integration of those advances into the broad clinical practice of primary care and specialty healthcare providers, the American College of Medical Genetics and Genomics (ACMG) announces the creation of a new online Continuing Medical Education (CME)* series, "Genetics101 for Healthcare Providers." The free educational series will be featured in the widely popular AMA Ed Hub, the online learning platform of the American Medical Association.

ACMG CEO Max Muenke, MD, MBA, FACMG said, "We're proud to collaborate with the AMA Ed Hub, an online platform bringing together high-quality education from the American Medical Association and other trusted sources, including ACMG. Designed to support the lifelong learning, licensure and certification needs of physicians and other health professionals, the AMA Ed Hub offers thousands of opportunities to earn CME, CEU and MOC."

This exciting new educational program addresses a key part of ACMG's Strategic Plan to develop customized education and resources for nongeneticists.

ACMG President Marc S. Williams, MD, FACMG said, "The ACMG's strategic plan states that we will take the lead in 'educating the medical community on the significant role that genetics and genomics will continue to play in understanding, preventing, treating and curing disease.' This partnership with the AMA Ed Hub is a significant milestone is achieving this objective."

In each module of the "Genetics101 for Healthcare Providers" course, a board-certified medical genetics expert will provide a case-based presentation, along with supporting reading materials. Initially, there will be 10 modules, with some modules covering general topics and others specific to a particular medical specialty area. Topics included in this initial series:

1. Neurogenetics

2. Prenatal Genetics

3. Key Principles in Pharmacogenomics

4. Online Genetics Resources

5. Inherited Cancer Syndromes

6. Genetics for the Primary Care Provider (Adult)

7. Genetics for Endocrinologists

8. Genetics for Cardiologists

9. Genetics Workup for the Pediatrician

10. General Overview of Genetics (Coming soon)

This course is supported by an independent medical education grant from Illumina, Inc.

ACMG is the largest group of medical geneticists in the country and the only medical society that represents the full spectrum of medical genetics disciplines including clinical and laboratory geneticists as well as genetic counselors in a single organization. ACMG's mission is to improve health through the practice of medical genetics, as well as through education and clinical research, and to guide the safe and effective integration of genetics and genomics into all of medicine and healthcare, resulting in improved personal and public health.

This activity has been approved for AMA PRA Category 1 Credit.

About the American College of Medical Genetics and Genomics (ACMG) and ACMG Foundation

Founded in 1991, the American College of Medical Genetics and Genomics (ACMG) is the only nationally recognized medical society dedicated to improving health through the clinical practice of medical genetics and genomics. The ACMG provides education, resources and a voice for more than 2,400 biochemical, clinical, cytogenetic, medical and molecular geneticists, genetic counselors and other healthcare professionals, nearly 80% of whom are board certified in the medical genetics specialties. The College's mission is to develop and sustain medical genetics-related initiatives in clinical and laboratory practice, education and advocacy. Four overarching strategies guide ACMG's work: 1) reinforce and expand ACMG's position as the leader and prominent authority in the field of medical genetics and genomics, including clinical research, while educating the medical community on the significant role that genetics and genomics will continue to play in understanding, preventing, treating and curing disease; 2) to secure and expand the professional workforce for medical genetics and genomics; 3) to advocate for the specialty; and 4) to provide best-in-class education to members and nonmembers. Genetics in Medicine, published monthly, is the official ACMG peer-reviewed journal. ACMG's website (www.acmg.net) offers resources including policy statements, practice guidelines, educational programs and a 'Find a Genetic Service' tool. The educational and public health programs of the ACMG are dependent upon charitable gifts from corporations, foundations and individuals through the ACMG Foundation for Genetic and Genomic Medicine.

Contact:

Kathy Moran, MBA

kmoran@acmg.net

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SOURCE American College of Medical Genetics and Genomics

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New "Genetics101 for Healthcare Providers" Online Course Addresses Gap in Education for Nongenetics Healthcare Providers: Course will be...

Scientists are getting their first peek at the genes of nearly 100,000 Americans in whats considered a uniquely diverse genomic database part of a quest to reduce health disparities and end cookie-cutter care.

The National Institutes of Health released the data Thursday to help researchers start unraveling how peoples genes, environments and lifestyles interact to affect their health. And half of the studys participants are from racial and ethnic groups historically left out of medical research.

That diversity will add a kind of knowledge that just isnt out there, said Dr. Josh Denny, who heads the NIHs massive All of Us study that eventually aims to have such data from 1 million Americans.

Until now, more than 90% of people in the worlds large genome studies have been of European descent, a lack of diversity that hinders scientific progress, he said.

Researchers have been awaiting the genetic information to study some of the most perplexing health disparities.

For example, African Americans have a fourfold higher risk of kidney failure than their white counterparts, everything else being equal, said Dr. Akinlolu Ojo of the University of Kansas Medical Center.

We will for the first time be able to tease out what are the underlying genetic factors behind that difference, he said.

This is not just a snapshot in time, Ojo said, adding that he hopes to finally track how genes and other factors work together to explain why some people survive for years with damaged kidneys while others rapidly worsen.

Todays healthcare is pretty much one size fits all. Most treatments are based on what has worked best for the average person in short studies of a few hundred or thousand patients.

All of Us is part of a push toward precision medicine, a way to customize care based on the complex combinations of factors that determine health, including your genes, habits and where you live as well as age, gender and socioeconomics.

The study is recruiting volunteers from all walks of life both the sick and the healthy to share DNA samples, medical records, fitness tracking and answer health questions. Researchers also will cull environmental information about participants communities.

While the pandemic delayed enrollment, the NIH said more than 474,000 people have agreed to participate so far and more than 325,000 have provided blood or saliva samples for researchers to start analyzing.

The database that opened Thursday contains the whole genome sequences of nearly 100,000 of the first volunteers meaning information on all their genes rather than the more common practice of studying a subset.

As with other genomic programs, the NIH team protects study participants privacy by removing all identifying information from the data. U.S. scientists seeking to use the database for their research must meet strict requirements.

Individual participants can request to learn the results of their own genetic testing. Last year, the NIH program began releasing ancestral information to participants who asked. Plans are underway to also notify participants who bear certain well-known genetic variants that cause inherited diseases or trigger medication problems.

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Big U.S. gene database will add racial and ethnic diversity to medical research - Los Angeles Times

2022 Harrington Prize for Innovation in Medicine Recognizes Breakthrough Innovations in the Use ofHuman Antibodies to Treat COVID-19

CLEVELAND, March 24, 2022 /PRNewswire/ -- The ninth annual Harrington Prize for Innovation in Medicine has been jointly awarded to James E. Crowe, Jr., MD, Director, Vanderbilt Vaccine Center and Professor, Departments of Pediatrics and Pathology, Microbiology and Immunology, Vanderbilt School of Medicine, and Michel C. Nussenzweig, MD, PhD, Investigator, HHMI, and Zanvil A. Cohn and Ralph M. Steinman Professor, The Rockefeller University. The award recognizes their groundbreaking work, which has elucidated fundamental principles of the human immune response and enabled the use of human antibodies to treat COVID-19.

The Harrington Prize for Innovation in Medicine, established in 2014 by the HarringtonDiscovery Institute at University Hospitals and the American Society for ClinicalInvestigation (ASCI), honors physician-scientists who have moved science forward withachievementsnotable forinnovation,creativityandpotentialforclinicalapplication.

Dr. Crowe has advanced the discovery of human monoclonal antibodies for many of the most pathogenic viruses that cause human disease. His team has discovered thousands of human monoclonal antibodies for SARS-CoV-2 (the virus that causes COVID-19) and facilitated their development, transferring clinical leads to multiple pharmaceutical partners including tixagevimab + cilgavimab, now in use in high risk patients. His work on the genetic and structural basis of virus neutralization has also revealed important principles that are being exploited in new vaccine and antibody development.

Dr. Nussenzweig addressed a critical issue in immunology the lack of a detailed understanding of the human antibody response by developing robust and scalable methods for cloning antibodies from single human B cells. Dr. Nussenzweig showed that antibodies cloned directly from humans can be a safe and effective treatment against viral infections when passively transferred to other humans. His work established a paradigm that made it possible for him and others to rapidly develop monoclonal antibody therapies against SARS-CoV-2.

A committee composed of members of the ASCI Council and the Harrington Discovery Institute Scientific Advisory Board reviewed nominations from leading academic medical centers from eight countries before selecting the 2022 Harrington Prize recipients.

"Drs. Crowe and Nussenzweig are extraordinary physician-scientists who took distinct and separate paths but arrived at the same endpoint. In doing so, they have taught us a great deal about the human immune response and have successfully translated those findings into therapies for patients. The creativity, innovation and clinical impact demonstrated by their work is precisely what The Harrington Prize seeks to recognize," said Hossein Ardehali, MD, PhD, Professor of Medicine in the Division of Cardiology at Northwestern Medicine and the 2021-2022 President of the ASCI.

"The translational implications of Dr. Crowe's and Dr. Nussenzweig's work are quite profound. Their antibody-based therapies have enabled the medical community to more effectively combat COVID, and will spare untold human suffering," said Jonathan S. Stamler, MD, President, Harrington Discovery Institute, Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation and Professor of Medicine and of Biochemistry at University Hospitals and Case Western Reserve University.

Inaddition tosharingthe Prize's$20,000honorarium,co-recipientsDr.Croweand Dr. Nussenzweigwill deliver The Harrington Prize Lecture at the 2022 AAP/ASCI/APSA Joint Meeting on April 8, will be featured speakers at the 2022 Harrington Scientific Symposium May 25-26, and will co-publish anessayin theJournal of Clinical Investigation.

Sinceitsestablishment,TheHarringtonPrizehasrecognized outstanding and diverse innovation in medicine:

SOURCE Harrington Discovery Institute

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International Harrington Prize Jointly Awarded to Drs. James Crowe and Michel Nussenzweig - PR Newswire

HOUSTON A multicenter research team co-led by The University of Texas MD Anderson Cancer Center developed the first drug to treat the uncontrolled secretion of mucins in the airways, which causes potentially life-threatening symptoms in millions of Americans with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), as well as lung disease resulting from cancer and cancer treatment. The study was published today in Nature.

Mucus is a significant problem in pulmonary medicine, because in people with these common lung diseases, thick mucus can block the airways and cause symptoms ranging from a mild cough to very serious decreases in lung function, said Burton Dickey, M.D., professor of Pulmonary Medicine and co-corresponding author of the study. Most drugs for these conditions work to reduce inflammation or expand the airways to help people breathe better, but mucus is the most serious issue. Our research has created the first drug that would stop the secretion of mucins in its tracks.

Muco-obstructive lung diseases affect hundreds of millions of people worldwide. In the U.S., about 25 million people have asthma, 16 million adults have been diagnosed with COPD and CF is the most common life-threatening, genetic disease. Many cancer patients end up with lung disease because their cancer treatments or the cancer itself leaves them immunocompromised.

Normally, mucins are gradually released into the airways, where they absorb water and form a thin layer of protective mucus that traps pathogens and is easily cleared by cilia. In muco-obstructive lung diseases, high volumes of mucins are suddenly released and, unable to absorb enough water, result in a thick mucus that can plug airways and impair lung function.

Dickeys lab began studying mucin secretion two decades ago and previously identified the key genes and proteins involved, showing how synaptotagmin and a SNARE complex, similar to that found in neurons, contribute to the key process of Ca2+-triggered membrane fusion.

We built up a picture of what the secretory machinery looked like and we knew all of the major players, Dickey said. Once we had an idea of how all the pieces worked together, we determined synaptotagmin-2 (Syt2) was the best protein to target to block mucin secretion because it only becomes activated with a high level of stimulation. Therefore, blocking the activity of Syt2 should prevent sudden massive mucin release without impairing slow, steady baseline mucin secretion that is required for airway health.

In this study, a collaborative effort between MD Anderson, Stanford Medicine and Ulm University, the researchers verified Syt2 as a viable therapeutic target protein in several types of preclinical models. Philip Jones, Ph.D., vice president of Therapeutics Discovery and head of the Institute for Applied Cancer Science, designed a hydrocarbon-stapled peptide, SP9, to block Syt2, based on structures developed by the Stanford collaborators, including senior co-corresponding author Axel Brunger, Ph.D., professor of Molecular and Cellular Physiology.

Stapled peptides are a recent therapeutic development involving modified amino acids that form hydrocarbon crossbridges to hold their structure rigid so they can bind to a protein target and show enhanced stability. Stapled peptides have been used to treat other diseases, including cancer, but SP9 would represent the first stapled peptide to be used as an inhaled therapeutic.

In a reconstituted system model in Brungers Stanford laboratory, Ying Lai, Ph.D., used SP9 to successfully disrupt Ca2+-triggered membrane fusion. The Ulm laboratory of Manfred Frick, Ph.D., used SP9 conjugated to a cell penetrating peptide in cultured epithelial cells to inhibit rapid mucin secretion. The Dickey laboratory then used an aerosolized version in a mouse model to confirm the drug reduced mucin secretion and airway blockage by mucus. Importantly, SP9 did not affect the slow-release pathway for normal mucin secretion.

An inhaled drug like this could help someone during an acute attack of airway disease by stopping the rapid secretion of mucin and, by extension, avoiding production of thick mucus. You cant move air through an airway thats plugged, Dickey said. In asthma, COPD and CF, its been shown that persistent plugs drive the most serious disease. Now we have a drug that could be very important if its shown to work in clinical trials.

The stapled peptide SP9 will be further refined before moving to human studies, as is typical for therapeutics at this stage of development, and may enter clinical trials in a couple of years.

Dickey and co-authors are inventors on a patent application related to SP9. The study was supported by the National Institutes of Health (R01 HL129795, R21 AI137319) and the Cystic Fibrosis Foundation. A full list of co-authors and their disclosures is available in the paper.

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Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides

23-Mar-2022

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Novel therapy could help people with asthma, COPD, cystic fibrosis and cancer-related lung disease - EurekAlert