Precise treatment leads to resolution of patient's debilitating symptoms and complete remodeling of her lymphatic system
PHILADELPHIA, Nov. 20, 2020 /PRNewswire/ -- Researchers at Children's Hospital of Philadelphia (CHOP) have resolved a severe lymphatic disorder in a girl with Noonan Syndrome that had led to upper gastrointestinal bleeding, fluid collection around the lungs, and numerous surgeries that had been unable to resolve her symptoms. By identifying a genetic mutation along a pathway related to lymphatic vessel development and function, the research team was able to target the pathway using an existing drug they had used in a previous case to remodel a patient's lymphatic system.
The case study, which was published today in Pediatrics, describes a resolution of the patient's symptoms within three months while on the medication.
"This study is quite significant," said first author Yoav Dori, MD, PhD, Director of the Jill and Mark Fishman Center for Lymphatic Disorders at CHOP. "Inhibiting this pathway seems to have sweeping, widespread effects on the lymphatic system. How this process occurs is not fully understood, but is remarkable in its speed and breadth. This gives us a lot of hope for treating other patients with genetic mutations along this same pathway in the future."
The patient described in the paper, Maria, first came to CHOP when she was 14, after experiencing severe anemia due to upper gastrointestinal bleeding, as well as other symptoms including fluid build-up in the cavity around her lungs, chronic fatigue, delayed puberty, and difficulty gaining weight. Maria had been born with Noonan Syndrome, a genetic disorder that prevents normal development in various parts of the body and often results in short stature, heart defects and other physical problems, including an abnormal lymphatic system. Despite aggressive medical therapy elsewhere, Maria continued to bleed internally, and she underwent multiple blood transfusions to try to stabilize her health.
Within two days of transferring to CHOP, the lymphatics team, led by Dori, determined Maria had many lymphatic irregularities, which were leading to internal bleeding and lung problems, so they scheduled Maria's first intervention, a lymphatic embolization procedure that would seal the leaky vessels in her gut.
However, within two months of the procedure, Maria's gastrointestinal bleeding recurred. Over the following 8 months, she underwent two additional procedures, as well as a cauterization procedure to close off some of the blood vessels in her gut, but the benefits of each procedure lasted only about three months before the bleeding and her symptoms returned.
Based on whole exome sequencing done at CHOP's Center for Applied Genomics, the research team learned that Maria had a genetic mutation in the SOS1 gene, which operates along the RAS-MAPK pathway. This pathway involves mitogen-activated protein kinase (MEK), and Maria's mutation caused an overproduction of MEK, which resulted in the uncontrolled proliferation of her lymphatic vessels.
The research team had previously used a MEK inhibitor in another patient with a severe lymphatic disorder with great success. That patient had a mutation in the ARAF gene, which is also on the RAS-MAPK pathway. Within months of beginning treatment with trametinib, a MEK inhibitor, the patient saw a resolution of his symptoms and a complete remodeling of his lymphatic system.
Given that SOS1 operates on the same pathway as ARAF, Jean Belasco, MD, an oncologist in CHOP's Cancer Center who co-led the study, applied for compassionate use of the drug in Maria's case, given the lack of other treatment options.
"The success of trametinib in another patient with a mutation on the RAS-MAPK pathway encouraged us to try this approach, since other procedures and therapies continued to be unsuccessful," Belasco said. "Although we are in the early days of this type of personalized medicine, the hope is that by looking at patients' mutations, we can find more drugs and better care for patients with genetic diseases."
Within three months of starting the drug, Maria's vital signs stabilized. The bleeding stopped, her electrolyte, hemoglobin, and albumin levels returned to normal, and she began to gain weight. Maria's mother noticed that Maria wasn't going through periods of exhaustion anymore, and her pallor improved.
"She looks better than she's ever looked," her mother said. "She looks like a normal teenager. It's like night and day. She's also a lot happier. I think she knew deep down she was dying. The medicine gave her hope."
Hakon Hakonarson, Director of the Center for Applied Genomics and co-author of the paper, said that although Maria's SOS1 mutation is distinctly different than the ARAF mutation seen in the other patient, the drug was equally effective because it targets and blocks the function of MEK. He likened the scenario to a pathway where 15 events need to occur for a cell to function. Maria's SOS1 mutation might occur at step nine, whereas the ARAF mutation might occur at step three, but both genes are on a chain that ultimately passes through a tunnel that leads to phosphorylation and overactivity of MEK. Since both mutations were so-called gain of function mutations, MEK and thus lymphatic activity was overexpressed in both patients. The MEK inhibitor put the brakes on a system in overdrive.
"Remarkable advances in genetics have allowed us to uncover these mutations and cluster them into selective pathways and determine effective therapies based on genetic mutations with very high precision," said Hakonarson. "No one could have guessed that this drug would have worked for Maria without knowing the underlying genetics. This discovery is extremely important because Noonan Syndrome has the biggest patient population with alterations in MEK signaling. Not all Noonan patients will have mutations that respond to this therapy, but a very good number of them will."
He added that the treatment could also benefit patients with other genetic defects, though he noted the ongoing use of the drug treats the symptoms caused by these mutations, but does not fix the gene or cure the underlying condition.
"MEK inhibition has the potential to have significant effects on other organ systems affected by RAS-MAPK gene defects, such as the heart, eyes, skin and the coagulation system," Hakonarson said.
Hakonarson is also part of CHOP's Comprehensive Vascular Anomalies Program (CVAP), a CHOP Frontier Program that uses state-of-the-art genomics and personalized research strategies to determine the causes of complex vascular conditions and identify targeted therapies. The program works closely with the Lymphatic Imaging and Interventions Frontier Program, which is led by Dori. CHOP's Frontier Programs conduct cutting-edge research that translates into advanced clinical care. The CVAP, in particular, draws on the extensive clinical and genomic research capacity within the Cancer Center and Center for Applied Genomics.
Even with the success of the breakthrough treatment pioneered by these programs, it is not entirely clear why MEK inhibitors not only resolve patients' symptoms but also completely remodel their lymphatic systems. Hakonarson said one possibility is that when mutated genes cause uncontrolled growth of the lymphatic system, the body's vessels leak fluid everywhere in the body. When you shut down the unregulated growth, other homeostatic mechanisms that are balancing the system come into effect, so the overreactive cells that were growing out of control die and are replaced by normal cells that gradually build up the lymphatic system.
Whatever the mechanism, Maria's mother said her daughter had no hesitation at being the first patient with Noonan Syndrome to try this treatment to resolve a lymphatic issue.
"Maria saw the value from the beginning," she said. "She saw the value for herself, but she was also thinking of other Noonan kids, some of whom have passed away from lymphatic issues. She was willing and eager."
Dori et al. "Severe Lymphatic Disorder Resolved with MEK Inhibition in a Noonan Patient with SOS1 Mutation," Pediatrics, published online November 20, 2020, doi: 10.1542/2020-000123
About Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 564-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu
Contact: Natalie SolimeoChildren's Hospital of Philadelphia267firstname.lastname@example.org
SOURCE Children's Hospital of Philadelphia
Read the original post:
- UC Davis Health's partnership in telegenomics improves accessibility to genetic medicine with telemedicine robots - The Aggie - The Aggie - September 5th, 2021
- Could gene therapies be used to cure more people with HIV? - aidsmap - September 5th, 2021
- What to expect at the FDA's two-day meeting on gene therapy safety - BioPharma Dive - September 5th, 2021
- Global DNA Sequencing Report 2021: There is a Move Toward a More Consumer-Focused Model - Yahoo Finance - September 5th, 2021
- Agathos Biologics Receives $900,000 from the North Dakota Bioscience Innovation Grant Program - Yahoo Finance - September 5th, 2021
- New gene therapies may soon treat dozens of rare diseases, but million-dollar price tags will put them out of reach for many - The Conversation US - September 5th, 2021
- An ethical analysis of divergent clinical approaches to the application of genetic testing for autism and s... - Physician's Weekly - September 5th, 2021
- Intense exercise could trigger ALS in those with genetic risk - Livescience.com - September 5th, 2021
- UT Southwestern selected top health care employer in Texas by Forbes - UT Southwestern - September 5th, 2021
- Opinion: Gene editing can be leveraged for the greater good with appropriate regulations - Varsity - September 5th, 2021
- Beefing up livestock disaster assistance | Farm & Ranch | willistonherald.com - Williston Daily Herald - September 5th, 2021
- Precision Medicine Platform Aims to Advance Cancer Gene Therapies - HealthITAnalytics.com - February 11th, 2021
- Celebrate the Third Annual Medical Genetics Awareness Week April 13-16, 2021 - PRNewswire - February 11th, 2021
- The race to treat a rare, fatal syndrome may help others with common disorders like diabetes - Science Magazine - February 11th, 2021
- Myriad Genetics to Participate in Multiple Upcoming Health and Technology Conferences - GlobeNewswire - February 11th, 2021
- Neurons from patient blood cells enable researchers to test treatments for genetic brain disease - Brown University - February 11th, 2021
- The science behind those afternoon naps Harvard Gazette - Harvard Gazette - February 11th, 2021
- Ensoma Launches to Pioneer Next-Generation In Vivo Approach to Deliver First Off-the-shelf Genomic Medicines - Business Wire - February 11th, 2021
- Im 28 and I Dont Know My Family HistoryHeres How That Affects My Health - Well+Good - February 11th, 2021
- Ensoma Launches with $70 Million Series A and Takeda Licensing Deal - BioSpace - February 11th, 2021
- Response to Cancer Immunotherapy May Be Affected by Genes We Carry from Birth - UCSF News Services - February 11th, 2021
- NeuBase Therapeutics Reports Financial Results for the First Quarter of Fiscal Year 2021 - GlobeNewswire - February 11th, 2021
- PM Modi Waives off Rs 6 Crore Tax on Imported Medicine for 6-month-old Baby Girl from Mumbai - News18 - February 11th, 2021
- GeneSight Psychotropic Test's Combinatorial Approach Proves Better than Single-Gene Testing at Predicting Patient Outcomes and Medication Blood Levels... - February 11th, 2021
- Reflections on the 20th Anniversary of the First Publication of the Human Genome - Scientific American - February 11th, 2021
- Stem Cell Study Illuminates the Cause of a Devastating Inherited Heart Disorder - Newswise - February 1st, 2021
- Mysterious untreatable fevers once devastated whole families. This doctor discovered what caused them - CNN - February 1st, 2021
- Decibel Therapeutics and Invitae Announce Launch of Amplify Genetic Testing Program - BioSpace - February 1st, 2021
- CCMB team identifies variants of genes that metabolise drugs - BusinessLine - February 1st, 2021
- Digbi Health's gut-microbiome and genetic-based obesity management program now allows 60,000 Doctors and Providers in Blue Shield of California's... - February 1st, 2021
- Copy number variations linked to autism have diverse but overlapping effects - Spectrum - February 1st, 2021
- Are Gene Therapies the Medicine of the Future? - BioSpace - February 1st, 2021
- Exploring the Relationship Between the Microbiome, Precision Medicine and Cancer - Technology Networks - February 1st, 2021
- Press Registration Is Now Open for the 2021 ACMG Annual Clinical Genetics Meeting - A Virtual Experience - PRNewswire - February 1st, 2021
- 4 New Life Sciences Licensing Deals and Investments to Watch - BioSpace - February 1st, 2021
- CRISPR Mutants - The Dawn of CRISPR Mutants - SAPIENS - SAPIENS - February 1st, 2021
- SMART Study Finds 22q11.2 Microdeletion Prevalence Much Higher than Expected - PRNewswire - February 1st, 2021
- Genomes, Maps, And How They Affect You - IFLScience - February 1st, 2021
- Are Phages Overlooked Mediators of Health and Disease? - The Scientist - February 1st, 2021
- Two Gene Therapies Fix Fault in Sickle Cell Disease and -thalassemia - MD Magazine - February 1st, 2021
- The First Targeted Therapy For Lung Cancer Patients With The KRAS Gene MutationExtraordinary Results With Sotorasib - SurvivorNet - February 1st, 2021
- Atsena Therapeutics Raises $55 Million Series A Financing to Advance LCA1 Gene Therapy Clinical Program, Two Preclinical Assets, and Novel Capsid... - December 17th, 2020
- Locanabio Announces $100 Million Series B Financing to Advance Portfolio of Novel RNA-Targeted Gene Therapies for Neurodegenerative, Neuromuscular and... - December 17th, 2020
- NeuBase Therapeutics Announces Positive Preclinical In Vivo Data for PATrOL-enabled Anti-gene for the Treatment of Myotonic Dystrophy Type 1 -... - December 17th, 2020
- Genetic Analysis Services Market: Uptake of Next-generation Sequencing and Multi-gene Tests to Drive Market - BioSpace - December 17th, 2020
- FDA Clears Genetic Modification in Pigs for Biomedicine and Food - The Scientist - December 17th, 2020
- Key Genes Related to Severe COVID-19 Infection Identified - The Scientist - December 17th, 2020
- UNLV Researcher on the Curious Case of COVID-19 Reinfection - UNLV NewsCenter - December 17th, 2020
- Genomics and medicine it's complicated | Health | willistonherald.com - Williston Daily Herald - December 17th, 2020
- Emedgene collaborates with Illumina to scale the interpretation of genomic data for rare diseases - PRNewswire - December 17th, 2020
- Polymerase Chain Reaction Market | Increased Outbreak of Infectious Diseases to Accentuate Demand in the Market - BioSpace - December 17th, 2020
- LogicBio Therapeutics names Daphne Karydas and Jeff Goater to Board of Directors - BioSpace - December 17th, 2020
- rBIO Achieves Crucial Milestone on Mission to Lower the Cost of Insulin by 30% - BioSpace - December 17th, 2020
- Report: More than 1,300 Medicines and Vaccines in Development to Help Fight Cancer - PRNewswire - December 17th, 2020
- San Diego's Locanabio raises $100 million for treatments aimed at degenerative diseases - The San Diego Union-Tribune - December 17th, 2020
- Worldwide SNP Genotyping Industry to 2025 - Pharmacogenomics Led the End-user Segment of the SNP Genotyping Market - ResearchAndMarkets.com - Business... - December 17th, 2020
- Potential Weakness in SARS-CoV-2 Discovered Single Protein Needed for COVID-19 Virus to Reproduce and Spread - SciTechDaily - December 17th, 2020
- Landing of $75M expansion of Texas-based Taysha adds to Triangle's growing gene therapy hub - WRAL Tech Wire - December 17th, 2020
- Track the Vax: What Do We Need to Know About the New Vaccines? - Everyday Health - December 17th, 2020
- Medical history from the year you were born - Quad City Times - December 5th, 2020
- Sarepta Therapeutics to Share Clinical Update for SRP-5051, its Investigational PPMO for the Treatment of Duchenne Muscular Dystrophy - GlobeNewswire - December 5th, 2020
- Biochip Market | Increased Popularity of Personalized Medicine to Boost the Market Growth | Technavio - Business Wire - December 5th, 2020
- December: Baby birth weight research | News and features - University of Bristol - December 5th, 2020
- Global Next Generation Sequencing Market (2020 to 2026) - Growth, Trends, Competitive Landscape, and Forecasts - GlobeNewswire - December 5th, 2020
- NIH researchers link cases of ALS and FTD to a mutation associated with Huntington's disease - National Institute on Aging - December 5th, 2020
- Precision Medicine Market Poised to Grow at 11.5% By 20227 - GlobeNewswire - December 5th, 2020
- Fact check: mRNA vaccines kept at very cold temperatures so that they do not break apart; COVID-19 vaccines will not genetically modify humans -... - December 5th, 2020
- Stoke Therapeutics Announces Presentations Related to the Company's Work to Advance STK-001, the First Potential New Medicine to Target the Underlying... - December 5th, 2020
- King George III's illness debunked as symptom 'caused by medicine prescribed to him' - Express - December 5th, 2020
- Stoke Therapeutics to Present at the Needham Virtual Epilepsy & Pain Specialty CNS Therapeutics Conference - Business Wire - December 5th, 2020
- Following the science: the writers who have made sense of Covid - The Guardian - December 5th, 2020
- Gene experts claim they identified human genes that can protect against Covid-19 - CNBC - November 23rd, 2020
- Genome Medical Reaches 90 Million Covered Lives in US - PRNewswire - November 23rd, 2020
- Sarepta Therapeutics Named One of The Boston Globe's Top Places to Work 2020 - GlobeNewswire - November 23rd, 2020
- New Study Highlights the Importance of Genetic Testing for Pancreatic Cancer Patients - PRNewswire - November 23rd, 2020
- Baylor Genetics Launches Combination Test for COVID-19 and Influenza A and B; Multi-Panel Test Seeks to Address Dilemma of "Overlapping symptoms... - November 23rd, 2020
- Myriad Genetics Announces Global Expansion of Myriad myChoice Tumor Testing in Europe and China - GlobeNewswire - November 23rd, 2020
- Epigenetics and pulmonary diseases in the horizon of precision medicine: a review - DocWire News - November 23rd, 2020
- Four years after landing in US, graduating ISU senior is on his way to medical school - Iowa State University News Service - November 23rd, 2020
- Lethal brain infections in mice thwarted by decoy molecule - Washington University School of Medicine in St. Louis - November 23rd, 2020