Making it personal: How genetic technologies are changing the face of medicine

The age of one-size-fits-all medicine is fading. Taking its place is an era of personalized medicine - the practice of tailoring disease prevention, diagnosis, and treatment to patients as individuals. Many cancers, for example, are resistant to conventional therapies but respond to medications that target specific cancer-causing genetic mutations. Scientists and clinicians at Children's Hospital Los Angeles developed a comprehensive genetic testing panel called OncoKids® to detect genetic markers that respond to targeted therapies. This technological advance has connected patients with life-saving clinical trials and medications.

Personalized medicine has expanded its capabilities as technology has grown. Scientists are now using a technology called metagenomic next-generation sequencing, or mNGS, to rapidly test clinical samples. This powerful assay can quickly compare unknown genetic material from a patient sample against thousands of known pathogen genomes. "Basically, we can determine the cause of the disease, whether it's a virus, bacteria, or something else," says Jeffrey Bender, MD, a physician specializing in infectious diseases at CHLA. "If it has genetic material, this test can identify the infection and provide information that allows us to select a treatment specific to fight it."

Now that science has the capability to sequence and compare genomes, it is becoming clear that genomic testing can, and should be, used to identify infectious pathogens. This is especially important in diseases that could stem from multiple potential causes. For example, meningitis and encephalitis are serious central nervous system conditions that often arise from infection. Proper and timely diagnoses of these infections are critical so that patients can receive treatments before complications develop. But many types of pathogens - bacteria, viruses, fungi, and parasites - can cause meningitis and encephalitis, making targeted testing difficult. Though laboratories can test samples for a handful of possible culprits, there is a limit to the number of pathogens they can test for at one time. Negative results can delay treatments and leave doctors, patients, and families searching for answers.

Now, clinicians at CHLA and sites nationwide are showing that broader genetic testing can deliver answers that standard laboratory tests fail to provide. Instead of one particular target, mNGS testing quickly compares sample genetic material to thousands of targets. Dr. Bender and Jennifer Dien Bard, PhD, Director of the Clinical Microbiology and Virology Laboratory at CHLA, participated in a multi-center clinical trial to evaluate the clinical use of mNGS testing in pediatric patients with suspected meningitis or encephalitis.

Their study, highlighted today in the New England Journal of Medicine showed that this 'agnostic' testing could lead to treatments for infections that were not identified using standard testing methods. More than 200 patients at 8 hospitals, including CHLA, were enrolled in this year-long study. Cerebrospinal fluid was sampled from patients who presented with meningitis- or encephalitis-like symptoms. Samples were then analyzed using either standard laboratory testing or mNGS. Out of 58 total diagnoses, sequencing identified 13 infections - more than 20% - that were not detected in standard clinical testing.

Dr. Dien Bard and her colleagues in the Center for Personalized Medicine envision a future in which these agnostic, genomic assays are integrated into routine clinical care. "The trial showed just how sequencing technology can really have a positive clinical impact on patients. In just this study alone, thirteen infections were diagnosed solely because of this technology," she says. "That's thirteen additional families who got answers."

Michael R Wilson, Hannah A Sample, Kelsey C Zorn, Shaun Arevalo, Guixia Yu, John Neuhaus, Scot Federman, Doug Stryke, Benjamin Briggs, Charles Langelier, Amy Berger, Vanja Douglas, S Andrew Josephson, Felicia C Chow, Brent D Fulton, Joseph L DeRisi, Jeffrey M Gelfand, Samia N Naccache, Jeffrey Bender, Jennifer Dien Bard, Jamie Murkey, Magrit Carlson, Paul M Vespa, Tara Vijayan, Paul R Allyn, Shelley Campeau, Romney M Humphries, Jeffrey D Klausner, Czarina D Ganzon, Fatemeh Memar, Nicolle A Ocampo, Lara L Zimmermann, Stuart H Cohen, Christopher R Polage, Roberta L DeBiasi, Barbara Haller, Ronald Dallas, Gabriela Maron, Randall Hayden, Kevin Messacar, Samuel R Dominguez, Steve Miller, Charles Y Chiu.
Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.
N Engl J Med 2019; 380:2327-2340. doi: 10.1056/NEJMoa1803396
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