Stories about: genetics

Patients’ individual genomes may affect efficacy, safety of gene editing

gene editing - truck delivering code
Subtle genetic variants in or near the gene editing target site could cause reagents to miss an address or arrive at the wrong one, researchers say.

Gene editing has begun to be tested in clinical trials, using CRISPR-Cas9, zinc finger nucleases (ZFN) and other technologies to directly edit DNA inside people’s cells. Multiple trials are in the recruiting or planning stages. But a study in PNAS this week raises a note of caution, finding that person-to-person genetic differences may undercut the efficacy of the gene editing process or, in more rare cases, cause a potentially dangerous “off target” effect.

The study adds to evidence that gene editing may need to be adapted to each patient’s genome, to ensure there aren’t variants in DNA sequence in or near the target gene that would throw off the technology.

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Mutations accumulate in our brain cells as we age. Do they explain cognitive loss?

the aging brain - do DNA mutations in neurons account for cognitive loss?

Scientists have long wondered whether somatic, or non-inherited, mutations play a role in aging and brain degeneration. But until recently, there was no good technology to test this idea.

Enter whole-genome sequencing of individual neurons. This fairly new technique has shown that our brain cells have a great deal of DNA diversity, making neurons somewhat like snowflakes. In a study published online today in Science, the same single-neuron technique provides strong evidence that our brains acquire genetic mutations over time.

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Why evolution is the challenge — and the promise — in developing a vaccine against HIV

HIV surrounds and attacks a cell.
HIV surrounds and attacks a cell.

To fight HIV, the development of immunization strategies must keep up with how quickly the virus modifies itself. Now, Boston Children’s Hospital researchers are developing models to test HIV vaccines on a faster and broader scale than ever before with the support of the Bill & Melinda Gates Foundation.

“The field of HIV research has needed a better way to model the immune responses that happen in humans,” says Frederick Alt, PhD, director of the Boston Children’s Program in Cellular and Molecular Medicine, who is leading the HIV vaccine research supported by the Gates Foundation.

The researchers are racing against HIV’s sophisticated attack on the human immune system. HIV, the human immunodeficiency virus, mutates much faster than other pathogens. Within each infected patient, one virus can multiply by the billions.

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Why do some people with cystic fibrosis live much longer than others?

Lung tissue, which can be compromised by the genetic disorder known as cystic fibrosis, is seen under microscopic view.
Lung tissue under microscope.

The answer may be hidden in their genes.

Cystic fibrosis is an inherited disorder caused by genetic mutations that disrupt the normal movement of chloride in and out of cells. Among other health problems, cystic fibrosis compromises the lungs’ ability to fight infection and breathe efficiently, making it the most lethal genetic disease in the Caucasian population. Patients have an average lifespan of just 30 to 40 years.

Despite this narrow average lifespan, there is a big range in how severely cystic fibrosis (CF) affects the lungs and other organs depending on an individual’s specific genetic variation, and even in how long patients sharing the same, most common genetic mutation are able to survive with CF.

This led researchers at Boston Children’s Hospital to wonder if other genetic mutations could be protective against CF’s effects. Recent findings published in the American Journal of Respiratory Cell and Molecular Biology suggest that may be the case.

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Can rare pain syndromes point the way to new analgesics?

analgesic drug discovery could reduce prescription opioid use
Boston Children’s Hospital and Amgen will collaborate to discover and accelerate non-addicting pain drugs.

As the opioid epidemic deepens and drug overdoses increase, effective non-addicting painkillers are desperately needed. Efforts to discover new pain pathways to target with new drugs have thus far had little success. Other promising research is investigating triggerable local delivery systems for non-opioid nerve blockers, but it’s still in the early stages.

A new collaboration between Boston Children’s Hospital and the biopharmaceutical company Amgen is aimed at accelerating new pain treatments. Announced yesterday, it will revolve around patients with rare, perplexing pain syndromes. The scientists hope that the genetic variants they find in these patients will shed new light on pain biology and lead to new ways of controlling pain. 

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Gene therapy halts progression of cerebral adrenoleukodystrophy in clinical trial

David Williams, MD, the principal investigator of the clinical trial, discusses gene therapy and its impact on children with adrenoleukodystrophy

Adrenoleukodystrophy — depicted in the 1992 movie “Lorenzo’s Oil” — is a genetic disease that most severely affects boys. Caused by a defective gene on the X chromosome, it triggers a build-up of fatty acids that damage the protective myelin sheaths of the brain’s neurons, leading to cognitive and motor impairment. The most devastating form of the disease is cerebral adrenoleukodystrophy (CALD), marked by loss of myelin and brain inflammation. Without treatment, CALD ultimately leads to a vegetative state, typically claiming boys’ lives within 10 years of diagnosis.

But now, a breakthrough treatment is offering hope to families affected by adrenoleukodystrophy. A gene therapy treatment effectively stabilized CALD’s progression in 88 percent of patients, according to clinical trial results reported in the New England Journal of Medicine. The study was led by researchers from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Massachusetts General Hospital.

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In search of young medical geneticists

Nina Gold, MD, is Chief Resident of Medical Genetics at Boston Children’s Hospital.

During a quiet stretch of my final year in medical school, I read Sir Arthur Conan Doyle’s Sherlock Holmes stories. A master observer, the detective found secrets in wrinkles of clothes, tints of hair, scents of perfume, never satisfied until the truth was revealed. Sherlock was, simply, an expert diagnostician.

In the spring of 2014, I became the first student in my medical school to pursue residency training in a combined pediatrics and medical genetics program. Like Sherlock, pediatric geneticists are stalwart investigators. They are often called into a case long after other consultants and tasked with bringing a family’s diagnostic odyssey to an end. But unlike the emotionally obtuse fictional detective, geneticists must describe their findings with empathy and clarity to concerned families after they solve a mystery.

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Making leaps and bounds in 10 years of genome-wide association studies

A Broad Institute cartoon explains what SNPs have to do with genome-wide association studies
A clip from a Broad Institute infographic explains what researchers look for during genome-wide association studies. Download full infographic here. Credit: Susanna Hamilton/Karen Zusi of the Broad Institute.

In 2007, when the first genome-wide association studies (GWAS) got underway, researchers began to realize just how poorly they had previously been able to predict which genes might be related to certain diseases.

“I think we were all surprised how bad our candidate gene lists were,” said Joel Hirschhorn, MD, PhD, in a recent podcast with the Broad Institute of MIT and Harvard. Hirschhorn, a pioneer in GWAS, now leads the international Genetic Investigation of Anthropometric Traits (GIANT) Consortium, which has analyzed the genomes of hundreds of thousands of people over the last several years.

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“Omics” study takes a comprehensive look at premature birth

Seven layers of omics study
Seven layers of “omics” included in the PREM-MAP study

Every year, one in 10 new babies in the United States is born preterm, or before 37 weeks of gestation. With the last few weeks of pregnancy crucial to proper development of the lungs and brain, prematurely born infants can suffer lifelong problems.

Now scientists at Boston Children’s Hospital and Beth Israel Deaconess Medical Center have launched a comprehensive study to understand the reasons and risk factors for premature births. Earlier this year, Olaf Bodamer, MD, PhD was awarded a grant for this work from uBiome, a microbial genomics company.

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If I knew then what I know now: The need for infrastructure to enable precision medicine

precision medicine - closing the infrastructure loop
For precision medicine to happen, we need to be able to close the loop when genetic discoveries are made.

Catherine Brownstein, MPH, PhD, is scientific director of The Manton Center for Orphan Disease Research at Boston Children’s Hospital. Kelsey Graber, MSc, is a research assistant in the Developmental Neuropsychiatry Program. Joseph Gonzalez-Heydrich, MD, is director of the Developmental Neuropsychiatry Program at Boston Children’s Hospital.

Research implicating rare genetic variants in medical and psychiatric diseases is quickly accumulating. This expanding knowledge should be taken into account when making treatment decisions for patients carrying these variants — as well as other family members — even when that knowledge comes after the patient is tested. But all too often, medical institutions are unable to go back and update the information given to families. We need a better infrastructure to enable precision medicine.

This problem recently surfaced in our psychiatry practice. It came to our attention because of a young boy with mild coordination delays and learning disabilities. At age 6, he started experiencing daily hallucinations such as voices telling him to kill his classmates.

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