Current newborn screening tests a baby’s blood for several dozen known, treatable conditions. Can full-on DNA sequencing at birth add more benefit? Interpreting sequencing results is complex: having a genetic variant doesn’t always mean having the disease, and many of the conditions identified may not currently be treatable.
Will Ward’s birthday falls on Rare Disease Day (Feb. 28). That’s an interesting coincidence because he has a rare disease: X-linked myotubular myopathy (MTM), a rare, muscle-weakening disease that affects only boys. Originally on Snapchat, this video captures the Ward family’s recent visit to the lab of Alan Beggs, PhD to learn more about MTM research.
Beggs, director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital, has known Will since he was a newborn in intensive care. In this lab walk-though you’ll see a freezer filled with muscle samples, stored in liquid nitrogen; muscle tissue under a microscope; gene sequencing to identify mutations causing MTM and other congenital myopathies and a testing station to measure muscle function in samples taken from animal models.
Beggs’s work, which began more than 20 years ago, led to pivotal studies in male Labrador retrievers who happen to have the same mutation and are born with a canine form of MTM. By adding back a healthy copy of the gene, Beggs’s collaborators got the dogs back on their feet running around again. (Read about Nibs, a female MTM carrier whose descendants took part in these studies.)
Based on the canine results, a clinical trial is now testing gene therapy in boys under the age of 5 with MTM. The phase I/II trial aims to enroll 12 boys and measure their respiratory and motor function and muscle structure after being dosed with a vector carrying a corrected MTM gene. In the meantime, observational and retrospective studies are characterizing the natural history of boys with MTM.
Boys born with X-linked myotubular myopathy (XLMTM) face a grim prognosis. Extreme muscle weakness leaves many ventilator-dependent from birth, and most infants need feeding tubes. About half pass away before 18 months of age.
Last week, the biotechnology company Audentes Therapeutics announced the dosing of the first patient in a gene-therapy clinical trial — 21 years after the MTM1 gene was first cloned.
Hopes are high. Gene therapy has already shown striking benefits in dogs with XLMTM in studies co-authored by Alan Beggs, PhD, director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital, and colleagues at Généthon and the University of Washington. In the most recent study, 10-week-old Labrador retrievers already showing signs of the disease showed improvements in breathing, limb strength and walking gait after a single dose of the gene therapy vector. …
For more than two decades, Alan Beggs, PhD, at Boston Children’s Hospital has explored the genetic causes of congenital myopathies, disorders that weaken children’s muscles, and investigated how the mutations lead to muscle weakness. For one life-threatening disorder, X-linked myotubular myopathy (XLMTM), the work is approaching potential payoff, in the form of a clinical gene therapy trial.
Boys with XLMTM are born so weak that they are dependent on ventilators and feeding tubes to survive. Almost half die before 18 months of age. …
It seems like a great idea. We all have our genomes sequenced at birth, and any findings that suggest a future medical problem are addressed with early interventions, optimizing our health and extending our lives. But are parents of newborns ready to embrace the vision? Yes and no, according to interim results of a first-of-its-kind randomized trial of newborn sequencing. Findings from what’s known as the BabySeq Project were presented last week at the American Society of Human Genetics (ASHG) 2016 Annual Meeting. …
President Obama’s Precision Medicine Initiative, first laid out in his 2015 State of Union Address, aims to develop individualized care that empowers patients and takes into account genetic, environmental and lifestyle differences. Obama is asking Congress for $309 million for the initiative next year.
One big component is the Department of Veteran Affairs’ Million Veteran Program, which has signed up more than 450,000 veterans to date and is now open to active-duty military personnel. Another is NIH support for cancer trials that match treatments with patients’ genomic profiles.
As Might detailed today at a White House summit on the Precision Medicine Initiative, he now has worms at the University of Utah modeling his son’s disease, whose symptoms include seizures, extreme developmental delay and an inability to make tears. He also has a molecular target and a list of 70 compounds that hit it, including 14 that are already approved by the FDA.
Can Might’s vision be scaled and made part of routine medical care, keeping the patient front and center? …
Back in the 1990s, rheumatologist Richard Weisbart, MD, of University of California, Los Angeles (UCLA), was studying lupus in a mouse model and found that the mice were making an antibody that had the intriguing ability to get inside tissues and cells.
Dustin Armstrong, PhD, a postdoc at Novartis at the time, was trying to find molecules that could activate growth in weakened muscles—without activating possibly cancerous growth in other tissues. He saw Weisbart’s work and contacted UCLA. In 2008, he obtained seed money and founded a company around 3E10-based therapeutics for muscular diseases, now known as Valerion Therapeutics (formerly 4s3 Bioscience).
“There’s a huge need for therapies for genetic muscle diseases, and muscle was a tissue we could target well with our technology,” says Armstrong. …
This two-part series examines two potential treatment approaches for myotubular myopathy, a genetic disorder that causes muscle weakness from birth.
Sixth-grader William Ward cruises the hallways at school with a thumb-driven power chair and participates in class with the help of a DynaVox speech device. Although born with a rare, muscle-weakening disease called X-linked myotubular myopathy, or MTM, leaving him virtually immobile, he hasn’t given up.
“From the very beginning, Alan connected with our family in a very human way,” says Will’s mother, Erin Ward. “In the scientific community, he’s been the bridge and the connector of researchers around the world. That makes him unique.”
Since the 1990s, Beggs has enrolled more than 500 patients with congenital myopathies from all over the world in genetic studies, seeking causes and potential treatments for congenital myopathies—rare, often fatal diseases that weaken children’s skeletal muscles from birth, often requiring them to breathe on a ventilator and to receive food through a gastrostomy tube. …