Stories about: Science

With no time to lose, parents drive CMT4J gene therapy forward

CMT4J
Talia Duff’s disorder, CMT4J, is a rare form of Charcot-Marie-Tooth. It has been modeled in mice that will soon undergo a test of gene therapy, largely through her parents’ behind-the-scenes work.

In honor of Rare Disease Day (Feb. 28), we salute “citizen scientists” Jocelyn and John Duff.

When Talia Duff was born, her parents realized life would be different, but still joyful. They were quickly adopted by the Down syndrome parent community and fell in love with Talia and her bright smile.

But when Talia was about four, it was clear she had a true problem. She started losing strength in her arms and legs. When she got sick, which was often, the weakness seemed to accelerate.

Talia was initially diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), an autoimmune disease in which the body attacks its own nerve fibers. Treated with IV immunoglobulin infusions to curb the inflammation, she seemed to grow stronger — but only for a time. Adding prednisone, a steroid, seemed to help. But it also caused bone loss, and Talia began having spine fractures.

“We tried a lot of different things, but she never got 100 percent better,” says Regina Laine, NP, who has been following Talia in Boston Children’s Hospital’s Neuromuscular Center the past several years, together with Basil Darras, MD.That’s when we decided to readdress the possibility that it was genetic.”

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A gene therapy advance for muscle-wasting myotubular myopathy

X-linked myotubular myopathy XLMTM gene therapy
Nibs, a carrier of MTM whose descendants provided the basis for the gene therapy study. (Read more of her story.)

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.

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Honoring rare disease ‘citizen scientists’

citizen scientists

The global theme of this year’s Rare Disease Day (February 28) is research, and in keeping with that, we salute a very important group of people: citizen scientists. These can-do patients and family members are putting previously undiagnosed rare diseases on the map and driving the search for treatments. Citizen scientists play multiple roles: They keep scientists focused on therapeutic development, conduct online research to connect ideas, set up patient networks and data registries, raise money and start companies. They’ve earned a voice in clinical trial design and were instrumental in the passage of the 21st Century Cures Act.

Meet a few citizen scientists who have inspired us recently.

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Gene therapy restores whisper-fine hearing, balance in Usher syndrome mice

gene therapy for deafness
Sensory hair cells contain tiny cilia that get wiggled by incoming sound waves, sparking a signal to the brain that ultimately translates to hearing. Gene therapy restored this tidy “V” formation. (Credit: Gwenaelle Géléoc and Artur Indzkykulian)

The ear is a part of the body that’s readily accessible to gene therapy: You can inject a gene delivery vector (typically a harmless virus) and it has a good chance of staying put. But will it ferry the corrected gene into the cells of the hearing and/or vestibular organs where it’s most needed?

Back in 2015, a Boston Children’s Hospital/Harvard Medical School team reported using gene therapy to restore rudimentary hearing in mice with genetic deafness. Previously unresponsive mice began jumping when exposed to abrupt loud sounds. But the vector used could get the corrected genes only into the cochlea’s inner hair cells. To really restore significant hearing, the outer hair cells need to be treated too.

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Why I’m tall and you’re short: GIANT effort finds rare, potent height genes

height genes that make us tall or short

Height is the “poster child” of complex genetic traits, meaning that it’s influenced by multiple genetic variants working together. Because height is easy to measure, it’s a relatively simple model for understanding traits produced by not one gene, but many.

“Mastering the complex genetics of height may give us a blueprint for studying multifactorial disorders that have eluded our complete understanding, such as diabetes and heart disease,” says Joel Hirschhorn, MD, PhD, a pediatric endocrinologist and researcher at Boston Children’s Hospital and the Broad Institute of MIT and Harvard.

Hirschhorn chairs the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, an international group that’s just probed more deeply into the genetics of height than ever before. Its findings, reported today in Nature, reveal previously unknown biological pathways tied to height.

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Seeking a way to keep organs young

Images of mouse hearts with fibrosis
These mouse hearts show differing levels of fibrosis (blue) resulting from cardiac stress. New Boston Children’s Hospital research suggests certain therapies could prevent or reduce fibrosis, like we see in the center and right images.

The wear and tear of life takes a cumulative toll on our bodies. Our organs gradually stiffen through fibrosis, which is a process that deposits tough collagen in our body tissue. Fibrosis happens little by little, each time we experience illness or injury. Eventually, this causes our health to decline.

“As we age, we typically accumulate more fibrosis and our organs become dysfunctional,” says Denisa Wagner, PhD, the Edwin Cohn Professor of Pediatrics in the Program in Cellular and Molecular Medicine and a member of the Division of Hematology/Oncology at Boston Children’s Hospital and Harvard Medical School.

Ironically, fibrosis can stem from our own immune system’s attempt to defend us during injury, stress-related illness, environmental factors and even common infections.

But a Boston Children’s team of scientists thinks preventative therapies could be on the horizon. A study by Wagner and her team, published recently by the Journal of Experimental Medicine, pinpoints a gene responsible for fibrosis and identifies some possible therapeutic solutions.

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Rare blood disorder sideroblastic anemia slowly reveals its genetic secrets

congenital sideroblastic anemia
Regardless of the gene, all patients with sideroblastic anemia have sideroblasts: red blood cell precursors with abnormal iron deposits in mitochondria, shown here ringing the cell nucleus. (Paulo Henrique Orlandi Mourao/Wikimedia)

A decade ago, Brooks McMurray’s routine check-up was anything but routine. The suburban Boston boy’s spleen was enlarged. His red blood cell count was low and the cells were very small and very pale, which suggested a serious iron deficiency anemia. The family pediatrician referred McMurray, now a 19-year-old college freshman, to Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

There hematologists discovered the boy had unexpectedly high iron levels. Together with pathologist Mark Fleming, MD, DPhil, they solved the mystery. McMurray has congenital sideroblastic anemia, an inherited blood disorder so rare that fewer than 1,000 cases have been reported worldwide. Iron was getting stuck in the wrong place in the precursor red blood cells developing in his bone marrow.

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Soft robot could aid failing hearts by mimicking healthy cardiac muscle

heart-failure

Every year, about 2,100 people receive heart transplants in the U.S., while 5.7 million suffer from heart failure. Given the scarcity of available donor hearts, clinicians and biomedical engineers from Boston Children’s Hospital and Harvard University have spent several years developing a mechanical alternative.

Their proof of concept is reported today in Science Translational Medicine: a soft robotic sleeve that is fitted around the heart, where it twists and compresses the heart’s chambers just like healthy cardiac muscle would do.

Heart failure occurs when one or both of the heart’s ventricles can no longer collect or pump blood effectively. Ventricular assist devices (VADs) are already used to sustain end-stage heart failure patients awaiting transplant, replacing the work of the ventricles through tubes that take blood out of the heart, send it through pumps or rotors and power it back into a patient’s bloodstream. But while VADs extend lives, they can cause complications.

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DNA methylation patterns linked to obesity and its complications

DNA methylation obesity
(Methylated DNA: Christoph Bock, Max Planck Institute for Informatics/Wikimedia Commons)

Why do some people seem to be prone to weight gain? Obesity has been linked to a variety of genetic changes, yet these differences don’t fully explain the variation in people’s body mass index (BMI). “Even though we’ve genetically sequenced more and more people at greater and greater breadth and depth, we haven’t completely explained who develops obesity and why,” says Michael Mendelson, MD, ScM, a pediatric cardiologist with Boston Children’s Hospital’s Preventive Cardiology Program.

Nor do prior studies explain why some overweight people develop health complications from obesity, like cholesterol problems, diabetes, hypertension and heart disease, while others don’t. Now comes strong evidence that an important factor is DNA methylation — a so-called epigenetic modification that influences whether genes are turned on or off.

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Zinc chelation: A better way to regenerate the optic nerve?

optic nerve zinc chelation

For more than two decades, researchers have tried to regenerate the injured optic nerve using different growth factors and/or agents that overcome natural growth inhibition. They’ve had partial success, sometimes even restoring rudimentary elements of vision in mouse models.

But at best, these methods get only about 1 percent of the injured nerve fibers to regenerate and reconnect the retina to the brain. That’s because most of the damaged cells, known as retinal ganglion cells (RGCs), eventually die, says Larry Benowitz, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

Benowitz and colleagues now show a surprising new approach that gets RGCs to live longer and regenerate robustly: using chelating agents to bind up zinc that’s released as a result of the injury.

These studies, too, were done in mice. If the findings hold up in human studies, they could spell hope for people with optic nerve injury due to trauma, glaucoma or other causes, and possibly even spinal cord injury.

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