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.
Boston Children’s Hospital is now enrolling patients age 3 to 35 in a clinical trial of gene therapy for sickle cell disease. Based on technology developed its own labs, it differs from other gene therapy approaches by having a two-pronged action. It represses production of the mutated beta hemoglobin that causes red blood cells to form the stiff “sickle” shapes that block up blood vessels. It also increases production of the fetal form of hemoglobin, which people normally stop making after birth.
Fetal hemoglobin doesn’t sickle and works fine for oxygen transport. The gene therapy being tested now restores fetal hemoglobin production by turning “off” a silencing gene called BCH11A.
“BCL11A represses fetal hemoglobin and also activates beta hemoglobin, which is affected by the sickle-cell mutation,” David Williams, MD, the trial’s principal investigator, told Vector last year. Williams is also president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in this disease.”
The therapy is the product of multiple discoveries, the first dating back 70 years. Click selected images below to enlarge. …
New tools and technologies fueled biomedicine to great heights in 2017. Here are just a few of our top picks. All are great examples of research informing better care for children (and adults).
1. Gene therapy arrives
In 2017, gene therapy solidly shed the stigma of Jesse Gelsinger’s 1999 death with the development of safer protocols and delivery vectors. Though each disease must navigate its own technical and regulatory path to gene therapy, the number of clinical trials is mounting worldwide, with seven gene therapy trials now recruiting at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. In August, the first gene therapy won FDA approval: CAR T-cell therapy for pediatric acute lymphoblastic leukemia. …
A therapeutic technique to transplant blood-forming (hematopoietic) stem cells directly into the brain could herald a revolution in our approach to treating central nervous system diseases and neurodegenerative disorders.
The technique, which could be used to transplant donor-matched hematopoietic stem cells (HSCs) or a patient’s own genetically-engineered HSCs into the brain, was reported in Science Advances today by researchers from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the San Raffaele Telethon Institute for Gene Therapy.
In their study, the team tested the technique in a mouse model to treat lysosomal storage disorders, a group of severe metabolic disorders that affect the central nervous system.
The team’s findings are groundbreaking because, until now, it was thought that HSCs — from a healthy, matched donor or a patient’s own genetically-corrected cells — needed to be transplanted indirectly …
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.
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. …
Today, the Food and Drug Administration approved a gene therapy known as CAR T-cell therapy that genetically modifies a patient’s own cells to help them combat pediatric acute lymphoblastic leukemia (ALL), the most common childhood cancer. It is the first gene therapy to be approved by the FDA.
“This represents the progression of the field of gene therapy, which has been developing over the last 30 years,” says gene therapy pioneer David A. Williams, MD, who is chief scientific officer of Boston Children’s Hospital and president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “It’s a realization of what we envisioned to be molecular medicine when this research started. The vision — that we could alter cells in a way to cure disease — is now coming true.” …
Gene therapy stalled in the early 2000s as adverse effects came to light in European trials (leukemias triggered by the gene delivery vector) and following the 1999 death of U.S. patient Jesse Gelsinger. But after 30 years of development, and with the advent of safer vectors, gene therapy is becoming a clinical reality. It falls into two main categories:
In vivo: Direct injection of the gene therapy vector, carrying the desired gene, into the bloodstream or target organ.
Ex vivo: Removal of a patient’s cells, treating the cells with gene therapy, and reinfusing them back into the patient, as in hematopoietic stem cell transplant and CAR T-cell therapy.
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.” …
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. …