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gene therapy

Hematopoietic hierarchy aging blood cell hematopoietic stem cell blood disorder Derrick Rossi

Blood-forming hematopoietic stem cells (top) give rise to all blood and immune cell types. In children with SCID, the steps leading to immune cells are broken.

In the world of fatal congenital immunodeficiency diseases, good news is always welcome, because most patients die before their first birthday if not treated. Babies with severe combined immunodeficiency disease, aka SCID or the “bubble boy disease,” now have more hope for survival thanks to two pieces of good news.

Transplants are looking up

First came a July paper in the New England Journal of Medicine (NEJM) by the Primary Immune Deficiency Treatment Consortium. This North American collaborative analyzed a decade’s worth of outcomes of hematopoietic stem cell transplant (HSCT), currently the only standard treatment option for SCID that has a chance of providing a permanent cure. Full story »

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genome editing CRISPR Cas9Technology sometimes unfolds at a slow, measured pace and sometimes at lightning speed. Right now, we are witnessing what is arguably one of the fastest moving fields in biomedical science: a form of genome editing aptly known as CRISPR.

CRISPR allows researchers to make very precise—some would say crisp—changes to the genomes of human cells and those of other organisms. You might think of it as a kind of guided missile. Its precision is opening the doors to a wide variety of research and, hopefully, medical applications. Indeed, the possibilities seem to be bound only by scientists’ imaginations.

“For a long time, we have been accumulating new knowledge about which gene mutation causes which disease. But until very recently, we haven’t had the ability to go in and correct those mutations,” explains Feng Zhang, PhD, a core member of the Broad Institute of Harvard and MIT, and one of the method’s pioneers. “CRISPR is one of the tools that is starting to allow us to directly go in and do surgery on the genome and replace the mutations.”

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. While this name is a bit verbose, it points to the technology’s origins: a set of genetic sequences first discovered in bacteria. Full story »

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Bioengineered blood vessels

A bioengineered network of blood vessels

Juan Melero-Martin, PhD, runs a cell biology and bioengineering lab in the department of Cardiac Surgery at Boston Children’s Hospital. In May, he received an Early Career Investigator Award from Bayer HealthCare, part of the prestigious Bayer Hemophilia Award.

In 1982, insulin became the first FDA-approved protein drug created through recombinant DNA technology. It was made by inserting the human insulin gene into a bacterial cell’s DNA, multiplying the bacteria and capturing and purifying the human insulin in bioreactors. Full story »

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Emir Seyrek Wiskott-Aldrich syndrome WAS gene therapy Dana-Farber/Boston Children's Cancer and Blood Disorders Center

Emir Seyrek was the first patient with Wiskott-Aldrich syndrome to be treated in the U.S. in an international gene therapy trial.

Seeing that his mother, Kadriye, wasn’t looking, Emir Seyrek got an impish grin on his face, the kind only a two-year-old can have. He quietly dumped his bowl of dry cereal out on his bed and, with another quick look towards his mother, proceeded to pulverize the flakes to dust with his toy truck. The rest of the room burst out laughing while his mother scolded him. Despite the scolding, though, the impish grin remained.

It was hard to believe that he arrived from Turkey six months earlier fighting a host of bacterial and viral infections. Emir was born with Wiskott-Aldrich syndrome (WAS), a genetic immunodeficiency that left him with a defective immune system. He was here because he was the first patient—of two so far—to take part in an international trial of a new gene therapy treatment for WAS at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. And that day he was having his final checkup at Boston Children’s Hospital’s Clinical and Translational Study Unit before going home. Full story »

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Ear-engraved styleThis post is adapted from a commentary in this week’s edition of Science by Jeffrey R. Holt, PhD, and Gwenaelle S. G. Géléoc, PhD, of the Department of Otolaryngology and F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

Hearing loss affects more than 300 million people worldwide, making it the most common sensory disorder. While there are no cures, recent efforts to develop biological treatments for hearing loss provide reason for cautious optimism. Three strategies—gene therapy, stem cells and drugs—have shown encouraging results in animal models, poising them for translation into potential therapies for humans.

Hearing loss can arise from many different causes, so it is unlikely that a single “magic bullet” will be developed to treat all forms of deafness. Rather, each individual cause may require a tailored and specific treatment strategy. Full story »

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Alison Frase with Nibs, a carrier of MTM whose descendants provided the basis for the gene therapy study.

Alison Frase with Nibs, a carrier of MTM whose descendants provided the basis for the gene therapy study.

Babies born with X-linked myotubular myopathy (MTM), which affects about one in 50,000 male births, are commonly referred to as “floppy.” They have very weak skeletal muscles, making it difficult to walk or breathe; survival requires intensive support, often including tube feeding and mechanical ventilation. Most children with MTM never reach adulthood.

One of these children, Joshua Frase, succumbed to MTM on Christmas Eve, 2010. The son of former NFL player Paul Frase, he lived to age 15. But his parents, who continue to actively support MTM research, now see a glimmer of hope for children born with the disease today.

A preclinical study on the cover of last week’s Science Translational Medicine, funded in part by the Joshua Frase Foundation, showed dramatic improvements in muscle strength using gene replacement therapy in mouse and dog models of MTM—paving the way for a potential clinical trial. Full story »

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Researchers have silenced the third copy of chromosome 21, at least in a dish. What might this mean for Down syndrome? (Wikimedia Commons)

Researchers have silenced the third copy of chromosome 21, at least in a dish. What might this mean for Down syndrome? (Wikimedia Commons)

Emily Jean Davidson, MD, MPH, is clinical director of the Down Syndrome Program at Boston Children’s Hospital. Walter Kaufmann, MD, and David Stein, PsyD, research co-directors for the Down Syndrome Program, contributed to this post, along with Nicole Baumer, MD, fellow in Neurodevelopmental Disabilities, and Down Syndrome Program Coordinator Angela Lombardo, BA.

Last week, researchers at the University of Massachusetts published a fascinating and important study on Down syndrome in Nature. Lisa Hall, PhD, Jeanne Lawrence, PhD, and their colleagues were able to effectively “shut down” the gene activity of one of the three copies of the 21st chromosome in cells with trisomy 21.

What exactly did they do?  The research team started with skin cells from a man with trisomy 21 that were transformed into induced pluripotent stem cells—cells that act like cells from an embryo and can develop into different cell types. They then took a gene from the X chromosome that is responsible for making sure that only one X chromosome is active in females—the X-inactivation gene—and inserted it in a specific location on chromosome 21. Full story »

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Will Ward at the NSTAR Walk for Boston Children’s Hospital in 2012—his family’s fifth year leading a team to raise funds for the Beggs Laboratory.

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.

Neither has Alan Beggs, PhD, who directs the Manton Center for Orphan Disease Research at Boston Children’s Hospital, and who has known Will since he was a newborn in intensive care.

“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. Full story »

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Agustín Cáceres, once a virtual "bubble boy," is no longer on infectious disease precautions.

For the Cáceres family of Argentina, it’s a joyous holiday homecoming. Agustín, who received gene therapy at 5½ months of age, journeyed with his family to Boston for a check-up and got a clean bill of health.

Agustín was born with the rare immune-deficiency disorder SCID-X1. More popularly known as “bubble boy” disease, it left him defenseless against infections, unable to make enough T-cells to fight them off. His baptism was the only time his family could come near him, all wearing masks, gloves and gowns. His infancy was spent in isolation with his mother.

Now, at age 2½, Agustín has been cleared to go to nursery school, ride a bus and attend large family gatherings without fear of contracting a life-threatening infection. When we caught up with him, he was chasing and tumbling with his older brother Jeremías while waiting to bid farewell to his care team. Full story »

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David Williams wants to turn cells from Fanconi anemia (FA) patients into stem-like iPS cells. To do that, though, he needs to get the patients' cells to reboot properly. (_rockinfree/Flickr)

About a decade ago, David Williams, MD, set out to solve a problem. The chief of Dana-Farber/Children’s Hospital Cancer Center’s Hematology/Oncology division wanted to treat Fanconi anemia (FA)—a rare, inherited bone marrow failure disease—using gene therapy. In the process, he’d be able to replace patients’ faulty bone marrow cells with ones corrected for the genetic defect that causes FA.

There was one big problem though. “The main bar to attempting gene therapy in FA is that you need to be able to collect a certain number of blood stem cells from a patient in order to be able to give enough corrected cells back,” he says. “In our early clinical trials, we were unable to provide enough corrected stem cells to reverse the bone marrow failure we see in these patients.”

One way around the supply issue would be to create the necessary blood stem cells from FA patients’ own cells by first reprogramming skin cells into what are called induced pluripotent stem (iPS) cells. Using one of several methods, scientist can reboot mature skin cells into an immature, stem cell-like state—essentially turning the cells’ biological clocks back to a time when they could grow into anything the body might need. Full story »

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