Clinical Trials Bring Hope to Kids with Spinal Muscular Atrophy

Faith Fortenberry

More than a decade ago, the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) launched a special project to accelerate the translation of basic scientific discoveries into new treatments for a rare and often fatal disease. Five-year-old Faith Fortenberry whom you see above is among the kids who may benefit from the success of this pioneering endeavor.

Faith was born with spinal muscular atrophy (SMA), a hereditary neurodegenerative disease that can affect movement, breathing, and swallowing. When the NIH project began, there was no treatment for SMA, but researchers had discovered that mutations in the SMN1 gene were responsible for the disorder. Such mutations cause a deficiency of SMN protein, leading to degeneration of neurons in the brain and spinal cord, and progressive muscle weakness throughout the body. The NIH effort supported research to discover ways of raising SMN levels in cells grown in lab dishes, and then worked closely with patient advocates and pharmaceutical companies to move the most promising leads into drug development and clinical testing.

Given the desperate need for SMA treatments and all of the scientific energy that’s been devoted to pursuing them, I’ve been following this field closely. So, I was very encouraged to learn recently about the promising results of human tests of not just one—but two—new treatments for SMA [1, 2]. Continue reading

Find and Replace: DNA Editing Tool Shows Gene Therapy Promise

Neutrophil being edited with CRISPR/Cas9

Caption: This image represents an infection-fighting cell called a neutrophil. In this artist’s rendering,  the cell’s DNA is being “edited” to help restore its ability to fight bacterial invaders.
Credit: NIAID, NIH

For gene therapy research, the perennial challenge has been devising a reliable way to insert safely a working copy of a gene into relevant cells that can take over for a faulty one. But with the recent discovery of powerful gene editing tools, the landscape of opportunity is starting to change. Instead of threading the needle through the cell membrane with a bulky gene, researchers are starting to design ways to apply these tools in the nucleus—to edit out the disease-causing error in a gene and allow it to work correctly.

While the research is just getting under way, progress is already being made for a rare inherited immunodeficiency called chronic granulomatous disease (CGD). As published recently in Science Translational Medicine, a team of NIH researchers has shown with the help of the latest CRISPR/Cas9 gene-editing tools, they can correct a mutation in human blood-forming adult stem cells that triggers a common form of CGD. What’s more, they can do it without introducing any new and potentially disease-causing errors to the surrounding DNA sequence [1].

When those edited human cells were transplanted into mice, the cells correctly took up residence in the bone marrow and began producing fully functional white blood cells. The corrected cells persisted in the animal’s bone marrow and bloodstream for up to five months, providing proof of principle that this lifelong genetic condition and others like it could one day be cured without the risks and limitations of our current treatments.

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Snapshots of Life: Lighting up the Promise of Retinal Gene Therapy

mouse retina

Caption: Large-scale mosaic confocal micrograph showing expression of a marker gene (yellow) transferred by gene therapy techniques into the ganglion cells (blue) of a mouse retina.
Credit: Keunyoung Kim, Wonkyu Ju, and Mark Ellisman, National Center for Microscopy and Imaging Research, University of California, San Diego

The retina, like this one from a mouse that is flattened out and captured in a beautiful image, is a thin tissue that lines the back of the eye. Although only about the size of a postage stamp, the retina contains more than 100 distinct cell types that are organized into multiple information-processing layers. These layers work together to absorb light and translate it into electrical signals that stream via the optic nerve to the brain.

In people with inherited disorders in which the retina degenerates, an altered gene somewhere within this nexus of cells progressively robs them of their sight. This has led to a number of human clinical trials—with some encouraging progress being reported for at least one condition, Leber congenital amaurosis—that are transferring a normal version of the affected gene into retinal cells in hopes of restoring lost vision.

To better understand and improve this potential therapeutic strategy, researchers are gauging the efficiency of gene transfer into the retina via an imaging technique called large-scale mosaic confocal microscopy, which computationally assembles many small, high-resolution images in a way similar to Google Earth. In the example you see above, NIH-supported researchers Wonkyu Ju, Mark Ellisman, and their colleagues at the University of California, San Diego, engineered adeno-associated virus serotype 2 (AAV2) to deliver a dummy gene tagged with a fluorescent marker (yellow) into the ganglion cells (blue) of a mouse retina. Two months after AAV-mediated gene delivery, yellow had overlaid most of the blue, indicating the dummy gene had been selectively transferred into retinal ganglion cells at a high rate of efficiency [1].

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Creative Minds: Applying CRISPR Technology to Cancer Drug Resistance

Patrick Hsu

Patrick Hsu

As a child, Patrick Hsu once settled a disagreement with his mother over antibacterial wipes by testing them in controlled experiments in the kitchen. When the family moved to Palo Alto, CA, instead of trying out for the football team or asking to borrow the family car like other high school kids might have done, Hsu went knocking on doors of scientists at Stanford University. He found his way into a neuroscience lab, where he gained experience with the fundamental tools of biology and a fascination for understanding how the brain works. But Hsu would soon become impatient with the tools that were available to ask some of the big questions he wanted to study.

As a Salk Helmsley Fellow and principal investigator at the Salk Institute for Biological Studies, La Jolla, CA, Hsu now works at the intersection of bioengineering, genomics, and neuroscience with a DNA editing tool called CRISPR/Cas9 that is revolutionizing the way scientists can ask and answer those big questions. (This blog has previously featured several examples of how this technology is revolutionizing biomedical research.) Hsu has received a 2015 NIH Director’s Early Independence award to adapt CRISPR/Cas9 technology so its use can be extended to that other critically important information-containing nucleic acid—RNA.Specifically, Hsu aims to develop ways to use this new tool to examine the role of a certain type of RNA in cancer drug resistance.

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Study Suggests Alternative Approach to AIDS Vaccine

Decoy protein

Caption: A decoy protein that mimics the CD4 receptor (red), the CCR5 receptor (green), and a natural antibody (grey), binds to the HIV envelope protein (three white blobs) and blocks it from infecting immune cells.
Credit: Michael Farzan

Over more than a century, researchers have succeeded in developing vaccines to prevent polio, smallpox, cervical cancer, and many other viral diseases. For three decades now, they have tried to design an effective vaccine for the human immunodeficiency virus (HIV) that causes AIDS. Despite plenty of hard work, lots of great science, and some promising advances along the way, an effective traditional vaccine still remains elusive. That has encouraged consideration of alternative approaches to block HIV infection.

Now in the journal Nature [1], an NIH-funded team reports promising early results with one of these interesting alternatives. The team hypothesized that producing a protein that binds to HIV and prevents it from entering cells might provide protection. So they designed such a protein, and, using an animal model, introduced multiple copies of a gene that makes this protein. In a small study of non-human primates, this gene-therapy approach blocked HIV infection, even when the animals were exposed repeatedly to large doses of the virus.

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