Skip to main content

2021

Welcoming President Biden

Posted on by

On December 2, President Joe Biden visited NIH for a briefing on the importance of vaccines and booster shots. They remain vital this holiday season to slowing the spread of the SARS-CoV-2 coronavirus, the cause of COVID-19, and saving lives. It was my honor to greet the President, though with a careful fist bump, and I got to speak with him briefly before he delivered his remarks about the White House’s strategy for fighting COVID-19 this winter. Credit: NIH

Tapping Into The Brain’s Primary Motor Cortex

Posted on by

If you’re like me, you might catch yourself during the day in front of a computer screen mindlessly tapping your fingers. (I always check first to be sure my mute button is on!) But all that tapping isn’t as mindless as you might think.

While a research participant performs a simple motor task, tapping her fingers together, this video shows blood flow within the folds of her brain’s primary motor cortex (gray and white), which controls voluntary movement. Areas of high brain activity (yellow and red) emerge in the omega-shaped “hand-knob” region, the part of the brain controlling hand movement (right of center) and then further back within the primary somatic cortex (which borders the motor cortex toward the back of the head).

About 38 seconds in, the right half of the video screen illustrates that the finger tapping activates both superficial and deep layers of the primary motor cortex. In contrast, the sensation of a hand being brushed (a sensory task) mostly activates superficial layers, where the primary sensory cortex is located. This fits with what we know about the superficial and deep layers of the hand-knob region, since they are responsible for receiving sensory input and generating motor output to control finger movements, respectively [1].

The video showcases a new technology called zoomed 7T perfusion functional MRI (fMRI). It was an entry in the recent Show Us Your BRAINs! Photo and Video Contest, supported by NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative.

The technology is under development by an NIH-funded team led by Danny J.J. Wang, University of Southern California Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles. Zoomed 7T perfusion fMRI was developed by Xingfeng Shao and brought to life by the group’s medical animator Jim Stanis.

Measuring brain activity using fMRI to track perfusion is not new. The brain needs a lot of oxygen, carried to it by arteries running throughout the head, to carry out its many complex functions. Given the importance of oxygen to the brain, you can think of perfusion levels, measured by fMRI, as a stand-in measure for neural activity.

There are two things that are new about zoomed 7T perfusion fMRI. For one, it uses the first ultrahigh magnetic field imaging scanner approved by the Food and Drug Administration. The technology also has high sensitivity for detecting blood flow changes in tiny arteries and capillaries throughout the many layers of the cortex [2].

Compared to previous MRI methods with weaker magnets, the new technique can measure blood flow on a fine-grained scale, enabling scientists to remove unwanted signals (“noise”) such as those from surface-level arteries and veins. Getting an accurate read-out of activity from region to region across cortical layers can help scientists understand human brain function in greater detail in health and disease.

Having shown that the technology works as expected during relatively mundane hand movements, Wang and his team are now developing the approach for fine-grained 3D mapping of brain activity throughout the many layers of the brain. This type of analysis, known as mesoscale mapping, is key to understanding dynamic activities of neural circuits that connect brain cells across cortical layers and among brain regions.

Decoding circuits, and ultimately rewiring them, is a major goal of NIH’s BRAIN Initiative. Zoomed 7T perfusion fMRI gives us a window into 4D biology, which is the ability to watch 3D objects over time scales in which life happens, whether it’s playing an elaborate drum roll or just tapping your fingers.

References:

[1] Neuroanatomical localization of the ‘precentral knob’ with computed tomography imaging. Park MC, Goldman MA, Park MJ, Friehs GM. Stereotact Funct Neurosurg. 2007;85(4):158-61.

[2]. Laminar perfusion imaging with zoomed arterial spin labeling at 7 Tesla. Shao X, Guo F, Shou Q, Wang K, Jann K, Yan L, Toga AW, Zhang P, Wang D.J.J bioRxiv 2021.04.13.439689.

Links:

Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke)

Laboratory of Functional MRI Technology (University of Southern California Mark and Mary Stevens Neuroimaging and Informatics Institute)

The Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

Show Us Your BRAINs! Photo and Video Contest (BRAIN Initiative)

NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Biomedical Imaging and Bioengineering; Office of the Director


Encouraging News on Gene Therapy for Hemophilia A

Posted on by

Factor VIII gene carried in AAV Vector plus Immunosuppressive drugs; person with hemophilia A; microscopic view of blood with Factor VIII

About 20,000 people in the U.S. live with hemophilia A. It’s a rare X-linked genetic disorder that affects predominantly males and causes their blood to clot poorly when healing wounds. For some, routine daily activities can turn into painful medical emergencies to stop internal bleeding, all because of changes in a single gene that disables an essential clotting protein.

Now, results of an early-stage clinical trial, published recently in the New England Journal of Medicine, demonstrate that gene therapy is within reach to produce the essential clotting factor in people with hemophilia A. The results show that, in most of the 18 adult participants, a refined gene therapy strategy produced lasting expression of factor VIII (FVIII), the missing clotting factor in hemophilia A [1]. In fact, gene therapy helped most participants reduce—or, in some cases, completely eliminate—bleeding events.

Currently, the most-common treatment option for males with hemophilia A is intravenous infusion of FVIII concentrate. Though infused FVIII becomes immediately available in the bloodstream, these treatments aren’t a cure and must be repeated, often weekly or every other day, to prevent or control bleeding.

Gene therapy, however, represents a possible cure for hemophilia A. Earlier clinical trials reported some success using benign adeno-associated viruses (AAVs) as the vector to deliver the therapeutic FVIII gene to cells in the liver, where the clotting protein is made. But after a year, those trial participants had a marked decline in FVIII expression. Follow-up studies then found that the decline continued over time, thought to be at least in part because of an immune response to the AAV vector.

In the new study, an NIH-funded team led by Lindsey George and Katherine High of the Children’s Hospital of Philadelphia and the University of Pennsylvania, tested their refined delivery system. High is also currently with Asklepios BioPharmaceutical, Inc., Chapel Hill, NC. (Back in the 1970s, she and I were medical students in the same class at the University of North Carolina.) The study was also supported by Spark Therapeutics, Philadelphia.

Trial participants received a single infusion of the novel recombinant AAV-based gene therapy called SPK-8011. It is specifically designed to produce FVIII expression in the liver. In this phase 1/2 clinical trial, which evaluates the safety and initial efficacy of a treatment, participants received one of four different doses of SPK-8011. Most also received steroids to prevent or treat the presumed counterproductive immune response to the therapy.

The researchers followed participants for a year after the experimental treatment, and all enrolled in a follow-up trial for continued observation. During this time, researchers detected no major safety concerns, though several patients had increases in blood levels of a liver enzyme.

The great news is all participants produced the missing FVIII after gene therapy. Twelve of the 16 participants were followed for more than two years and had no apparent decrease in clotting factor activity. This is especially noteworthy because it offers the first demonstration of multiyear stable and durable FVIII expression in individuals with hemophilia A following gene transfer.

Even more encouraging, the men in the trial had more than a 92 percent reduction in bleeding episodes on average. Before treatment, most of the men had 8.5 bleeding episodes per year. After treatment, those events dropped to an average of less than one per year. However, two study participants lost FVIII expression within a year of treatment, presumably due to an immune response to the therapeutic AAV. This finding shows that, while steroids help, they don’t always prevent loss of a therapeutic gene’s expression.

Overall, the findings suggest that AAV-based gene therapy can lead to the durable production of FVIII over several years and significantly reduce bleeding events. The researchers are now exploring possibly more effective ways to control the immune response to AAV in expansion of this phase 1/2 investigation before pursuing a larger phase 3 trial. They’re continuing to monitor participants closely to establish safety and efficacy in the months and years to come.

On a related note, the recently announced Bespoke Gene Therapy Consortium (BGTC), a partnership between NIH and industry, will expand the refined gene therapy approach demonstrated here to more rare and ultrarare diseases. That should make these latest findings extremely encouraging news for the millions of people born with other rare genetic conditions caused by known alterations to a single gene.

Reference:

[1] Multiyear Factor VIII expression after AAV Gene transfer for Hemophilia A. George LA, Monahan PE, Eyster ME, Sullivan SK, Ragni MV, Croteau SE, Rasko JEJ, Recht M, Samelson-Jones BJ, MacDougall A, Jaworski K, Noble R, Curran M, Kuranda K, Mingozzi F, Chang T, Reape KZ, Anguela XM, High KA. N Engl J Med. 2021 Nov 18;385(21):1961-1973.

Links:

Hemophilia A (National Center for Advancing Translational Sciences/NIH)

FAQ About Rare Diseases (National Center for Advancing Translational Sciences/NIH)

Bespoke Gene Therapy Consortium (BGTC) (NIH)

Accelerating Medicines Partnership® (AMP®) (NIH)

Lindsey George (University of Pennsylvania, Philadelphia)

Katherine High (University of Pennsylvania)

NIH Support: National Heart, Lung, and Blood Institute


A Special Thanksgiving Day Concert

Posted on by

What an inspiring afternoon I spent at the NIH Clinical Center. Caesar Sant, a 13-year-old violinist and child prodigy whose family now lives in the Memphis area, gave a special Thanksgiving Day concert. I got to accompany on guitar, but the moment belonged to his amazing talent. Caesar was born in August 2008 with sickle cell disease. As a participant in an NIH clinical trial, Caesar recently received a bone marrow transplant in hopes of curing his disease. So far so good.


Feeling Grateful This Thanksgiving for Biomedical Research

Posted on by

Credit: Lucky Business/Shutterstock

Yes, we can all agree that 2021 has been a tough year. But despite all that, Thanksgiving is the right time to stop and count our many blessings. My list starts with my loving wife Diane and family, all of whom have been sources of encouragement in these trying times. But also high up on the list this Thanksgiving is my extreme gratitude to the scientific community for all the research progress that has been made over the past 23 months to combat the pandemic and return our lives ever closer to normal.

Last year, we were busy learning how to celebrate a virtual Thanksgiving. This year, most of us are feeling encouraged about holding face-to-face gatherings once again—but carefully!—and coordinating which dishes to prepare for the annual feast.

The COVID-19 vaccines, developed by science in record time and with impressive safety and effectiveness, have made this possible. The almost 230 million Americans who have chosen to receive at least one dose of a COVID-19 vaccine have taken a critical step to protect themselves and others. They have made this season a much safer one for themselves and those around them than a year ago. That includes almost all adults ages 65 and up. While vaccination rates aren’t yet as high as they need to be in younger age groups, about 70 percent of Americans ages 12 and up are now fully vaccinated.

But with evidence that the effectiveness of the vaccines can wane over time and with the continued threat of the Delta variant, I was happy to see the recent approval by both FDA and CDC that all adults 18 and over are now eligible to receive a booster. That is, provided you are now more than 6 months past your initial immunization with the Moderna or Pfizer or 2 months past your immunization with the Johnson & Johnson vaccine. I recently got my Moderna booster and I’m glad for that additional protection. Don’t wait—the booster is the best way to defend against a possible winter surge.

Children age 5 and up are also now eligible to get the Pfizer vaccine, a development that I know brought a sense of relief and gratitude for many parents with school-aged children at home. It will take a little time for full vaccination of this age group. But more than 2.5 million young kids around the country already have rolled up their sleeves and have some immunity against COVID-19. These children are on track to be fully vaccinated before Christmas.

I’m also extremely grateful for all the progress that’s been made in treating COVID-19. Developing new treatments typically takes many years, if not decades. But NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, a public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies, has helped lead the way to this rapid progress.

We’ve seen successes in the use of monoclonal antibodies and in the repurposing of existing drugs, such as blood thinning treatments, to keep folks hospitalized with COVID-19 from becoming severely ill and needing some form of organ support. Now it looks as though our hopes for safe and effective oral antiviral medicines to reduce the risk of severe illness in individuals just diagnosed with COVID-19 could soon be realized, too.

To combat COVID-19, rapid and readily accessible testing also is key, and NIH’s Rapid Acceleration of Diagnostics (RADx®) initiative continues to speed innovation in COVID-19 testing. RADx® also recently launched a simple online calculator tool to help individuals make critical decisions about when to get a test [1]. Meanwhile, a new initiative called Say Yes! COVID Test (SYCT) is exploring how best to implement home-testing programs in our communities.

More research progress is on the way. But, until the pandemic is history, please remember to stay safe this holiday season. The best way to do so is to get fully vaccinated [2]. As I noted above, most adults who got vaccinated earlier this year are now eligible for a booster shot to ensure they remain well protected. Go to vaccines.gov to find the site closest to you that can provide the shot.

The best way to protect young children who aren’t yet eligible or fully vaccinated and others who may be at higher risk is by making sure you and others around them are vaccinated. It’s still strongly recommended to wear a well-fitting mask over your nose and mouth when in public indoor settings, especially if there’s considerable spread of COVID-19 in your community.

If you are gathering with multiple households or people from different parts of the country, consider getting tested for COVID-19 in advance and take extra precautions before traveling. By taking full advantage of all the many scientific advances we’ve made over the last year, we can now feel good about celebrating together again this holiday season. Happy Thanksgiving!

References:

[1] When to Test offers free online tool to help individuals make informed COVID-19 testing decisions. National Institutes of Health. November 3, 2021.

[2] Safer ways to celebrate holidays. Centers for Disease Control and Prevention. October 15, 2021.

Links:

COVID-19 Research (NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)

Rapid Acceleration of Diagnostics (RADx®) (NIH)

When To Test (Consortia for Improving Medicine with Innovation & Technology, Boston)


Next Page