In the summer of 2015, a team at Boston Children’s Hospital and Harvard Medical School reported restoring rudimentary hearing in genetically deaf mice using gene therapy. Now the Boston Children’s research team reports restoring a much higher level of hearing — down to 25 decibels, the equivalent of a whisper — using an improved gene therapy vector developed at Massachusetts Eye and Ear.
While previous vectors have only been able to penetrate the cochlea’s inner hair cells, the first Nature Biotechnology study showed that a new synthetic vector, Anc80, safely transferred genes to the hard-to-reach outer hair cells when introduced into the cochlea (see images). This study’s three Harvard Medical School senior investigators were Jeffrey R. Holt PhD, of Boston Children’s Hospital; Konstantina Stankovic, MD, PhD, of Mass. Eye and Ear and Luk H. Vandenberghe, PhD, who led Anc80’s development in 2015 at Mass. Eye and Ear’s Grousbeck Gene Therapy Center.
“We have shown that Anc80 works remarkably well in terms of infecting cells of interest in the inner ear,” says Stankovic, an otologic surgeon at Mass. Eye and Ear and associate professor of otolaryngology at Harvard Medical School. “With more than 100 genes already known to cause deafness in humans, there are many patients who may eventually benefit from this technology.”
The second study, led by Gwenaëlle Géléoc, PhD, of the Department of Otolaryngology and F.M. Kirby Neurobiology Center at Boston Children’s, used Anc80 to deliver a specific corrected gene in a mouse model of Usher syndrome, the most common genetic form of deaf-blindness that also impairs balance function.
“This strategy is the most effective one we’ve tested,” Géléoc says. “Outer hair cells amplify sound, allowing inner hair cells to send a stronger signal to the brain. We now have a system that works well and rescues auditory and vestibular function to a level that’s never been achieved before.”
Ushering in gene therapy for deafness
Géléoc and colleagues at Boston Children’s Hospital studied mice with a mutation in Ush1c, the same mutation that causes Usher type 1c in humans. The mutation causes a protein called harmonin to be nonfunctional. As a result, the sensory hair cell bundles that receive sound and signal the brain deteriorate and become disorganized, leading to profound hearing loss.
When a corrected Ush1c gene was introduced into the inner ears of the mice, the inner and outer hair cells in the cochlea began to produce normal full-length harmonin. The hair cells formed normal bundles (see images) that responded to sound waves and signaled the brain, as measured by electrical recordings.
Most importantly, deaf mice treated soon after birth began to hear. Géléoc and colleagues showed this first in a “startle box,” which detects whether a mouse jumps in response to sudden loud sounds. When they next measured responses in the auditory regions of the brain, a more sensitive test, the mice responded to much quieter sounds: 19 of 25 mice heard sounds quieter than 80 decibels, and a few could heard sounds as soft as 25-30 decibels, like normal mice.
“Now, you can whisper, and they can hear you,” says Géléoc, also an assistant professor of otolaryngology at Harvard Medical School.
Margaret Kenna, MD, MPH, a specialist in genetic hearing loss at Boston Children’s who does research on Usher syndrome, is excited about the work. “Anything that could stabilize or improve native hearing at an early age would give a huge boost to a child’s ability to learn and use spoken language,” she says. “Cochlear implants are great, but your own hearing is better in terms of range of frequencies, nuance for hearing voices, music and background noise, and figuring out which direction a sound is coming from. In addition, the improvement in balance could translate to better and safer mobility for Usher Syndrome patients.”
Restoring balance and potentially vision
Since patients (and mice) with Usher 1c also have balance problems caused by hair-cell damage in the vestibular organs, the researchers also tested whether gene therapy restored balance. It did, eliminating the erratic movements of mice with vestibular dysfunction (see images) and, in another test, enabled the mice to stay on a rotating rod for longer periods without falling off.
Further work is needed before the technology can be brought to patients. One caveat is that the mice were treated right after birth; hearing and balance were not restored when gene therapy was delayed 10-12 days. The researchers will do further studies to determine the reasons for this. However, when treated early, the effects persisted for at least six months, with only a slight decline between 6 weeks and 3 months. The researchers also hope to test gene therapy in larger animals, and plan to develop novel therapies for other forms of genetic hearing loss.
Usher syndrome also causes blindness by causing the light-sensing cells in the retina to gradually deteriorate. Although these studies did not test for vision restoration, gene therapy in the eye is already starting to be done for other disorders.
“We already know the vector works in the retina,” says Géléoc, “and because deterioration is slower in the retina, there is a longer window for treatment.”
“Progress in gene therapy for blindness is much further along than for hearing, and I believe our studies take an important step toward unlocking a future of hearing gene therapy,” says Vandenberghe, also an assistant professor of ophthalmology at Harvard Medical School. “In the case of Usher syndrome, combining both approaches to ultimately treat both the blinding and hearing aspects of disease is very compelling, and something we hope to work toward.”
“This is a landmark study,” says Holt, director of otolaryngology research at Boston Children’s Hospital, who was also a co-author on the second paper. “Here we show, for the first time, that by delivering the correct gene sequence to a large number of sensory cells in the ear, we can restore both hearing and balance to near-normal levels.”
At 300 Longwood Avenue, Children’s is adjacent both to its teaching affiliate, Harvard Medical School, and to Dana-Farber Cancer Institute. (Dana-Farber and Children’s jointly operate Dana-Farber/Children’s Hospital Cancer Care, a 60-year-old partnership established to deliver comprehensive care to children with and survivors of all types of childhood cancers.) In 2012, Children’s was ranked by U.S. News & World Report as the nation’s number one pediatric hospital, along with the Children’s Hospital of Philadelphia.
With more than 680,000 square feet (63,000 m2) of state-of-the-art laboratory space, Children’s is home to the world’s largest research enterprise based at a pediatric medical center. Its discoveries have benefited children and adults since 1869. More than 1,100 scientists, including 9 members of the National Academy of Sciences, 13 members of the Institute of Medicine and 15 members of the Howard Hughes Medical Institute, comprise Children’s research community. Children’s current initiatives are supported by a record US $225 million in funding, which includes more federal funding than is awarded to any other pediatric facility.
In the John F. Enders Pediatric Research laboratories, named for the Children’s researcher and Nobel Prize recipient who cultured the polio and measles viruses, hundreds of laboratory researchers and physician investigators search for answers to some of the most perplexing diseases.
In 2003, Children’s dramatically increased its research capacity with the opening of the 295,000-square-foot (27,400 m2) Karp Family Research Laboratories. The Karp family gift is one of many important gifts that support Children’s vital research enterprise.
In an effort to support the research community, Children’s Stem Cell Program investigator George Q. Daley, M.D., Ph.D., has made dozens of iPS lines developed at Boston Children’s Hospital available for use by other scientists through the Harvard Stem Cell Institute. To date, cell lines have been distributed to over 65 laboratories worldwide.
In 2010, a drug that boosts numbers of blood stem cells, originally discovered in zebrafish in the Boston Children’s Hospital laboratory of Leonard I. Zon, M.D., went to clinical trial in patients with leukemia and lymphoma.
Through the years, scientists at Children’s have set the pace in pediatric research, identifying treatments and therapies for many debilitating diseases, including those of adulthood.
Boston Children’s Hospital research articles from Innovation Toronto
- Drug ‘cocktail’ plus gene therapy could restore vision in optic nerve injury – January 17, 2016
- Medical millirobots offer hope for less-invasive surgeries – May 31, 2015
- Researchers Regrow Human Corneas: First Known Tissue Grown from a Human Stem Cell – July 5, 2014
- ‘Heart disease-on-a-chip’
- Potential peanut allergy breakthrough garners Genentech’s interest at Children’s Hospital
- Injectable ‘Smart Sponge’ Holds Promise for Controlled Drug Delivery
Sleeve attaches directly around the heart
Harvard University and Boston Children’s Hospital researchers have developed a customizable soft robot that fits around a heart and helps it beat, potentially opening new treatment options for people suffering from heart failure.
The soft robotic sleeve twists and compresses in synch with a beating heart, augmenting cardiovascular functions weakened by heart failure. Unlike currently available devices that assist heart function, Harvard’s soft robotic sleeve does not directly contact blood. This reduces the risk of clotting and eliminates the need for a patient to take potentially dangerous blood thinner medications. The device may one day be able to bridge a patient to transplant or to aid in cardiac rehabilitation and recovery.
“This research demonstrates that the growing field of soft robotics can be applied to clinical needs and potentially reduce the burden of heart disease and improve the quality of life for patients,” said Ellen T. Roche, the paper’s first author and former PhD student at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and The Wyss Institute of Biologically Inspired Engineering at Harvard University. Roche is currently a postdoctoral fellow at the National University of Ireland Galway.
“This work represents an exciting proof of concept result for this soft robot, demonstrating that it can safely interact with soft tissue and lead to improvements in cardiac function. We envision many other future applications where such devices can delivery mechanotherapy both inside and outside of the body,” said Conor Walsh, senior author of the paper and the John L. Loeb Associate Professor of Engineering and Applied Sciences at SEAS and Core Faculty Member at the Wyss Institute.
Heart failure affects 41 million people worldwide. Today, some of the options to treat it are mechanical pumps called ventricular assist devices (VADs), which pump blood from the ventricles into the aorta, and heart transplant. While VADs are continuously improving, patients are still at high risk for blood clots and stroke.
To create an entirely new device that doesn’t come into contact with blood, Harvard researchers took inspiration from the heart itself. The thin silicone sleeve uses soft pneumatic actuators placed around the heart to mimic the outer muscle layers of the mammalian heart. The actuators twist and compress the sleeve in a similar motion to the beating heart.
The device is tethered to an external pump, which uses air to power the soft actuators.
The sleeve can be customized for each patient, said Roche. If a patient has more weakness on the left side of the heart, for example, the actuators can be tuned to give more assistance on that side. The pressure of the actuators can also increase or decrease over time, as the patient’s condition evolves.
The sleeve is attached to the heart using a combination of a suction device, sutures and a gel interface to help with friction between the device and the heart.
The SEAS and Wyss engineers worked with surgeons at Boston Children’s Hospital to develop the device and determine the best ways to implant the device and test it on animal models.
“The cardiac field had turned away from idea of developing heart compression instead of blood-pumping VADs due to technological limitations, but now with advancements in soft robotics it’s time to turn back,” said Frank Pigula, a cardiothoracic surgeon and co-corresponding author on the study, who was formerly clinical director of pediatric cardiac surgery at Boston Children’s Hospital and is now a faculty member at University of Louisville and division chief of pediatric cardiac surgery at Norton Children’s Hospital. “Most people with heart failure do still have some function left; one day the robotic sleeve may help their heart work well enough that their quality of life can be restored.”
More research needs to be done before the sleeve can be implanted in humans but the research is an important first step towards an implantable soft robot that can augment organ function.
Harvard’s Office of Technology Development has filed a patent application and is actively pursuing commercialization opportunities.
“This research is really significant at the moment because more and more people are surviving heart attacks and ending up with heart failure,” said Roche. “Soft robotic devices are ideally suited to interact with soft tissue and give assistance that can help with augmentation of function, and potentially even healing and recovery.”
Learn more: Soft robot helps the heart beat
Early influenza detection and the ability to predict outbreaks are critical to public health. Reliable estimates of when influenza will peak can help drive proper timing of flu shots and prevent health systems from being blindsided by unexpected surges, as happened in the 2012-2013 flu season.
The Centers for Disease Control and Prevention collects accurate data, but with a time lag of one to two weeks. Google Flu Trends began offering real-time data in 2008, based on people’s Internet searches for flu-related terms. But it ultimately failed, at least in part because not everyone who searches “flu” is actually sick. As of last year, Google instead now sends its search data to scientists at the CDC, Columbia University and Boston Children’s Hospital.
Now, a Boston Children’s-led team demonstrates a more accurate way to pick up flu trends in near-real-time — at least a week ahead of the CDC — by harnessing data from electronic health records (EHRs).
As Mauricio Santillana, PhD, John Brownstein, PhD, and colleagues describe in Scientific Reports, the team combined EHR data, historical patterns of flu activity and a machine-learning algorithm to interpret the data. This clinical “big data” approach produced predictions of national and local influenza activity that closely matched the CDC’s subsequent reporting.
“Our study shows the true value of considering multiple data streams in disease surveillance,” says Brownstein, the study’s senior investigator and Chief Innovation Officer at Boston Children’s Hospital. “While Google data provide incredible real-time, population-wide information, clinical data add a more accurate and precise assessment of disease state.”
Crunching EHR data
Instrumental to the study were data from collaborator Athenahealth, encompassing more than 72,000 healthcare providers and EHRs for more than 23 million patients.
The investigators first trained their flu-prediction algorithm, called ARES, with data captured from June 2009 through January 2012: weekly total visit counts, visit counts for flu and flu-like illness, visit counts for flu vaccination and more. ARES then used that intelligence to estimate flu activity over the next three years, through June 2015.
The team showed that ARES’ estimates of national and regional flu activity had error rates two to three times lower than earlier predictive models. ARES also correctly estimated the timing and magnitude of the national flu “peak week.” It was slightly less accurate in predicting regional peak weeks, but clearly outperformed Google Flu Trends on all measures.
The idea of capturing data directly from health care encounters definitely makes sense — assuming such data can be liberated from proprietary, HIPAA-bound healthcare IT systems. “As EHR data become more ubiquitously available, we will see major leaps in our ability to monitor and track disease outbreaks,” says Brownstein.
“Having access to near-real-time aggregated EHR information has enabled us to significantly improve our flu tracking and forecasting systems,” agrees Santillana, a member of Boston Children’s Computational Health Informatics Program (CHIP), and also affiliated with Harvard Medical School and the Harvard Institute for Applied Computational Sciences. “Real-time tracking will enable local public health officials to better prepare for unusual flu activity and potentially save lives.”