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New Gene therapy trial shows restored hearing and speech in children born deaf, treated in both ears
A novel gene therapy designed to target a form of inherited deafness restored hearing function in five children who were treated in both ears. The children also experienced better speech perception and gained the ability to localize and determine the position of sound. The study, the world’s first clinical trial to administer a gene therapy to both ears (bilaterally), demonstrates additional benefits than what were observed in the first phase of this trial, published earlier this year, when children were treated in one ear. The research was led by investigators from Mass Eye and Ear (a member of the Mass General Brigham healthcare system) and Eye & ENT Hospital of Fudan University in Shanghai, and findings were published June 5th in Nature Medicine.
The researchers noted their team’s goal was always to treat children in both ears to achieve the ability to hear sound in three dimensions, a capability important for communication and common daily tasks such as driving.
“Restoring hearing in both ears of children who are born deaf can maximize the benefits of hearing recovery,” said lead study author Yilai Shu MD, PhD, professor, director of Diagnosis and Treatment Center of Genetic Hearing Loss affiliated with the Eye & ENT Hospital of Fudan University in Shanghai, “These new results show this approach holds great promise and warrant larger international trials.”
Over 430 million people around the world are affected by disabling hearing loss, of which congenital deafness constitutes about 26 million of them. Up to 60 percent of childhood deafness is caused by genetic factors. Children with DFNB9 are born with mutations in the OTOF gene that prevent the production of functioning otoferlin protein, which is necessary for the auditory and neural mechanisms underlying hearing.
This new study is the first clinical trial to use bilateral ear gene therapy for treating DFNB9. The new research presents an interim analysis of a single-arm trial of five children with DFNB9 who were observed over either a 13-week or 26-week period at the Eye & ENT Hospital of Fudan University in Shanghai, China. Shu injected functioning copies of the human OTOF transgene carried by adeno-associated virus (AAV) into the inner ears of patients through a specialized, minimally invasive surgery. The first case of bilateral treatment was conducted in July 2023. During follow-up, 36 adverse events were observed, but no dose-limiting toxicity or serious events occurred. All five children showed hearing recovery in both ears, with dramatic improvements in speech perception and sound localization. Two of the children gained an ability to appreciate music, a more complex auditory signal, and were observed dancing to music in videos captured for the study. The trial remains ongoing with participants continuing to be monitored.
In 2022, this research team delivered the first gene therapy in the world for DFNB9 as part of a trial of six patients in China treated in one ear. That trial, which had results published in The Lancet in January 2024, showed five of six children gained improvements in hearing and speech. Shu initially presented the data at the 30th annual congress of European Society of Gene and Cell Therapy (ESGCT) in Brussels, Belgium in October 2023, becoming the first in the world to report clinical data on using gene therapy to restore hearing.
“These results confirm the efficacy of the treatment that we previously reported on and represent a major step in gene therapy for genetic hearing loss,” said Shu. Shu trained under Chen for four years as a postdoctoral fellow at Mass Eye and Ear, with their collaboration continuing for more than a decade since he returned to Shanghai.
“Our study strongly supports treating children with DFNB9 in both ears, and our hope is this trial can expand and this approach can also be looked at for deafness caused by other genes or non-genetic causes,” added Chen, who is also an associate professor of Otolaryngology-Head and Neck Surgery at Harvard Medical School. “Our ultimate goal is to help people regain hearing no matter how their hearing loss was caused.”
Currently, there are no drugs available to treat hereditary deafness, which has made room for novel interventions like gene therapies.
Mass General Brigham’s Gene and Cell Therapy Institute is helping to translate scientific discoveries made by researchers into first-in-human clinical trials. Chen and his colleagues are working with the Institute to develop platforms and vectors with good manufacturing practice standards that would enable his team to more easily test this therapeutic approach with other genes in the future.
The authors note that more work is needed to further study and refine the therapy. The bilateral study requires more consideration compared to the unilateral (one-ear) study as operations in both ears, in the course of one surgery, doubles the surgical time. Furthermore, by injecting double doses of AAVs into the body, the immune response is likely to be stronger and the potential for adverse effects could be greater. Looking ahead, more patients as well as a longer follow-up duration are necessary, and continued analysis of gene therapies and cochlear implants in larger randomized trials will be valuable.
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Early dark energy could resolve cosmology’s two biggest puzzles
A new study by MIT physicists proposes that a mysterious force known as early dark energy could solve two of the biggest puzzles in cosmology and fill in some major gaps in our understanding of how the early universe evolved.
Now, the MIT team has found that both puzzles could be resolved if the early universe had one extra, fleeting ingredient: early dark energy. Dark energy is an unknown form of energy that physicists suspect is driving the expansion of the universe today. Early dark energy is a similar, hypothetical phenomenon that may have made only a brief appearance, influencing the expansion of the universe in its first moments before disappearing entirely.
Some physicists have suspected that early dark energy could be the key to solving the Hubble tension, as the mysterious force could accelerate the early expansion of the universe by an amount that would resolve the measurement mismatch.
The MIT researchers have now found that early dark energy could also explain the baffling number of bright galaxies that astronomers have observed in the early universe. In their new study, reported in the Monthly Notices of the Royal Astronomical Society, the team modeled the formation of galaxies in the universe’s first few hundred million years. When they incorporated a dark energy component only in that earliest sliver of time, they found the number of galaxies that arose from the primordial environment bloomed to fit astronomers’ observations.
“You have these two looming open-ended puzzles,” says study co-author Rohan Naidu, a postdoc in MIT’s Kavli Institute for Astrophysics and Space Research. “We find that in fact, early dark energy is a very elegant and sparse solution to two of the most pressing problems in cosmology.”
The study’s co-authors include lead author and Kavli postdoc Xuejian (Jacob) Shen, and MIT professor of physics Mark Vogelsberger, along with Michael Boylan-Kolchin at the University of Texas at Austin, and Sandro Tacchella at the University of Cambridge.
Big city lights
Based on standard cosmological and galaxy formation models, the universe should have taken its time spinning up the first galaxies. It would have taken billions of years for primordial gas to coalesce into galaxies as large and bright as the Milky Way.
But in 2023, NASA’s James Webb Space Telescope (JWST) made a startling observation. With an ability to peer farther back in time than any observatory to date, the telescope uncovered a surprising number of bright galaxies as large as the modern Milky Way within the first 500 million years, when the universe was just 3 percent of its current age.
“The bright galaxies that JWST saw would be like seeing a clustering of lights around big cities, whereas theory predicts something like the light around more rural settings like Yellowstone National Park,” Shen says. “And we don’t expect that clustering of light so early on.”
For physicists, the observations imply that there is either something fundamentally wrong with the physics underlying the models or a missing ingredient in the early universe that scientists have not accounted for. The MIT team explored the possibility of the latter, and whether the missing ingredient might be early dark energy.
Physicists have proposed that early dark energy is a sort of antigravitational force that is turned on only at very early times. This force would counteract gravity’s inward pull and accelerate the early expansion of the universe, in a way that would resolve the mismatch in measurements. Early dark energy, therefore, is considered the most likely solution to the Hubble tension.
Galaxy skeleton
The MIT team explored whether early dark energy could also be the key to explaining the unexpected population of large, bright galaxies detected by JWST. In their new study, the physicists considered how early dark energy might affect the early structure of the universe that gave rise to the first galaxies. They focused on the formation of dark matter halos — regions of space where gravity happens to be stronger, and where matter begins to accumulate.
“We believe that dark matter halos are the invisible skeleton of the universe,” Shen explains. “Dark matter structures form first, and then galaxies form within these structures. So, we expect the number of bright galaxies should be proportional to the number of big dark matter halos.”
The team developed an empirical framework for early galaxy formation, which predicts the number, luminosity, and size of galaxies that should form in the early universe, given some measures of “cosmological parameters.” Cosmological parameters are the basic ingredients, or mathematical terms, that describe the evolution of the universe.
Physicists have determined that there are at least six main cosmological parameters, one of which is the Hubble constant — a term that describes the universe’s rate of expansion. Other parameters describe density fluctuations in the primordial soup, immediately after the Big Bang, from which dark matter halos eventually form.
The MIT team reasoned that if early dark energy affects the universe’s early expansion rate, in a way that resolves the Hubble tension, then it could affect the balance of the other cosmological parameters, in a way that might increase the number of bright galaxies that appear at early times. To test their theory, they incorporated a model of early dark energy (the same one that happens to resolve the Hubble tension) into an empirical galaxy formation framework to see how the earliest dark matter structures evolve and give rise to the first galaxies.
“What we show is, the skeletal structure of the early universe is altered in a subtle way where the amplitude of fluctuations goes up, and you get bigger halos, and brighter galaxies that are in place at earlier times, more so than in our more vanilla models,” Naidu says. “It means things were more abundant, and more clustered in the early universe.”
“A priori, I would not have expected the abundance of JWST’s early bright galaxies to have anything to do with early dark energy, but their observation that EDE pushes cosmological parameters in a direction that boosts the early-galaxy abundance is interesting,” says Marc Kamionkowski, professor of theoretical physics at Johns Hopkins University, who was not involved with the study. “I think more work will need to be done to establish a link between early galaxies and EDE, but regardless of how things turn out, it’s a clever — and hopefully ultimately fruitful — thing to try.”
“We demonstrated the potential of early dark energy as a unified solution to the two major issues faced by cosmology. This might be an evidence for its existence if the observational findings of JWST get further consolidated,” Vogelsberger concludes. “In the future, we can incorporate this into large cosmological simulations to see what detailed predictions we get.”
This research was supported, in part, by NASA and the National Science Foundation.
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Plant-derived secondary organic aerosols can act as mediators of plant-plant interactions
A new study published in Science reveals that plant-derived secondary organic aerosols (SOAs) can act as mediators of plant-plant interactions. This research was conducted through the cooperation of chemical ecologists, plant ecophysiologists and atmospheric physicists at the University of Eastern Finland.
The study showed that Scots pine seedlings, when damaged by large pine weevils, release VOCs that activate defences in nearby plants of the same species. Interestingly, the biological activity persisted after VOCs were oxidized to form SOAs. The results indicated that the elemental composition and quantity of SOAs likely determines their biological functions.
“A key novelty of the study is the finding that plants adopt subtly different defence strategies when receiving signals as VOCs or as SOAs, yet they exhibit similar degrees of resistance to herbivore feeding,” said Professor James Blande, head of the Environmental Ecology Research Group. This observation opens up the possibility that plants have sophisticated sensing systems that enable them to tailor their defences to information derived from different types of chemical cue.
“Considering the formation rate of SOAs from their precursor VOCs, their longer lifetime compared to VOCs, and the atmospheric air mass transport, we expect that the ecologically effective distance for interactions mediated by SOAs is longer than that for plant interactions mediated by VOCs,” said Professor Annele Virtanen, head of the Aerosol Physics Research Group. This could be interpreted as plants being able to detect cues representing close versus distant threats from herbivores.
The study is expected to open up a whole new complex research area to environmental ecologists and their collaborators, which could lead to new insights on the chemical cues structuring interactions between plants.
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Folded or cut, this lithium-sulfur battery keeps going
Most rechargeable batteries that power portable devices, such as toys, handheld vacuums and e-bikes, use lithium-ion technology. But these batteries can have short lifetimes and may catch fire when damaged. To address stability and safety issues, researchers reporting in ACS Energy Letters have designed a lithium-sulfur (Li-S) battery that features an improved iron sulfide cathode. One prototype remains highly stable over 300 charge-discharge cycles, and another provides power even after being folded or cut.
The team coated iron sulfide cathodes in different polymers and found in initial electrochemical performance tests that polyacrylic acid (PAA) performed best, retaining the electrode’s discharge capacity after 300 charge-discharge cycles. Next, the researchers incorporated a PAA-coated iron sulfide cathode into a prototype battery design, which also included a carbonate-based electrolyte, a lithium metal foil as an ion source, and a graphite-based anode. They produced and then tested both pouch cell and coin cell battery prototypes.
After more than 100 charge-discharge cycles, Wang and colleagues observed no substantial capacity decay in the pouch cell. Additional experiments showed that the pouch cell still worked after being folded and cut in half. The coin cell retained 72% of its capacity after 300 charge-discharge cycles. They next applied the polymer coating to cathodes made from other metals, creating lithium-molybdenum and lithium-vanadium batteries. These cells also had stable capacity over 300 charge-discharge cycles. Overall, the results indicate that coated cathodes could produce not only safer Li-S batteries with long lifespans, but also efficient batteries with other metal sulfides, according to Wang’s team.
The authors acknowledge funding from the National Natural Science Foundation of China; the Natural Science Foundation of Sichuan, China; and the Beijing National Laboratory for Condensed Matter Physics.
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