Regenxbio said Thursday that its experimental gene therapy for Duchenne muscular dystrophy produced sufficiently high levels of a miniaturized muscle protein broken in the fatal neuromuscular disease, paving the way for a submission to the Food and Drug Administration.
The company is seeking to create a Duchenne gene therapy that is more effective and safer than Sarepta Therapeutics’ Elevidys, which has been hampered by safety concerns, particularly following the deaths of two recipients from liver failure.
“I think our data checks every single box that you would want for accelerated approval,” Regenxbio CEO Curran Simpson told STAT.
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Kyle Diamantas, the acting commissioner of the Food and Drug Administration — newly installed following Marty Makary’s resignation — is expected to be a drama-free, stabilizing caretaker at the top of the agency.
Leadership turnover is always going to cause some angst, but based on what I’m hearing, biotech and the investors who track the sector have little to fear from Diamantas. He is stepping into the new role after serving as the FDA’s top food regulator.
The Tesla Semi has officially arrived. The company recently released a photo of the first vehicle rolling off its new full-scale production line.
This moment has been nearly a decade in the making: The company first announced the Tesla Semi in late 2017. And now we’ve got final battery specs, official prices, and big news about big orders.
The Semi is a relatively affordable electric semitruck with pretty impressive performance. It also comes at a moment when Tesla has lost its grip on the global electric vehicle market. Let’s talk about what’s new with the Tesla Semi and why this could be a breakout moment for electric trucking.
Medium- and heavy-duty vehicles, like buses and semitrucks, make up a small fraction of vehicles on the road but contribute an outsize fraction of pollution, including both carbon dioxide emissions and other pollutants like nitrogen oxides (NOx) and small particles. Globally, trucks and buses represent about 8% of total vehicles on the road, but they create 35% of carbon dioxide emissions from road transport.
Tesla’s latest addition to its vehicle lineup, the Class 8 Semi, could be part of the solution to cleaning up this polluting sector. (I’ll note here that I briefly interned at Tesla in 2016. I don’t have any ties to or financial interest in the company today.)
In November 2017, Elon Musk took to the stage at a lavish event in LA to announce the Semi. At that event, Musk promised a truck that could go from zero to 60 miles per hour in five seconds, could achieve a range of 500 miles, and would come with thermonuclear-explosion-proof glass. (Remember the era before the Twitter takeover and DOGE, when this was what Musk was known for? A simpler time.)
Soon after the unveiling, major corporations including Walmart put in early orders for Tesla Semis. Deliveries were expected in 2019.
That deadline obviously didn’t work out. The date was pushed back several times, and Tesla did start delivering a small number of pilot trucks, beginning in 2022. But this year, things got more serious, with the company releasing its final production specifications in February and rolling its first Semi off its high-volume production line in late April.
And last week, WattEV announced an order of 370 Tesla Semis. WattEV offers electric freight operations, essentially providing trucks as a service to companies so they don’t have to purchase their own or supply their own charging infrastructure. The company will pay over $100 million for the new trucks, and the first 50 should be delivered this year, with the full fleet expected by the end of 2027. Those trucks will be supported by megawatt-charging systems located in Oakland, Fresno, Stockton, and Sacramento.
With the factory up and running and a huge order on the books, it feels like the Tesla Semi has truly arrived. And some of Musk’s claims from 2017 ring true: The base model has a range of about 320 miles, and the long-range version about 480 miles (quite close to his 500-mile claim).
Delivering this much range for this big truck means a whopping battery. The base model Tesla Semi battery pack has a usable capacity of 548 kilowatt-hours, according to a document filed with the California Air Resources Board (CARB). But the battery is even more massive in the long-range version, which boasts a whopping 822 kilowatt-hour battery. Compare these to the Tesla Model 3, which typically comes with a 64 kilowatt-hour pack.
I reached out to Tesla to confirm the battery size and ask other questions for this article—the company didn’t respond.
These trucks cost quite a bit more than they were expected to in 2017, though. At that time, the expected price was $150,000 for the base model and $180,000 for the long-range. Today, Tesla is pricing the trucks at $260,000 and $300,000, respectively, according to documentation filed with CARB.
That’s considerably more expensive than the median diesel truck being sold today, which rang in at $172,500 for the 2025 model year, according to research from the International Council on Clean Transportation. But it’s much cheaper than similar battery-electric trucks available today, where the median is about $411,000.
And in California, where companies can get vouchers that cover $120,000 towards the purchase price of an electric truck, the Tesla Semi is competitive right away, especially since electric trucks tend to be much cheaper to run and maintain than diesel ones.
Over the years, it wasn’t always clear that the Tesla Semi would ever actually hit the roads. (At that same 2017 event, Musk announced a new Roadster sports car, and that’s nowhere to be seen.) So it’s encouraging to see the factory starting up, and a large order that looks like it could lend this project some commercial momentum.
Tesla had a massive impact on the electric vehicle market, and if it can scale production and support charging infrastructure, it could help do the same for trucking.
This article is from The Spark, MIT Technology Review’s weekly climate newsletter. To receive it in your inbox every Wednesday, sign up here.
When Jennifer got a job doing research for a nonprofit in 2023, she ran her new professional headshot through a facial recognition program. She wanted to see if the tech would pull up the porn videos she’d made more than 10 years before, when she was in her early 20s. It did in fact return some of that content, and also something alarming that she’d never seen before: one of her old videos, but with someone else’s face on her body.
“At first, I thought it was just a different person,” says Jennifer, who is being identified by a pseudonym to protect her privacy.
But then she recognized a distinctly garish background from a video she’d shot around 2013, and she realized: “Somebody used me in a deepfake.”
Eerily, the facial recognition tech had identified her because the image still contained some of Jennifer’s features—her cheekbones, her brow, the shape of her chin. “It’s like I’m wearing somebody else’s face like a mask,” she says.
“It’s like I’m wearing somebody else’s face like a mask.”
Conversations about sexualized deepfakes—which fall under the umbrella of nonconsensual intimate imagery, or NCII—most often center on the people whose faces are featured doing something they didn’t really do or on bodies that aren’t really theirs. These are often popular celebrities, though over the past few years more people (mostly women and sometimes youths) have been targeted, sparking alarm, fear, and even legislation. But these discussions and societal responses usually are not concerned with the bodies the faces are attached to in these images and videos.
As Jennifer, now 37 and a psychotherapist working in New York City, says: “There’s never any discussion about Whose body is this?”
For years, the answerhas generally been adult content creators. Deepfakes in fact earned their name back in November 2017, when someone with the Reddit username “deepfakes” uploaded videos showing faces of stars like Scarlett Johansson and Gal Gadot pasted onto porn actors’ bodies. The nonconsensual use of their bodies “happens all the time” in deepfakes, says Corey Silverstein, an attorney specializing in the adult industry.
But more recently, as generative AI has improved, and as “nudify” apps have begun to proliferate, the issue has grown far more complicated—and, arguably, more dangerous for creators’ futures.
Porn actors’ bodies aren’t necessarily being taken directly from sexual images and videos anymore, or at least not in an identifiable way. Instead, they are inevitably being used as training data to inform how new AI-generated bodies look, move, and perform. This threatens the livelihood and rights of porn actors as their work is used to train AI nudes that in turn could take away their business. And that’s not all: Advancements in AI have also made it possible for people to wholly re-create these performers’ likenesses without their consent, and the AI copycats may do things the performers wouldn’t do in real life. This could mean their digital doubles are participating in certain sex acts that they haven’t agreed to do, or even that they’re perpetrating scams against fans.
Adult content creators are already marginalized by a society that largely fails to protect their safety and rights, and these developments put them in an even more vulnerable position. After Jennifer found the deepfake featuring her body, she posted on social media about the psychological effects: “I’ve never seen anyone ask whether that might be traumatic for the person whose body was used without consent too. IT IS!” Several other creators I spoke with shared the mental toll that comes with knowing their bodies have been used nonconsensually, as well as the fear that they’ll suffer financially as other people pirate their work. Silverstein says he hears from adult actors every day who “are concerned that their content is being exploited via AI, and they’re trying to figure out how to protect it.”
One law professor and expert in violence against women calls these creators the “forgotten victims” of NCII deepfakes. And several of the people I spoke with worry that as the US develops a legal framework to combat nonconsensual sexual content online, adult actors are only at risk of further injury; instead of helping them, the crackdown on deepfakes may provide a loophole through which their content and careers could be stripped from the internet altogether.
How deepfakes cause “embodied harms”
During his preteen years in the 1970s, Spike Irons, now a porn actor and president of the adult content platform XChatFans, was “in love” with Farrah Fawcett. Though Fawcett did not pose nude, Jones managed to get his hands on what looked like pictures of her naked. “People were cutting out faces and pasting them on bodies,” Irons says. “Deepfakes, before AI, had been going around for quite a while. They just weren’t as prolific.”
The early public internet was rife with websites capitalizing on the idea that you could use technology to “see” celebrities naked. “People would just use Microsoft Paint,” says Silverstein, the attorney. It was a simple way to mash up celebrities’ faces with porn.
People later used software like Adobe After Effects or FakeApp, which was designed to swap two individuals’ faces in images or videos. None of these programs required serious expertise to alter content, so there was a low barrier to entry. That, plus the wealth of porn performers’ videos online, helped make face-swap deepfakes that used real bodies prevalent by the 2010s. When, later in the decade, deepfakes of Gal Gadot and Emma Watson caused something of a broader panic, their faces were allegedly swapped onto the bodies of the porn actors Pepper XO and Mary Moody, respectively.
But it wasn’t just high-profile actors like them whose bodies were being used. Jennifer was “a very minor performer,” she says. “If it happened to me, I feel like it could happen to anybody who’s shot porn.” Since he started his practice in 2006, Silverstein says, “numerous clients” have reached out to report “This is my body on so-and-so.”
Both people whose faces appear in NCII deepfakes and those whose bodies are used this way can feel serious distress. Experts call this type of damage “embodied harms,” says Anne Craanen, who researches gender-based violence at the UK’s Institute for Strategic Dialogue, an organization that analyzes extremist content, disinformation, and online threats.
The term reflects the fact that even though the content exists in the virtual realm, it can cause physiological effects, including body dysmorphia. The face-swapped entity occupies the uncanny valley, distorting self-perception. After discovering their faces in sexual deepfakes, many people feel silenced, experts told me; they may “self-censor,” as Craanen puts it, and step back from public-facing life. Allison Mahoney, an attorney who works with abuse survivors, says that people whose faces appear in NCII can experience depression, anxiety, and suicidal ideation: “I’ve had multiple clients tell me that they don’t sleep at night, that they’re losing their hair.”
Independent creators aren’t just “having sex on camera.” For someone to rip off their work “for their own entertainment or financial gain fucking sucks.”
Though the impact on people whose bodies are used hasn’t been discussed or studied as often, Jennifer says that “it’s just a really terrible feeling, knowing that you are part of somebody else’s abuse.” She sees it as akin to “a new form of sexual violence.”
The uncertainty that comes with not being aware of what your body is doing online can be highly unsettling. Like Jennifer, many adult actors don’t really know what’s out there. But some devoted followers know the actors’ bodies well—often recognizing tattoos, scars, or birthmarks—and “very quickly they bring [deepfakes] to the adult performer’s attention,” says Silverstein. Or performers will stumble upon the content by chance; some 20 years ago, for instance, the first such client to tell Silverstein her body was being used in a deepfake happened to be searching Nicole Kidman online when she found that one of the results showed Kidman’s face on her porn. “She was devastated, obviously, because they took her body,” he says, “and they were monetizing it.”
Otherwise, this imagery may be found by an organization like Takedown Piracy, one of several copyright enforcement companies serving adult content creators. US copyright violations can be challenging to prove if someone’s body lacks distinguishing features, says Reba Rocket, Takedown Piracy’s chief operating and marketing officer. But Rocket says her team has added digital fingerprinting technology to clients’ material to help flag and remove problematic videos, often finding them before clients realize they’re online.
By capturing “tens of thousands of tiny little visual data points” from videos, digital fingerprinting creates unique corresponding files that can be used to identify them, Rocket says—kind of like an invisible watermark. The prints remain even if pirates alter the videos or replace performers’ faces. Takedown Piracy has digitally fingerprinted more than half a billion videos and the organization has gotten 130 million copyrighted videos taken down from Google alone (though, of those videos, Rocket hasn’t tracked how many of these specifically include someone else’s face on a performer’s body).
Besides copyright, a range of legal tools can be used to try and combat NCII, says Eric Goldman, a law professor at Santa Clara University. For example, victims can claim invasion of privacy. But using these tools isn’t particularly straightforward, and they may not even apply when it comes to someone’s body. If there aren’t, for instance, unique markers indicating that a body in a deepfake belongs to the person who says it does, US law “doesn’t really treat [this content] as invasion of privacy,” Goldman says, “because we don’t know who to attribute it to.”
In a 2018 study that reviewed “judicial resolution” of cases involving NCII, Goldman found that one successful way plaintiffs were able to win cases was to assert “intentional affliction of emotional distress.” But again, that hinges on the ability to clearly identify the person in the content. Relevant statutes, he adds, might also require “intent to harm the individual,” which may be hard to show for people whose bodies alone are featured.
“AI girls will do whatever you want”
In the last few years, Silverstein says, it’s become less and less common to see the bodies of real adult content creators in deepfakes, at least in a way that makes them clearly identifiable.
Sometimes the bodies have been manipulated using AI or simpler editing tools. This can be as basic as erasing a birthmark or changing the size of a body part—minor edits that make it impossible to identify someone’s image beyond a reasonable doubt, so even porn actors who can tell that an altered image used their body as a base won’t get very far in the legal realm. “A lot of people are like, That looks like my body,” says Silverstein, but when he asks them how, they’ll reply, It just does.
At the same time, other users are now creating NCII with wholly AI-generated bodies. In “nudify” apps, anyone with a minimal grasp of technology can upload a photo of someone’s clothed body and have it replaced with a fake naked one. “So [much] of this content being created is just someone’s face on an AI body,” Silverstein says.
Such apps have drawn a ton of attention recently, from Grok “nudifying” minors to Meta running ads for—and then suing—the nudify app Crushmate. But there’s been relatively little attention paid to the content being used to train them. They almost certainly draw on the more than 10,000 terabytes of online porn, and performers have virtually zero recourse.
One reason is that creators aren’t able to demonstrate with any certainty that their content is being used to train AI models like those used by nudify apps. “These things are all a black box,” says Hany Farid, a professor at the University of California, Berkeley, who specializes in digital forensics. But “given the ubiquity” of adult content, he adds, it’s a “reasonable assumption” that online porn is being used in AI training.
“It’s just not at all difficult to come up with pornographic data sets on the internet,” says Stephen Casper, a computer science PhD student at MIT who researches deepfakes. What’s more, he says, plenty of shadowy online communities provide “user guides” on how to use this data to train AI, and in particular programs that generate nudes.
It’s not certain whether this activity falls within the US legal definition of “fair use”—an issue that’s currently being litigated in several lawsuits from other types of content creators—but Casper argues that even if it does, it’s ethically murky for porn created by consenting adults 10 years ago to wind up in those training data sets. When people “have their stuff used in a way that doesn’t respect or reflect reasonable expectations that they had at that time about what they were creating and how it would be used,” he says, there’s “a legitimate sense in which it’s kind of … nonconsensual.”
Adult performers who started working years ago couldn’t possibly have consented to AI anything; Jennifer calls AI-related risks “retroactively placed.” Contracts that porn actors signed before AI, adds Silverstein, might provide that “the publisher could do anything with the content using technology that now exists or here and after will be discovered.” That felt more innocuous when producers were talking about the shift from VHS to DVD, because that didn’t change the content itself, just the way it was conveyed. It’s a far different prospect for someone to use your content to train a program to create new content … content that could replace your work altogether.
Of course, this all affects creators’ bottom line—not unlike the way Google’s AI overviews affect revenue for online publishers who’ve stopped getting clicks when people are content with just reading AI-generated summaries. Performers’ “concern is … it’s another way to pirate [their] content,” says Rocket.
After all, independent creators aren’t just “having sex on camera,” as the adult content creator Allie Eve Knox says. They’re paying for filming equipment and location rentals, and then spending hours editing and marketing. For someone to then rip off and distort that content “for their own entertainment or financial gain,” she says, “fucking sucks.”
KIM HOECKELE
Tanya Tate, a longtime adult content creator, tells me about another highly unsettling AI-created situation: She was recently chatting with a fan on Mynx, a sexting app, when he asked her if she knew him. She told him no, and “his eyes just started watering,” Tate says. He was upset because he thought she did know him. Turns out he’d sent $20,000 to a scammer who’d used an AI-generated deepfake of Tate to seduce him.
Several men, Tate subsequently learned, had been scammed by an AI version of her, and some of them began blaming her for their losses and posting false statements about her online. When she reported one particularly aggressive harasser to the police, they told her he was exercising his “freedom of speech,” she says. Rocket, too, is familiar with situations where AI is used to take advantage of fans. “The actual content creator will get nasty emails from these people who’ve been scammed,” she says.
Other porn actors say they fear that their likenesses have been used without consent to do other things they wouldn’t do. One, Octavia Red, tells me she doesn’t do anal scenes, “but I’m sure there’s tons of deepfake anal videos of me that I didn’t consent to.” That could cost her, she fears, if viewers choose to watch those videos instead of subscribing to her websites. And it could cause fans to develop false expectations about what kind of porn she’ll create.
“I saw one AI creator saying, ‘Well, AI girls will do whatever you want. They don’t say no,’” says Rocket. “That horrifies me … especially if they’re training those AI models on real people. I don’t think they understand the damage to mental health or reputation that that can create. And once it’s on the internet, it’s there forever.”
Efforts to “scrub adult content from the internet”
As AI technology improves, it’s increasingly difficult for people to discern any type of real video from the best AI-generated ones on their own. In one 2025 study, UC Berkeley’s Farid found that participants correctly identified AI-generated voices about 60% of the time (not much better than random chance), while advances like false heartbeats make AI-generated humans tougher than ever to spot.
Nevertheless, most lawyers and legal experts I spoke with said copyright laws are still adult performers’ best bet in the US legal system, at least for getting their face-swapped content taken down. For his clients, Silverstein says, he tries to figure out the content’s origins and then issue takedown requests under the Digital Millennium Copyright Act, a 1998 law that adapted copyright law for the internet era. “Even recently, I had a performer who has an insanely well-known tattoo,” he says, and with a DMCA subpoena he managed to identify the poster of the content, who voluntarily removed it.
But this way of working is becoming increasingly rare.
These days it’s nearly “impossible,” Silverstein says, to determine who produced a deepfake, because many platforms that host pirated content operate facelessly. They’re also often based in places that “don’t really care about US law when it comes to copyrights,” says Rocket—places like Russia, the Seychelles, and the Netherlands.
While governments in the EU, the UK, and Australia have said they will ban or restrict access to nudify apps, it’s not an easily executed proposition. As Craanen notes, when app stores remove these services, they often simply reappear under different names, providing the same services. And social platforms where people share NCII deepfakes, argues Rocket, are slacking in getting them removed. “It’s endless, and it’s ridiculous, because places like Twitter and Facebook have the same technology we do,” Rocket says. “They can identify something as an infringement instantly, but they choose not to.”
(Apple spokesperson Adam Dema emailed, “’nudification’ apps are against our guidelines” in the app store, and it has “proactively rejected many of these apps and removed many others,” flagging a reporting portal for users. A Google spokesperson emailed, “Google Play does not allow apps that contain sexual content,” noting it takes “proactive steps to detect and remove apps with harmful content” and has suspended hundreds of apps for violating its policy. Meta spokesperson shared a blog post about actions it’s taken against nudify apps, but did not respond to follow-up questions about copyrighted material. X did not respond to a request for comment.)
As porn performers are forced to navigate AI-related threats, the only current federal law to address deepfakes may not help them much—and could even make matters worse. The Take It Down Act, which became US law last year, criminalizes publishing NCII and requires websites to remove it within 48 hours. But, as Farid notes, people could weaponize the measure by reporting porn that was made legally and with consent and claiming that it’s NCII. This could result in the content’s removal, which would hurt the performers who made it. Santa Clara’s Goldman points to Project 2025, the Heritage Foundation’s policy blueprint for the second Trump administration, which aims to wipe porn from the web. The Take It Down Act, he argues, “allows for the coordinated effort to scrub adult content from the internet.”
US lawmakers have a history of hurting sex workers in their attempts to regulate explicit content online. State-level age verification laws are an example; visitors can pretty easily get around these measures, but they can still result in reduced revenue for adult performers (because of lower traffic to those sites and the high price of age-checking services they have to purchase).
“They’re always doing something to fuck with the porn industry, but not in a way that actually helps sex workers,” says Jennifer. “If they do something, they’re taking away your income again—as opposed to something like giving you more rights to your image, [which] would be tremendously helpful.”
But as generative AI plays an increasingly large role in NCII deepfakes, the types of images to which adult performers have rights moves deeper into a gray area. Can actors lay claim to AI images likely trained on their bodies? How about AI-generated videos that impersonate them, like the one that tricked Tanya Tate’s fan?
The biggest challenge will be creating “legitimate, effective laws that will absolutely protect content creators from abusing their likeness to train and create AI,” Rocket says. “Absent that, we’re just going to have to keep pulling content down from the internet that’s fake.”
In the meantime, a few porn actors tell me, they’re trying to take advantage of copyright laws that weren’t really made for them; they’ve signed with platforms that host their AI-generated duplicates, with whom fans pay to chat, in part so they’ll have contracts that protect ownership of their AI likenesses. When I spoke with the actor Kiki Daire in September 2025 for a story on adult creators’ “AI twins,” she said she “own[ed] her AI” because she’d signed a contract with Spicey AI, a site that hosted AI duplicates of adult performers. If another company or person created her AI-generated likeness, she added, “I have a leg to stand on, as far as being able to shut that down.”
Even this, though, is not a sure thing; Spicey AI, for instance, shut down several months after I spoke with Daire, so it’s unlikely that her contract would hold. And when I spoke in October with Rachael Cavalli, another adult actor who had signed with an AI duplicate site in hopes it’d help protect her AI image, she admitted, “I don’t have time to sit around and look for companies that have used my image or turned something into a video that I didn’t actually do … it’s a lot of work.” In other words, having rights to your AI image on paper doesn’t make it easier to track down all the potentially infinite breaches of those rights online.
If she’d known what she knows about technology today, Jennifer says she doesn’t think she would have done porn. The risks have increased too much, and too unpredictably. She now does in-person sex work; it’s “not necessarily safer,” she says, “but it’s a different risk profile that I feel more equipped to manage.”
Plus, she figures AI is unlikely to replace in-person sex workers the way it could porn actors: “I don’t think there’s going to be stripper robots.”
Jessica Klein is a Philadelphia-based freelance journalist covering intimate partner violence, cryptocurrency, and other topics.
As spindly, elongated cells, neurons must be able to transport proteins and receptors between distant sites in their cell bodies and axons to function properly. A new imaging study by researchers at Johns Hopkins University has now visualized the ebb and flow of the nerve growth factor receptor TrkA within neurons, via an unusual process known as transcytosis. Their study also explains how this phenomenon supports neuronal function and connectivity in mice.
Senior and corresponding author Rejji Kuruvilla, PhD, at Johns Hopkins University Department of Biology, and colleagues reported on their findings in Science Signaling, in a paper titled “Transcytosis-mediated anterograde transport of the receptor TrkA mediates the formation of presynaptic sites in sympathetic neurons.” In their paper, the authors concluded, “These findings provide mechanistic insight into an atypical mode of receptor trafficking and demonstrate its physiological relevance in sympathetic neuron connectivity in mice … Our study suggests that transcytosis might be a more general mechanism than now appreciated for the targeted transport of trophic and guidance receptors, adhesion and synaptic proteins, as well as ion channels.”
The axons of neurons are extremely long compared to their main cell bodies, with axon terminals sometimes residing a long distance from the cell nucleus. “Axon terminals can be meters away from cell bodies where many axonal membrane proteins with critical functions in regulating axon guidance and growth, neuronal survival, presynaptic organization, and synaptic transmission are made,” the authors wrote.
Neurons need to be able to transport these proteins efficiently across these relatively vast distances. They do this by either directly sending the protein through a secretory pathway or via an indirect mechanism called transcytosis. The latter occurs when the central cell body takes in newly synthesized proteins or surface receptors, after which they move to axons through the cell cytoplasm. “Transcytosis is an atypical endocytosis-based mechanism, where newly synthesized proteins are first inserted on cell body surfaces, internalized, and anterogradely transported to axons,” the team continued.
Transcytosis is still relatively obscure and enigmatic compared with the direct secretion method, and questions remain about how exactly it sustains the function and connectivity of neurons. “In contrast to the considerable progress made in understanding the direct secretory pathway, there is limited knowledge about transcytosis, specifically the underlying transport kinetics and organelles involved, whether it occurs in vivo, and its contributions to neuronal connectivity and function,” the investigators noted.
Seeking answers, first author Kuruvilla, together with first author Guillermo Moya-Alvarado, PhD, and colleagues, used live cell imaging and electron microscopy to peer at the movement of receptors across compartments within mouse neurons.
They visualized the trafficking dynamics and transcytosis of a receptor named TrkA. “The family of tropomyosin-related kinase (Trk) receptors provides a prominent example of membrane proteins that undergo long-distance axonal trafficking to control neuronal survival, axon growth, and synaptic transmission,” the scientists explained.
Through their study, the authors noted various shifts in speed and direction as vesicles carried TrkA from the soma to axons. Using labeled TrkA proteins, the scientists also confirmed that transcytosis occurred within nerve terminals of living mice. “Live imaging and electron microscopy of compartmentalized cultures revealed that soma surface–derived TrkA proteins underwent dynamic transport within axons, with changes in speed, direction, and the vesicular organelles that carried them as they moved from proximal to distal axon compartments,” they stated. “In mice, soma surface–labeled TrkA proteins were observed in sympathetic nerve terminals, demonstrating that transcytosis occurs in vivo.”
Assessing TrkA receptors transcytosis from cell bodies to nerve terminals in vivo. Superior cervical ganglion (SCG) in Ntrk1Flag mice, at postnatal day 2 to day 3, were injected in one of each paired ganglia per animal with the contralateral ganglion and target tissues (noninjected side) serving as internal controls to assess any systemic leakage of injected label. Representative image of the injected side. Flag (green) and sympathetic neurons (Tuj1, red) immunofluorescence in the superior cervical ganglia. DAPI is shown in blue. Scale bars, 50 μm. [All images and movies were generated by Guillermo Moya Alvarado]
They also found that disrupting its transcytosis by introducing a point mutation into TrkA reduced the number and size of presynaptic sites and decreased synaptic transmission in culture and in rodents in vivo, confirming the importance of the process for neuronal physiology. “These findings provide mechanistic insight into an atypical mode of receptor trafficking and demonstrate its physiological relevance in sympathetic neuron connectivity in mice,” the team concluded “Uncovering mechanisms of axon delivery has implications that extend beyond the healthy nervous system to understanding cell biological pathways that contribute to nerve repair after injury or neurodegeneration, because the correct complement of membrane proteins must be accurately targeted to regenerating axons to ensure functional recovery.”
Two doctors with the Centers for Disease Control and Prevention said on Wednesday that the risk to Americans from the deadly hantavirus outbreak remains low, saying the agency is “engaged at every step.”
In a media briefing, they described the agency’s response, which has been criticized by some infectious disease and public health experts as taking a back seat to the World Health Organization and other groups.
Background: Due to demographic changes, the number of older people is increasing, often accompanied by limitations in mobility, nutrition, and independence. Preventive monitoring is rare, as care systems struggle with staff shortages and limited resources. Technical assistance systems can support older people in self-assessing their health and maintaining independence. We developed the AS-Tra system, which combines an application with a measurement and training station (MuTS), to enable early detection of nutrition and mobility-related deficits and risks. Objective: This paper presents the pilot study of the AS-Tra system with the aim of evaluating its usability and testing the feasibility of collecting health-related data from older adults (≥70 y) with early/mild deficiencies in nutritional state and mobility in preparation for a future randomized controlled trial. Methods: The system used in this 4-week pilot study was developed as a complex intervention in accordance with the Medical Research Council framework. Participants (target n=10) were recruited through a participant registry. They completed standardized mobility assessments (grip strength, Timed “Up and Go,” and 5-Time Chair Rise) at baseline and after 1, 2, and 4 weeks (T0, T1, and T2, respectively). Mini Nutritional Assessment—Short Form and short physical performance battery were recorded at baseline and at T2. Participants received a tablet app for regularly documenting nutrition and an activity sensor for 7 days of physical activity monitoring and performed weekly training starting at T0. At T2, the System Usability Scale (SUS) and feedback questionnaires (Evaluation Overall System [EOS] questionnaire—the evaluation of all subcomponents on a scale of 1-5, weekly Experience Report) were additionally collected. Data were analyzed descriptively using IBM SPSS Statistics, in which data were shown as total numbers, percentages, and means with SDs, and data from the activity sensor were displayed and analyzed using Python. Results: A total of 9 older adults, with 1 dropout (mean 80, SD 5 y, 50% female), participated in this study. The SUS score was good (mean 79, SD 13.4 points). The MuTS devices had minor technical problems (in <17% of MuTS sessions), while 57% (17/30) of the users experienced instability issues with the food diary in the tablet app. The average overall system ratings were positive, with an EOS score of 2.01 (SD 0.99). Conclusions: The usability of the technical assistance system used in this study was rated as good. The data collection using questionnaires, sensors, and automated assessments proved feasible. The biggest challenge was the tablet-based food diary, which still needs improvement before the effectiveness of the AS-Tra system regarding mobility and nutritional status can be evaluated in a randomized controlled trial.
This research letter reports the development and preliminary user testing of MusicAlzheimer, an AI-driven digital music therapy prototype designed to deliver culturally tailored, real-time adaptive interventions for people with Alzheimer’s disease.
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BOSTON – Timothy Yu, MD, PhD, a leading neurogeneticist at Boston Children’s Hospital and Harvard Medical School, was awarded one of the top honors by the American Society of Gene and Cell Therapy (ASGCT), the Jerry Mendell Award.
Yu was recognized for his trailblazing work over the past decade in devising bespoke oligonucleotide therapies for patients with ultra-rare genetic disorders. He entitled his talk: “The paradox of N-of-1: Scaling the logic of genetic intervention.” A suitable sub-title, Yu said, could be: “A neurogeneticist’s accidental injection into the field of gene therapy.”
Timothy Yu, MD, PhD
Yu’s research has progressed from gene discovery to clinical applications of N-of-1 therapies. The long tail challenge of developing gene therapies for patients with rare diseases is actually immense. There are some 400 million individuals worldwide who suffer one of some 8,000 monogenic disorders. Three out of ten affected children do not see their fifth birthday, while most lack any kind of medical treatment.
But progress over the past 10-20 years has provided hope in the form of various molecular therapies—antisense, mRNA, gene therapy, siRNAs, CRISPR, and newer flavors of gene editing. The concept of “therapeutic programmability is very important,” Yu said.
Yu’s injection into the field began with a single patient, Mila Makovec, a young girl from Colorado, whom he met in 2018. This index patient was eventually diagnosed with a form of Batten disease, CLN7—a rare subtype that was progressive and fatal.
Mila’s gene mutation was private but correctable, an insertion sitting deep within an intron. This offered Yu’s team hope that they could block abnormal splicing. Clearly, no company could progress a therapy for a single patient, Yu recalled.
Allele-specific oligonucleotides are simple to manufacture and can boost gene expression, following the model of Spinraza for spinal muscular atrophy.
Yu’s team developed a customized ASO therapy in about a year, which was published in 2019. The therapy brought about a reduction in Mila’s seizures, but not in time to result in a cure. In May 2019, Yu’s team met with the FDA to establish a path forward. The first guidances were published in 2021.
Moving on
Yu recounted several other therapies designed for other patients with different genetic disorders. The second program, working with Jennifer Puck, MD, and colleagues, was for ataxia telangiectasia (A-T). One A-T mutation created a new splice site that appeared to be reversible with a custom ASO.
The pilot clinical study was initiated in 2018, when the child was two years old. It is, Yu said, the longest running N-of-1 trial. The child is now nine years old and shows no worsening of clinical symptoms. Various measurements and assays confirm there has been no clinical progression. “We have converted a classic case of A-T to a milder form,” Yu said. The trial is expanding in Europe, including ten additional children in Turkey.
A member of Yu’s lab, Claudia Lentucci, PhD, is among the team leading a third program treating infants with neonatal epilepsy (KCNT1-related epileptic encephalopathy). One patient had seizures halted but developed ventricular enlargement. The team has since modified the protocol to use intracerebroventricular injection, which reduces seizures by 60-70%.
A fourth example presented by Yu was a treatment for Grace, a 15-year-old girl with a rare form of retinitis pigmentosa. She presented seven years ago with vision loss and pain insensitivity. Launched in August 2023, the therapy corrects a deep intronic mutation. It has been well tolerated and resulted in a stabilization of her vision.
Yu summarized similar therapies developed for patients with Zellweger syndrome, Niemann Pick Type C, and Batten disease. In total, 35 N-of-1 oligonucleotides have been administered to more than 80 patients.
On hearing the news of Baby KJ last year, “we all stood up and took notice,” Yu said.
“Our motivations are to help patients without other options. We have expanded from a sick child in Colorado to generate pilot learnings for childhood neurologic diseases.” His team’s work is not only offering hope in a compassionate sense but is also leading the exploration of new delivery models for precision medicine.
Yu has built a large network of collaborators, including clinicians, regulators, and industry professionals. The N=1 Collaborative has grown to more than 2,000 members worldwide and will be holding its third conference this October in Denver.
A new approach
From what was once called “interventional genetics,” Yu said, “the data is inviting us to take a new approach” that he called “genetic surgery.”
N-of-1 therapies are “more akin to a complex surgery, [using] customized tools and procedures for therapeutic benefit akin to organ transplant or cardiac surgery,” he said.
Yu also highlighted the FDA’s Plausible Mechanism Pathway, announced last February, which offers opportunities to approve medicines on the basis of very small numbers of patients. But the guidance emphasized the importance of data sharing—an issue that required the community’s full attention.
“You can’t build a modular system in a silo,” Yu said. “If you want cures that are greater than the sum of their parts, you must share the data to see how the pieces fit together.”