For years, HIV has resisted traditional vaccine strategies. The virus’s staggering antigenic diversity, rapid mutation rate, and glycan‑shielded envelope have made it extraordinarily difficult for the immune system to generate antibodies capable of recognizing HIV’s vulnerable sites. Yet a small number of people living with HIV do develop broadly neutralizing antibodies (bnAbs)—rare antibodies that can target conserved regions of the virus despite its shape‑shifting defenses. These bnAbs have long been viewed as templates for next‑generation vaccine design, but reliably eliciting them through vaccination has remained out of reach.
A team led by scientists at La Jolla Institute for Immunology (LJI) and Scripps Research now reports a potential breakthrough. In a study published in Nature, the researchers demonstrated that a germline‑targeting HIV vaccine can elicit bnAbs in outbred nonhuman primates. The study is titled, “Vaccination elicits HIV broadly neutralizing antibodies in primates.”
Germline targeting represents a fundamentally different vaccine design philosophy. As the authors wrote, it is “a conceptually radical vaccine design approach to elicit bnAbs, aiming to prime rare bnAb‑precursor B cells possessing pre‑determined human genetic and structural features shared with template bnAbs, and then guide B cell affinity maturation to potent bnAb evolution with heterologous boosters.”
To test this strategy, the team engineered protein immunogens that mimic key HIV envelope structures known to initiate bnAb development. Rhesus macaques received a priming immunogen designed to activate naive B cells, followed by a sequence of booster shots that guided those cells through the necessary maturation steps. “This series of vaccinations will guide, or ‘walk,’ a B cell from its naive state to its broadly neutralizing state,” explained co-first author and LJI instructor Patrick Madden, PhD.
The researchers reported that bnAb‑class memory B cells emerged in at least half of the animals, and “serum bnAb activity developed in 44% of animals.” In the strongest responder, bnAb titers reached titers “expected to confer protection against diverse HIV isolates,” according to the authors.
Human translation is already underway. The priming immunogen used in this study has been evaluated in the HVTN 144 trial and is currently being tested in the Phase I IAVI G004 trial. Shane Crotty, PhD, LJI professor and CSO, noted that the approach may perform even better in humans due to immunogenetic factors.
The next challenge is optimization—refining booster sequences, improving response rates, and ultimately demonstrating protection. But this study provides long‑sought proof of principle, according to the authors: “Germline-targeting vaccines can reproducibly elicit prespecified classes of bnAbs to prespecified epitopes under endogenous conditions, supporting further optimization of this approach for HIV vaccine development.”
Vertex Pharmaceuticals has agreed to acquire Crinetics Pharmaceuticals for $10 billion cash, the companies said, in a deal that would expand the buyer’s rare disease portfolio beyond its anchor indication of cystic fibrosis (CF), by adding an approved treatment and a pipeline anchored by two Phase III candidates, all predicted to generate more than $5 billion in annual revenue.
Based in San Diego, Crinetics focuses on discovering, developing, and commercializing therapeutics for endocrine diseases. The company’s first marketed drug Palsonify® (paltusotine), an oral SST2 agonist, was approved by the FDA in September as the first and to date only once-daily oral therapy for adults with acromegaly, a debilitating condition which affects an estimated 20,000 Americans. Palsonify won European Commission approval in April and is under review by regulators elsewhere in the world.
Palsonify has enjoyed rapid uptake among acromegaly patients, with Crinetics reporting the drug generated net product revenue of $10.3 million during the first quarter, with 232 patients enrolling for treatment. Approximately 70% of patients treated with Palsonify at the end of Q1 were on reimbursed therapy—reflecting payers increasingly agreeing to cover the treatment, according to the company.
Within the first two quarters of its U.S. launch, Palsonify was prescribed by 263 unique healthcare providers.
Under its generic name paltusotine, the drug is in Phase III study for a second indication of carcinoid syndrome, a rare condition resulting from neuroendocrine tumors.
‘Excellent strategic fit’
Reshma Kewalramani, MD, Vertex Pharmaceuticals CEO and President
“Crinetics is an excellent strategic fit for Vertex, with its focus on serious diseases in specialty markets with significant unmet need, well-understood causal human biology, and potentially best-in-class medicines that could deliver transformative benefit to patients,” Reshma Kewalramani, MD, Vertex’s CEO and president, said in a statement. “We believe Vertex can build on the strong momentum of the Palsonify launch by applying our experience in commercializing medicines for rare genetic diseases.”
Crinetics investors agreed, roaring their approval of the pending acquisition as the company’s shares all but doubled in early trading Tuesday, zooming 99% to $83.54 as of 10:28 am ET from yesterday’s closing price of $42.03. Vertex shares dipped 2% to $516.48 from $529.59 at Monday’s closing bell.
Also in late-stage development is Crinetics’ lead pipeline candidate atumelnant, an oral adrenocorticotropic hormone (ACTH) antagonist now under development for congenital adrenal hyperplasia (CAH) and ACTH-dependent Cushing’s syndrome.
In classic CAH, a rare chronic genetic disease with 17,000 addressable patients in the U.S., atumelnant is in a pair of clinical trials. One is a Phase III study in adults with the most common cause of the disease, 21-hydroxylase deficiency (21-OHD). The study’s estimated primary completion date is May 2027 (NCT07144163). The other trial is a Phase II/III study in children ages one to <18, which has an estimated primary completion date of March 2030 (NCT07159841).
Earlier Phase II studies of atumelnant showed that patients treated with the therapy achieved near normalization of excess androgen levels on physiologic replacement doses of glucocorticoids—a therapeutic profile that Crinetics has said positions atumelnant to become the leading treatment for people with CAH.
Atumelnant (formerly CRN04894) is also being developed for ACTH-dependent Cushing’s syndrome, and is under study in a Phase Ib/IIa open-label, multiple-ascending dose exploratory study (NCT05804669) designed to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamic biomarker responses associated with the treatment.
‘Significant potential’
“We are also excited by the significant potential of atumelnant to transform the treatment landscape for CAH, setting a new standard of care where patients do not have to choose between managing their excess adrenal androgens and enduring the side effects of high-dose steroids,” Kewalramani said.
One analyst said a Vertex buyout would be good news for Crinetics.
“This is a solid outcome for CRNX, given stock pressure from the near-term Palsonify launch (generally slow and steady launch but (+) [positive] progress by CRNX so far) and the fact that key Phase III catalyst for CAH isn’t until late 2027/28,” Jefferies equity analyst Dennis Ding wrote today in a research note.
In a regulatory filing yesterday, Crinetix shared an email it sent to employees, stating: “We have always been confident in the ability of Crinetics to achieve our plan and were not actively looking to sell the company when Vertex approached us. However, after careful consideration, our board unanimously determined that the transaction is in the best interests of our shareholders.”
Crinetics’ pipeline of more than 10 disclosed candidates includes:
CRN09682, a Phase I nonpeptide drug conjugate candidate being developed to treat somatostatin receptor 2 (SST2) expressing neuroendocrine tumors and other SST2 expressing solid tumors.
Discovery-phase preclinical programs focused on endocrine targets that include thyroid stimulating hormone (TSH), parathyroid hormone (PTH), somatostatin receptor 3 (SST3), growth hormone (GH), glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), as well as GPCR-targeted oncology indications.
Vertex said the deal was expected to contribute immediately to revenue growth via the ongoing launch of Palsonify, which the company says has blockbuster (greater than $1 billion in annual sales) potential in acromegaly. Longer term, Vertex says, atumelnant could also generate multiple billions of dollars in CAH, with additional revenue potential in Cushing’s syndrome.
$5B revenue forecast
R. Scott Struthers, PhD, Crinetics’ Co-founder and CEO
At peak year, Palsonify and atumelnant could deliver more than $5 billion in combined annual revenue, Vertex said, and thus contribute toward its goal of delivering sustained double-digit revenue growth, plus industry leading operating margins. The transaction is expected to add to non-GAAP operating income as of 2029.
Jefferies analyst Ding commented that atumelnant in CAH is expected to generate the largest share of the projected $5 billion, as in $2 billion to $3 billion, plus another $1 billion to $2 billion for Cushing’s syndrome–with the remaining $1 billion to be generated by Palsonify in acromegaly.
Scotiabank analyst Louise Chen told Reuters: “The deal adds a fifth vertical, endocrinology, which helps diversify VRTX’s concentration in CF.”
That concentration has proven lucrative for Vertex: During Q1, CF treatments generated $2.915 billion in total revenues, 98% of the company’s total revenue of $2.987 billion.
Vertex has agreed to acquire all outstanding shares of Crinetics common stock for $85 per share cash, in a deal valued at $8.8 billion net of estimated cash acquired. Vertex said it expects to finance the acquisition using a combination of cash on hand and debt, supported by $4.5 billion of fully committed bridge financing from Bank of America and Morgan Stanley Senior Funding.
Vertex finished the first quarter with cash, cash equivalents, and total marketable securities of $13 billion, up from $12.3 billion as of December 31, 2025. The company attributed the increase primarily due to cash flows from operating activities, partially offset by repurchases of Vertex’s common stock.
The transaction is expected to close in the third quarter subject to customary closing conditions, including receipt of regulatory approvals and approval by Crinetics shareholders.
“Nearly 18 years ago, we founded Crinetics with a clear goal of transforming the lives of patients living with endocrine-related diseases. Today marks a historic milestone as we embark on this next chapter with Vertex,” stated R. Scott Struthers, PhD, Crinetics’ co-founder and CEO. “Vertex’s global infrastructure and commercial footprint will serve to amplify the reach of our science and allow us to maximize the impact of Palsonify, atumelnant and our pipeline.”
Background: Digital remote monitoring technologies, including smartphones and wearables, offer promising avenues for early detection of psychosis relapse. However, selecting devices that are acceptable to participants and produce high-quality data remains challenging. Objective: The aim of this nested pilot study was to assess the acceptability and data quality of 3 commercially available wearable devices in people with psychosis recruited to the CONNECT cohort study. Methods: Participants recruited to the CONNECT study before July 31, 2024, were included in the pilot study and selected 1 of 3 wearable devices: a Fitbit Charge 5, Samsung Galaxy Watch 5, or Apple Watch SE. Baseline demographics were compared between device groups. Acceptability of devices to participants was assessed through a Wearable Device Satisfaction Questionnaire after 3 months of use, with the proportion of positive responses to each question calculated and compared. Data completeness was also assessed by calculating the number (and percentage) of valid days of step count, heart rate, and sleep data, and comparing between groups. Data quality was assessed through summarizing the amount of troubleshooting required, additional metrics available from the wearables, and continuity of data completeness by calculating the proportion of participants with at least 3 days of heart rate data per week for the first 20 weeks of follow-up. Predefined criteria were used to determine the next steps for the wider CONNECT study: if one device was superior, this would be selected; if none were found to be superior and the Fitbit was found to be noninferior, then Fitbit would be retained. Results: Of the first 107 participants recruited to CONNECT, 105 were included in the pilot study evaluation. The Samsung Galaxy Watch was selected most frequently by participants (46/105, 43.8%), followed by the Apple Watch (27/105, 25.7%), and Fitbit Charge (23/105, 21.9%). Differences in participant demographics were observed across device groups. Self-reported acceptability after use did not differ substantially between devices. However, in terms of data completeness, the median proportion of valid heart rate data days was significantly lower for Samsung Galaxy (median 31.2%, IQR 8.5%-46.0%) compared to Fitbit (median 80.1%, IQR 26.7%-95.0%; =.003) and Apple Watch (median 49.3%, IQR 21.5%-86.0%; =.02). There was no significant difference between Fitbit and Apple Watch. Similar patterns were observed for step count and sleep data. The Samsung Galaxy Watch required more frequent troubleshooting for data flow issues and lacked additional physiological metrics, available from the other devices. Conclusions: Due to comparatively lower data quality and technical performance, the Samsung Galaxy Watch was discontinued for use in the subsequent phase of the CONNECT study. The study highlights the importance of incorporating nested evaluations of devices in long-term research.
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Background: Loneliness is a prevalent concern across the United Kingdom. While validated scales exist to quantify the severity of loneliness across populations, there remains a gap in understanding how loneliness manifests and is addressed within therapeutic practice. Given the associated stigma surrounding loneliness, practitioner perspectives offer crucial insights into how clients express loneliness within digital therapeutic environments. These insights can inform more nuanced conceptualizations of loneliness. Objective: This study aimed to gather the practitioners’ perspectives on loneliness within a digital therapeutic context and were defined as follows: (1) understand how practitioners identify loneliness concerns, (2) identify how loneliness is elicited in digital mental health interventions, and (3) identify co-occurring themes (such as grief, shame, and social disconnection) that signal loneliness concerns in client communications within digital therapeutic environments. Methods: Semistructured interviews were conducted with 9 practitioners. Participants included specialists in grief counseling, lesbian, gay, bisexual, transgender, and queer or questioning plus support; and digital mental health therapists. Interview transcripts were analyzed using thematic analysis, using an inductive, data-driven approach to allow themes to emerge from participant accounts rather than fitting data to preexisting theoretical frameworks. Results: The following four themes were identified: (1) Conceptualizing Loneliness: practitioners distinguished between social contact and meaningful connection; (2) Contextual Causes: loneliness emerged from life transitions, stigmatized identities, and resource reduction (eg, youth services closures and social support); (3) Expressions and Language: clients rarely expressed loneliness directly, instead using proxy terms, with disclosure patterns varying by age; and (4) Mental Health Co-occurrence: severe mental health conditions created bidirectional cycles of loneliness, exacerbated by symptoms of mental health difficulties. Practitioners reported that many clients experienced loneliness concerns, yet direct disclosure was absent across all participants’ experiences. Conclusions: Practitioners identified multiple stigmatizing experiences as contextual drivers of loneliness, particularly demonstrating how loneliness emerges not only from individual experiences but from broader patterns of social exclusion and marginalization. For therapeutic practice, these insights suggest that practitioners can use awareness of stigmatizing experiences as potential indicators when assessing loneliness risk. The presence of contextual patterns was consistent across practitioners’ experiences, providing a foundation for developing more targeted interventions to address both the emotional experience of loneliness and the underlying social drivers.
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Biomedical engineering graduate and certificate programs are coming to Auburn University. Led by the department of chemical engineering and the Biomedical Engineering Advisory Committee, the state‑approved programs will serve the entire college of engineering and the broader Auburn University community, according to university officials.
These offerings include a doctoral degree, thesis and non‑thesis master’s degrees, and two graduate certificates, all drawing on the university’s expertise in advanced biomedical technologies and biotechnology.
“The biotechnology and biomanufacturing sectors within the state of Alabama are growing quickly, and they need engineers who are prepared to contribute on day one,” said Mario Eden, PhD, dean of engineering. “These offerings position Auburn as a conduit for that workforce, producing graduates with the technical depth and hands‑on experience industry partners are asking for and enhancing the college’s capacity to support the state’s growing innovation economy.”
Biomedical engineering blends principles of engineering, biology, physics, and medicine to advance human health. It focuses on developing technologies and systems that improve how diseases and injuries are understood, diagnosed, monitored, and treated. This interdisciplinary field includes:
Biomanufacturing, tissue engineering, and regenerative medicine
Drug delivery and pharmaceutical engineering
Computational modeling, data science, and artificial intelligence
Biomechanics, biomaterials, and rehabilitation engineering
Medical imaging, medical devices, wearable technologies, biosensors, and diagnostics
Auburn’s biomedical engineering lineup will involve more than 20 faculty members across the college.
“This effort gives us a clear framework for graduate study in a field where our faculty have already built real momentum,” said Selen Cremaschi, PhD, chair of the department of chemical engineering. “It brings that activity into a coordinated structure that supports rigorous graduate experiences and reflects our identity as a research driven college.
The biomedical engineering certificate program is expected to launch in Fall 2026 with a full program launch scheduled for Fall 2027.
It has long been known that brain gray matter plays a key role in multiple sclerosis (MS) disease progression and cognitive impairment, but because magnetic resonance imaging (MRI) has only been able to detect lesions in white matter, neither clinicians nor researchers have had a way to detect or monitor gray matter (cortical) lesions. And while many new drugs developed in the past decade can slow disease progression significantly, they primarily work on reducing white matter lesions.
A University at Buffalo (UB)-led team now reports that it has found a way to use artificial intelligence to reveal these otherwise invisible cortical lesions by reviewing existing MRI scans. The researchers say the significance of finally being able to see what has been known as one of the most important indicators in MS disease progression cannot be overstated.
“Detecting previously invisible cortical lesions on conventional legacy MRI scans has major implications for MS research and clinical care,” commented Robert Zivadinov, MD, PhD, SUNY distinguished professor in the Department of Neurology and director of the Buffalo Neuroimaging Analysis Center (BNAC) in the Jacobs School of Medicine and Biomedical Sciences at UB. “The ability to see for the first time these previously hidden indicators of MS disease progression, including cognitive impairment and disability, is an important advance.”
Added Michael G. Dwyer, PhD, associate professor of neurology and biomedical informatics in the Jacobs School and a researcher with BNAC, “What this collaboration has been able to accomplish is a real success story for applying AI in the medical arena. We now have access to these incredibly useful data on MRI scans that were there but you couldn’t see them without using AI to pull them out. The computational methods are finally at the point where we can do this.”
“Multiple sclerosis (MS) affects both the inner, connectivity-oriented portions of the brain (white matter) and the outer layer of the brain (the cortex),” the authors explained. While the involvement of cortical lesions in MS has been known almost since the identification of MS in the late 19thcentury, they weren’t included on diagnostic criteria until the 21st century. And even when they were included, it was noted that their use would be greatly limited due to the current capabilities of clinical MRI.
“Historically, research and clinical care in MS have focused on white matter, where focal demyelinating lesions are a hallmark of the disease,” they continued. And although there are now many therapies that can almost completely halt the incidence of new white-matter lesions in individuals with MS, they haven’t had the same impact on clinical progression, the team continued.
Over more recent decades it’s been found that gray matter is affected from the earliest MS disease stages, and it’s become evident that gray matter pathology is more than secondary to white matter damage. “From a clinical perspective, cortical lesions are strongly associated with clinical disability and cognitive impairment,” the authors stated. “They may also have more prognostic value than white matter lesions for disability and disease course.”
There’s an urgent need for in vivo imaging methods that can show gray matter lesions, they stressed. Dwyer added, “We have all been very frustrated, knowing that these cortical lesions were there but not being able to see them. There’s a lot of ongoing damage that continues to happen in MS that you won’t see with conventional MRI, but that histopathologists have been clearly demonstrating for decades on postmortem tissue.”
For their newly reported study the team applied advanced image processing techniques, including artificial intelligence, to standard MRI scans from a large MS clinical trial. “Recently, several post-processing methods, including synthetic contrasts and artificial intelligence (AI)-based approaches, have shown potential for enhancing cortical lesion detection on conventional MRI data,” they noted. “These methods have the potential to reanalyze existing clinical-trial data to answer key mechanistic questions about both MS development and about treatment effects.”
The AI approaches the researchers used, building on work from co-authors from the Netherlands, were designed to extrapolate vital information from the relationships between multiple images that can’t be seen on a single image.
The researchers combined multiple image-processing techniques, including a new one they developed called MMCLE, or multimodal cortical lesion enhancement. They then applied these techniques to MRI scans from the large, phase III FDA regulatory ORATORIO clinical trial, a study of the MS drug Ocrelizumab that included more than 700 participants.
They found that while individual images of a patient’s brain revealed mostly white matter lesions, once they applied the AI-based image processing methods to multiple different contrast images, they were able to see anywhere from 15 to 20 cortical lesions for each patient, more than 11,000 for the whole dataset. “We confirmed that cortical lesions can be clearly visualized and quantified with these methods,” they stated. “Using deep learning, we also confirmed that the simultaneous use of multiple contrasts improves quantification.”
Dwyer explained further, “If you look on the original scans, you generally can’t see the cortical lesions, but generative AI is very powerful because it can look between the scans and detect tiny differences between them. Because it sees those minor discrepancies, AI can reveal that there’s something going wrong there, that the tissue is not behaving like healthy tissue. The trained models can view multiple MRI images together and synthesize them and synthesize what had been missing.”
Zivadinov added “This work, which has revealed that there is so much invisible pathology in the brain, will have tremendous impact for reviewing data from past clinical trials and also for those going forward,” he says.
A targeted therapy already transforming treatment for hypertrophic cardiomyopathy (HCM) may be effective across a broader range of disease-causing genetic mutations than previously understood, according to new preclinical research published in Nature Cardiovascular Research.
The study identifies a previously unknown molecular mechanism underlying one of the most common inherited forms of HCM and demonstrates that the cardiac myosin inhibitor mavacamten—the first targeted therapy available for this condition—can reverse disease-associated changes, even when the underlying biology differs from that of the patients for whom the drug was originally developed.
HCM affects approximately one in 200 to 500 people and is the leading cause of sudden cardiac death in young adults and athletes. The disease is characterized by abnormal thickening of the heart muscle, impaired relaxation, and excessive contractility, which can ultimately lead to heart failure, arrhythmias, and sudden cardiac death.
Most inherited cases are caused by variants in either MYH7, which encodes the molecular motor myosin, or MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), an important regulator of cardiac muscle contraction.
While truncating mutations in MYBPC3 reduce levels of cMyBP-C and promote excessive myosin activity, much less has been known about how missense mutations—which preserve protein levels but alter protein function—drive disease.
To investigate this question, researchers generated a knock-in mouse model carrying the R502W missense mutation, one of the most common pathogenic MYBPC3 variants found in patients with HCM. Unlike mice lacking cMyBP-C, the R502W animals maintained normal amounts and localization of the protein yet still developed hallmark features of hypertrophic cardiomyopathy, including cardiac hypertrophy, fibrosis, impaired cardiac function, and hypercontractility.
“Our findings support that mutation-induced loss of interactions between the central domains of cMyBP-C and myosin is a molecular pathomechanism in HCM that can be targeted by myosin inhibitors,” the authors write.
Rather than reducing protein abundance, the mutation weakened the interaction between cMyBP-C and myosin, shifting more myosin molecules into an active structural state capable of generating contraction. The mutation also increased calcium sensitivity, together producing excessive contractile force.
Importantly, these abnormalities arose through a mechanism distinct from the loss-of-protein pathway associated with truncating MYBPC3 mutations.
Despite these divergent disease mechanisms, treatment with mavacamten significantly reduced pathological remodeling in both the R502W mice and animals lacking cMyBP-C. The drug also restored a more normal inactive structural state of myosin in mutant heart muscle and reduced excessive contraction in engineered human heart tissues carrying the same mutation.
“Hence, our data and evidence in the literature suggest that mavacamten is equally effective for carriers of any pathogenic variant in MYH7 or MYBPC3,” the authors conclude. The findings may help explain why genetic differences alone are unlikely to account for the variable clinical responses observed in patients receiving mavacamten.
The work also has implications beyond current therapies. Because some emerging gene therapies aim to replace cMyBP-C rather than correct mutant protein function, the authors suggest those approaches may be less effective for patients carrying missense mutations such as R502W. By contrast, gene-editing strategies capable of directly correcting single-base mutations may prove particularly promising.
The researchers also propose that the newly developed mouse model more closely resembles the relatively mild progression of human hypertrophic cardiomyopathy than previous models based on complete cMyBP-C deficiency, making it a valuable platform for testing future therapies and studying disease biology.
Looking ahead, the investigators suggest that most patients carrying pathogenic MYBPC3 variants could potentially benefit from myosin inhibition regardless of the mutation’s underlying molecular mechanism.
“Our preclinical data indicate that all carriers of pathogenic variants in MYBPC3, arguably the most common cause of HCM, may similarly benefit from myosin inhibition regardless of diverging specific pathomechanisms,” the authors conclude. They add that the limited effectiveness of mavacamten observed in some patients is “probably due to reasons other than the specific HCM variants they carry,” including disease stage, environmental influences, or other genetic factors.
Although genome editing was not a new concept, as zinc finger and TALEN platforms were already in use, the discovery of CRISPR-Cas9 shifted genome-editing research and clinical translation into high gear. But just like other platforms, this new kid on the block was not applicable to every editing situation for every genetic disease.
A longstanding desire in the field is a one-and-done, mutation-agnostic cure for genetic diseases that result from numerous mutations in a gene or from large-scale chromosomal structural variations, including deletions, duplications, inversions, and translocations. Gene therapies for these genetic indications require large-scale DNA manipulation, presenting different technical and regulatory challenges than correcting single-nucleotide point mutations.
Scientists donned their Indiana Jones hats to search for this holy grail of genome editing. Promising approaches under exploration included bridge recombinases, large serine recombinases, and CRISPR-associated transposases (CASTs), as well as immune-evasive DNA cargoes like circular single-stranded DNA (cssDNA), which may address the innate toxicity of double-stranded DNA (dsDNA) payloads.
Still, delivery can remain a conundrum for large payloads. For the most part, current delivery mechanisms are size-limited in terms of payloads, as are the workarounds using mRNA formats and leveraging reverse transcriptase.
The thirst is there, and the quest will continue. New genome-editing tools applicable to large DNA cargoes and delivery mechanisms will be refined, putting potential cures in sight for some deplorable diseases.
Bridge recombinases
A new class of programmable genome-editing tools, bridge recombinases are the first RNA-guided DNA recombinases providing a distinct mechanism for manipulating DNA.1,2
The system has two key components: the recombinase enzyme, which catalyzes the DNA rearrangement, and a bridge RNA guide with two independently programmable loops. The target-binding loop controls genomic locus targeting, and the donor-binding loop specifies the donor payload.
Reprogramming the bridge RNA to change the configuration and orientation of the target and donor sites allows the system to be redirected to perform excision of a desired sequence from the genome or inversion of a DNA segment in place. The modularity means a single two-component system can perform all three fundamental DNA rearrangements—insertion, excision, and inversion—through a single unified mechanism.
“The most immediate advantage is the scale of DNA that bridge recombinases can manipulate,” said Patrick Hsu, PhD, co-founder and core investigator of the Arc Institute and assistant professor of pathology at Stanford University. “A technology that can operate at the scale of whole-gene replacement or correct structural variants opens up a new class of genetic interventions.” Multi-kilobase insertions, inversions up to 0.93 Mb, and excisions up to 0.13 Mb have all been demonstrated in human cells.3
Bridge recombination also does not rely on dsDNA breaks. The recombinase catalyzes strand exchange directly through a covalent intermediate, making the outcome deterministic in a way that nuclease-dependent approaches are not. This indicates that the system may have advantages in post-mitotic cells for therapeutic applications. About a quarter of the size of Cas9, the system can be encoded in delivery vectors with limited capacity.
“The technology is still in development. While our current efficiency and specificity numbers (20% insertion efficiency with 82% on-target) represent a meaningful proof-of-concept in human cells, improving both metrics will be necessary for safe and effective therapeutic applications,” said Hsu. The diversity of bridge-recombinase systems found in nature continues to be explored.
Large serine recombinases
“For simpler cases where we want to insert a DNA payload into a fixed safe harbor site, we are working on large serine recombinases (LSRs),” said Hsu. While these enzymes lack the RNA programmability of bridge recombinases, they offer very high efficiency and specificity of insertion and are effectively unidirectional, leading to very stable insertions of large DNA cargoes into the human genome.
Bridge recombinases have a dual targeting capability that enables these systems to insert new genetic material, delete unwanted regions, or flip existing DNA segments, all in a single, programmable step. [Chiara Ricci-Tam, Arc Institute]
A 2025 Nature Biotechnology paper described an LSR enzyme engineered to enable site-specific insertions of multi-kilobase DNA payloads with 53% efficiency and 97% genome-wide specificity. Importantly, it was demonstrated that LSRs work well in non-dividing cells, including primary human T cells.4
Stylus Medicine, a company Hsu co-founded, intends to advance LSRs for in vivo genetic therapies. “I am excited to see the new therapies that will emerge from combining recombinase technology with machine learning-assisted protein engineering and advances in DNA and effector delivery for challenging disease contexts,” said Hsu.
CRISPR-associated transposases
CASTs are naturally occurring bacterial systems that utilize nuclease-deficient CRISPR machinery to integrate DNA at genomic locations specified by guide RNAs (gRNA). “While CRISPR is often used to cut DNA, CASTs instead use CRISPR systems to guide site-specific DNA transposition,” said Isaac Witte, PhD, department of chemistry and chemical biology at Harvard University.
In 2019, two research groups—one at Columbia University led by Sam Sternberg, PhD, and the other at the Broad Institute of MIT and Harvard, headed by Feng Zhang, PhD—found that CASTs use CRISPR systems to target DNA transposition by a transposase complex. Further work demonstrated that CASTs were very efficient bacterial genome editors.
CASTs can mobilize multi-kilobase-scale DNA cargoes, and their naturally evolved transposition mechanism avoids forming dsDNA breaks in the genome. The problem was that the wild-type systems exhibited extremely low (often ≤0.1% of treated cells) or undetected integration activity in human cells.
Collaborating with the Sternberg lab, the lab of David Liu, PhD, from the Broad Institute of MIT and Harvard, used PACE (phage-assisted continuous evolution), a directed evolution platform developed by the Liu lab, to enhance the efficiency of CAST transposition.
In PACE, bacteriophages, which infect host bacteria, encode evolving genes in place of an essential gene for phage replication. This essential gene is instead encoded by host bacteria. “In PACE, you link the desired activity of the evolving biomolecule to the expression of this essential gene. In this case, we linked targeted DNA integration to the replication of phages encoding evolving CAST protein components,” said Witte.
A series of modifications ensured efficient enhancement of activity, resulting in the generation of an evolved variant of the CAST transposase protein TnsB that mediated over 200-fold improved integration activity in human cells. The TnsB protein contained ten individual mutations scattered throughout the predicted structure, which contributed to improved activity.
The evolved TnsB was combined with other PACE-evolved and rationally engineered CAST components to yield evoCAST, a system optimized for human-cell integration activity, published in Science.5
The evoCAST DNA integration does not require formation of dsDNA breaks in the genome, resulting in undetected levels of insertion and deletion mutations (indels) commonly found in traditional methods of gene insertion like nuclease-stimulated, homology-directed repair (HDR). In addition, evoCAST can be easily reprogrammed to genomic sites of interest by changing the gRNA sequence, and it supports a variety of DNA payload sizes, ranging from less than 1 kb to at least 15 kb.
A potential limitation, however, is that evoCAST is molecularly complex, containing seven distinct protein subunits, making the total coding size (~8.5kb) relatively large compared to around 5 kb for Cas9.
Big-picture limitations center on delivery, according to Witte, such as mitigating the cytotoxicity of foreign dsDNA in most therapeutically relevant cell types. Additionally, reducing the size and the number of distinct components required for integration activity may facilitate evoCAST applications in vivo. Next steps include harnessing the naturally existing diversity of CAST systems to develop a more diverse repertoire of CASTs for genome editing in human cells.
Circular single stranded DNA
Full Circle Therapeutics’ genome writing technology centers on an immune evasive DNA modality, a mini-cssDNA, called C4DNA—circular, clean, concealed, and customizable up to 20 kb.
The image illustrates the use of cssDNA as a novel, immune-evasive large DNA modality for immune cell engineering via DNA writing, for potential treatment of cancer, autoimmunity, and other diseases. [Caitlin Rausch for Full Circle Therapeutics]
“The holy grail of gene editing is kilobase DNA integration. While most studies focus on new editing enzyme discovery, we address the challenge from the donor side. To integrate gene-size DNA in a specific locus, the choices of donor cargo templates are ds, ss, circular, or linear DNA. Workarounds using RNA formats and leveraging reverse transcriptase are still size-limited,” said Howard Wu, PhD, co-founder and CSO at Full Circles Therapeutics.
The company has commercialized over 350 research-grade cssDNA for primary sequences and is developing processes for GMP-grade products for clinical applications. According to Wu, initially, the company’s founder, Richard Shan, intended to supply linear cssDNA as a DNA commodity for researchers in the gene-integration field. The starting material was cssDNA that was cleaved into linear strands. A serendipitous benchmark experiment using cssDNA as a control demonstrated surprisingly better integration performance than its linear counterpart.6 The unexpected results led to a foundational patent describing the use of cssDNA for targeted genomic integration.
After benchmarking the different DNA formats, cssDNA appeared superior and compatible with various CRISPR-Cas systems, along with other meganuclease editing systems such as TALEN. Next, they evaluated the hypothesis that immunogenicity due to dsDNA could be eliminated if mobile genetic elements like transposase systems and LSRs could use cssDNA.
Collaborating with a team at Harvard Medical School led by Benjamin Kleinstiver, PhD, they demonstrated that naked unmodified cssDNA, combined with piggyback transposases or LSRs, enables kilobase writing, albeit inefficiently. One way to improve integration efficiency was to design an oligo that could fuse to the cssDNA with hydrogen bonding to form a partial duplex. A 30- to 60-mer partial duplex showed good integration efficiency when compared to dsDNA, while remaining immune silent.
In another approach, the team modified the nuclear editor and installed a peptide sequence identified from a bacterial genome with a strong binding affinity with cssDNA. In this case, the modified Cas9 became an engineered molecular chaperone to recruit the DNA molecule and form a complex, effectively loading and delivering the genome engineering complex into the nucleus and direct to the targeted genome.7
Continued collaboration with Kleinstiver’s lab aimed to improve integration efficiency. The approach, in this case, used a partial duplex cssDNA that reconstituted a recombinase recognition sequence. The scientists termed this integration through nucleus-synthesized template addition of large lengths (INSTALL). INSTALL is compatible with diverse genome engineering nucleases and RNA-guided recombinases for high-fidelity kilobase-scale human genome writing.8
“We welcome partners,” said Wu. “It is prime time to talk about DNA medicines.”
References
Hiraizumi, M, Perry NT, Durrant, MG, et al. Structural mechanism of bridge RNA-guided recombination. Nature2024; 630:994-1002. doi:10.1038/s41586-024-07570-2
Durrant, MG, Perry NT, Pai JJ, et al. Bridge RNAs direct programmable recombination of target and donor DNA. Nature2025:630:984-993. doi:10.1038/s41586-024-07552-4
Perry NT, Bartie LJ, Katrekar D, et al. Megabase-scale human genome rearrangement with programmable bridge recombinases. Science. 2026 Mar 12;391(6790):eadz0276. doi:10.1126/science.adz0276
Fanton, A, Bartie, LJ, Martins JQ, et al. Site-specific DNA insertion into the human genome with engineered recombinases. Nat Biotechnol. 2025 Nov 6. doi:10.1038/s41587-025-02895-3
Witte IP, Lampe GR, Eitzinger S, et al. Programmable gene insertion in human cells with a laboratory-evolved CRISPR-assoc iated transposase. Science. 2025 May 15;388(6748). doi:1126/science.adt5199
Xie K, Starzyk J, Majumdar I, et al. Efficient non-viral immune cell engineering using circular single-stranded DNA-mediated genomic integration. Nat Biotechnol. 2025 Nov;43(11):1821-1832. doi:10.1038/s41587-024-02504-9
Nam H, Xie K, Majumdar I, et al. Engineering tripartite gene editing machinery for highly efficient non-viral targeted genome integration. Nat Commun. 2025; 16:4569. doi:1038/s41467-025-59790-3
Tou CJ, Xie K, Ferreira da Silva J, et al. Immune evasive DNA donors and recombinases license kilobase-scale writing. Nature. 2026 Mar 11. doi:10.1038/s41586-026-10241-z
Background: Asynchronous online forums provide flexible, accessible peer support for many people living with dementia and carers. Moderators are central to the functioning of these communities, yet little is known about their experiences. Objective: This study explored the experiences of individuals moderating an online dementia forum, including their motivations, perceived benefits, challenges, and suggestions for improvements. Methods: Moderators from a UK-based online dementia support forum were recruited using purposive sampling via forum administrators. Between January and March 2025, 5 moderators, all with dementia care experience, participated in remote semistructured interviews. Interview topics included pathways into moderation, perceptions of the moderator role, experiences of supporting forum members, challenges encountered, perceived personal benefits, and views on the future development of online support communities. Interviews were transcribed verbatim and analyzed using reflexive thematic analysis. Results: Four themes were produced: (1) “from support seeker to support provider”: moderators primarily identified as community members rather than authority figures, following a trajectory from receiving support as a carer to actively facilitating community support; (2) “understanding through shared experience”: lived experience of dementia was seen as essential for empathy, credibility, and sensitive responses, though sometimes prompted strong emotional reactions; (3) “giving back and gaining in return”: moderation offered purpose, structure, and social connection, particularly postretirement and following transition out of caring; (4) “balancing growth with community preservation”: forum expansion increased workload, spam management demands, and safeguarding responsibilities, and moderators were cautious about social media–style features and artificial intelligence–generated content undermining the effectiveness of support exchanges. Conclusions: Moderators play a crucial, value-driven role in sustaining dementia support forums, extending beyond administrative duties. The findings suggest that moderators occupy a distinctive position as both recipients and providers of peer support, drawing on experiential expertise to maintain trust and community cohesion. Forum growth and technological innovations present opportunities and challenges, highlighting the need to balance scalability with authenticity in online support communities.
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