According to Clare Gillis, a researcher in bioinformatics and computational biology, the app has the potential to help companies begin process development. “It can help them if they already know their antibody binds as they want, but they need to know if it will pass through the whole developability and manufacturability pipeline,” she says.
TAP2 uses five easily calculable physiochemical metrics based on surface residues of the antibody, Gillis says. These are more likely to affect manufacturability.
The web app metrics are selected to model aspects of antibody behavior, such as hydrophobicity, she adds. If there are big patches of hydrophobic residues on the outside of the antibody, then it’s more likely to be reactive and, thus, less likely to remain stable as a formulated drug product.
Likewise, Gillis explains, if the surface of the antibody features large patches of positive or negative charge, it is likely to have nonspecific reactions that will cause destabilization and aggregation.
With the TAP2 app, companies can flag early amber or red warnings for antibodies where manufacturability might be an issue. In addition, the group also offers a web app profiler for therapeutic nanobodies, TNP, as well as Humatch, an app that can help tweak antibodies to be more ”human-like” and less likely to cause immune reactions in patients, she says.
About Humatch, Gillis says, “you can add a best single point mutation and then iterate over and over until the model believes the antibody is fully humanized.” The app works for any antibody with paired heavy and light chain variable domains (VH and VL), she says, and can potentially help manufacturers of harder-to-produce products that don’t exist in nature.
Viral vector production and training schemes designed to foster development of an AI-ready workforce dominate the list of projects selected for support by the U.S. National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL).
The institute, a public-private partnership focused on advancing manufacturing and solving industry challenges, announced its latest funding awards, explaining that the 39 recipients would support U.S. production and talent development.
Sandeep Kedia, NIIMBL senior technology fellow and project call program lead, says the projects “represent the kind of innovation needed to strengthen the nation’s biopharmaceutical manufacturing capabilities.
“By bringing together advanced process analytical technologies, AI-driven optimization, and next-generation production platforms, our members are helping accelerate the adoption of transformative technologies across the industry,” he adds.
Several of the selected projects focus on the production of adeno-associated viral (AAV) vectors—hollow viruses used to deliver genetic information—which play a crucial role in cell and gene therapy manufacturing.
For example, researchers at Michigan Technological University will work with industry partners on an aqueous two-phase continuous vector purification system. The aim is to boost yield while reducing cost, labor, and analytical complexity.
Similarly, a team at North Carolina State aims to develop “improved purification materials that can better capture full AAVs, along with machine-learning software that identifies optimal process conditions.”
The third vector-focused project will see an MIT group work with EMD Millipore, Landmark Bio, and Virica Biotech to try to reduce the number of empty viral capsids inadvertently made during vector production.
The researchers will combine an approach called decoupled replication-initiated vector encapsulation, or DRIVE, with various process control strategies to create a platform that makes high-titer, high-quality rAAVs.
According to the MIT team, “By reducing [the proportion of] empty capsids, the approach can streamline downstream purification, reduce time and cost, and improve the overall quality of gene therapy products.”
AI-ready workforce
In addition to the technology projects, NIIMBL will support several training programs with an emphasis on ensuring the next generation of biopharmaceutical engineers are AI-ready, according to workforce director John Balchunas.
“Our workforce initiatives are designed to meet talent needs head‑on by creating more innovative pathways into biomanufacturing careers,” he says, adding, “These new projects will strengthen partnerships and ensure that learners can gain the skills needed to thrive in a rapidly evolving biopharma industry.”
One such project will see a team at Texas A&M University’s National Center for Therapeutics Manufacturing expand an existing effort called NeuroPipes, which seeks to interest neurodiverse people in careers in biopharma. The aim is to provide technical skills training that prepares neurodivergent adults for careers in drug manufacturing.
Another project will see Wistar Institute researchers set up BioPATH, a national consortium focused on advancing workforce training in biomanufacturing, AI, and automation.
The idea, according to the Wistar team and collaborators at the International Academy of Automation Engineering, is to “bridge the gap between foundational bioprocess and GMP knowledge and the emerging needs of automation, data-driven manufacturing, and digitally enabled quality systems.”
Erdinc Sezgin, PhD, leads the Cell Signalling, Immunity and Nanoimaging (CSI:Nano) Lab at Karolinska Institutet and SciLifeLab in Stockholm, Sweden. His lab works on biophysical principles underlying cellular processes in health and disease, developing advanced imaging, chemical biology, and synthetic biology tools to reveal the molecular mechanisms governing cellular physiology and disease processes.
Hanna van Ooijen, PhD
Scientific Affairs Manager Pixelgen Technologies
Panelist
Hanna van Ooijen, PhD
Hanna van Ooijen, PhD, serves as the scientific affairs manager at Pixelgen Technologies, a Stockholm-based biotechnology company advancing spatial proteomics and single-cell protein interactomics. In her role, she works at the intersection of immunology, translational research, and emerging spatial biology technologies, helping researchers apply advanced tools to better understand immune cell behavior in areas such as oncology, cell therapy, and autoimmune disease research. Hanna is particularly interested in how nanoscale organization and protein interactions shape immune cell activity, and she has contributed to scientific outreach and presentations on next-generation approaches for profiling immune cells at single-cell resolution. She earned her PhD from KTH Royal Institute of Technology, where her research focused on understanding the factors that regulate cytotoxic immune cell function, with a particular emphasis on cellular heterogeneity and immune cell dynamics.
Broadcast Date:
Time:
The biophysical properties of the plasma membrane actively shape immune cell function, providing key insights into chronic disease and immune dysfunction. Measuring membrane order across immune cell populations can reveal functionally distinct cell states invisible to canonical surface markers and open new avenues for therapeutics.
In this GEN webinar, Erdinc Sezgin, PhD, Karolinska Institutet, will present how his lab profiled plasma membrane order across 12 immune cell subtypes simultaneously in healthy donors and patients with long COVID and chronic lymphocytic leukemia. He will also share how sorting NK cells by membrane order, combined with transcriptomics and the Proximity Network Assay (PNA) from Pixelgen Technologies, uncovered distinct subsets differing in cytotoxic potential, migratory capacity, and surface protein organization for biomedical applications.
Key takeaways include:
How plasma membrane order varies across immune cell types in chronic disease
Using biophysical membrane order to identify NK cell subsets that cannot be distinguished by surface markers alone
How spatial surface proteomics via PNA separates functionally distinct NK cell populations
How membrane order profiling can complement standard immunophenotyping workflows
A live Q&A session will follow the presentation offering you a chance to pose questions to our expert panelists.
In a new study published in Nature Communications titled, “Native long-read RNA sequencing of human monocytes reveals activation-induced alternative splicing toward functional isoforms,” researchers at University Medical Center (UMC) Utrecht have uncovered a previously underappreciated mechanism that helps immune cells respond rapidly to infections. The team showed that alternative RNA splicing plays a central role in shaping immune responses. The results provide new insights into immune-mediated diseases, such as infections, rheumatoid arthritis and lupus, and open the door to more targeted therapies.
The study focused on monocytes, a type of innate immune cell that acts as a first responder to pathogens. Using long-read RNA sequencing, the authors generated a comprehensive map of full-length RNA transcripts in human monocytes before and after activation. They identified more than 24,000 isoforms, the majority of which have never been described, revealing a previously hidden layer of molecular complexity.
Notably, immune activation triggers widespread ‘isoform switching.’ Rather than simply turning genes on or off, monocytes shift toward producing longer, fully functional RNA variants that are more likely to be translated into proteins. These isoforms contain complete coding sequences, fewer non-coding interruptions, and greater structural complexity, all features associated with more effective protein production.
“In our study we also confirmed that these RNA changes have real functional consequences,” said Jorg van Loosdregt, PhD, associate professor at UMC Utrecht and corresponding author of the study. “By integrating data on protein synthesis and ribosome activity, we demonstrated that the observed isoform shifts are linked to increased production of immune effector proteins. This shows that alternative splicing directly enhances the cell’s ability to respond to infection or inflammation.”
While previous studies have linked conditions, such as rheumatoid arthritis and lupus, to genetic variation affecting RNA splicing, the study demonstrates that disease mechanisms may also depend on which isoforms are produced and how efficiently they are translated into proteins.
“Our study underscores the importance of studying gene regulation at the isoform level. Traditional methods may overlook critical changes that only become visible with full-length RNA analysis,” said van Loosdregt. “The adoption of long-read sequencing technologies could therefore transform research into immune function and disease mechanisms.”
Emerging approaches, such as antisense oligonucleotides or drugs that influence splicing factors, may enable more precise modulation of the immune system and the development of targeted treatments for immune-mediated diseases.
Assistant Professor of Pediatrics, The Perelman School of Medicine University of Pennsylvania Director, Clinical In Vivo Gene Therapy Children’s Hospital of Philadelphia
Panelist
Lindsey A. George, MD
Dr. George is a physician-scientist whose clinical expertise is in disorders of hemostasis and thrombosis with a particular interest in hemophilia and hemophilia gene therapy. Her basic science laboratory studies the molecular basis of coagulation that in diminished or excess functional states leads to disorders of hemostasis and thrombosis, respectively. The current focus of the George lab is to merge mechanistic studies aimed at understanding the regulation of factor VIII cofactor function with translational efforts in hemophilia A gene therapy. Her group is additionally interested in understanding the mechanistic basis of questions that have emerged from current hemophilia gene therapy clinical trials as well as general studies of adeno-associated viral vectors (AAV). Dr. George was previously the lead clinical principal investigator of multiple early phase hemophilia A and B adeno-associated virus-mediated gene addition trials. In addition to her clinical practice and laboratory, she directs the Clinical In Vivo Gene Therapy at the Children’s Hospital of Philadelphia that long-term aims to safely and efficiently advance translational and clinical research for in vivo gene therapy for children with genetic disorders.
Steven Gray, PhD
Professor, Department of Pediatrics Co-Director, Gene Therapy Program Director, Viral Vector Facility University of Texas Southwestern Medical Center
Panelist
Steven Gray, PhD
Dr. Steven Gray is a Professor of Pediatrics at the University of Texas Southwestern Medical Center, where he co-directs the Gene Therapy Program and leads the Viral Vector Facility. An expert in AAV gene therapy vector engineering and nervous system gene delivery, his research has helped advance gene therapies for neurological disorders including Rett syndrome, Tay-Sachs disease, Batten disease, and Giant Axonal Neuropathy. Dr. Gray has authored more than 90 peer-reviewed publications, holds over 20 patents, and has contributed to multiple approved and ongoing clinical trials. His work has earned numerous honors, including the American Society of Gene and Cell Therapy’s Outstanding Young Investigator Award.
Broadcast Date:
Time:
Adeno-associated viruses (AAVs) have emerged as one of the most promising platforms for in vivo gene delivery. Ongoing innovation in vector engineering, delivery, and clinical translation is expanding the therapeutic potential of AAV-based approaches across a range of genetic disorders.
This episode of GEN Live will explore the rapidly evolving field of AAV gene therapy. Leaders from clinical and translational research will discuss current advances and challenges in AAV vector development, delivery, safety, and long-term therapeutic efficacy.
The session will provide a broad overview of the current state of the field and foster discussion to define the next era of gene therapy. We will also take questions from the audience, so please bring your questions on AAVs for our panelists as well.
Want to stay on top of the science and politics driving biotech today? Sign up to get our biotech newsletter in your inbox.
Good morning. Yesterday was a brutal day for biotech stocks, but one company withstood the broad selloff. We also look at investor excitement for longevity startups and yet another licensing deal made by Eli Lilly.
Legend Biotech emerged as a rare market winner
Shares of Legend Biotech soared over 40% yesterday after the company disclosed early data on its in vivo CAR-T therapy that showed promise in Non-Hodgkin’s lymphoma.
The SONAR system enables RNA-level control of bacterial operons using a single engineered Cas13 effector that can be modified to control transcript degradation, translation inhibition and translation activation through simple changes in crRNA design.
China’s integration of national reforms with institutional redesign has accelerated drug development and access to medicines. As momentum shifts globally, what can other nations learn from this experience?
Eli Lilly has expanded its genetic medicines pipeline and capabilities, agreeing to partner with Ascidian Therapeutics to develop RNA exon editors intended to treat inherited kidney diseases, through a collaboration that could generate more than $1.9 billion for the Boston biotech.
The companies have agreed to launch a global research collaboration focused on discovering and developing treatments for undisclosed monogenic kidney diseases, with the option to expand into additional targets.
At the heart of the collaboration are Ascidian’s RNA exon editors, which are designed to repair genetic instructions causing disease. A single RNA exon editor can address multiple mutations spanning multiple exons, resulting in the editing of multiple disease-causing exons simultaneously.
“What that allows us to do is to replace many exons at once, thousands of bases at a time, and use endogenous cellular machinery,” Michael Ehlers, MD, PhD, Ascidian’s president and CEO, told GEN. “We’re not editing letters in the genetic code. We’re rewriting whole chapters at the kilobase scale.
“It’s a very versatile technology to address a fairly wide-ranging set of genetic diseases, and potentially beyond as well,” he added.
Since only exons need to be replaced within the diseased protein, the exon editing payload is small enough to fit in an adeno-associated virus (AAV) or in other viral or nonviral delivery vehicles, including lipid nanoparticles.
Michael Ehlers, MD, PhD, president and CEO of Ascidian Therapeutics [Credit: Kevin Trimmer, courtesy Ascidian Therapeutics]
“The therapeutic is an AAV that expresses the designed RNA exon editor. The AAV infects the target cells. The episome of the AAV dwells in the nucleus and expresses this engineered RNA molecule, our exon editor, that then conducts the trans-splicing,” Ehlers explained. “We very intentionally, across programs and things, really emphasized being a differentiated cargo company in designing these RNAs, and tried where we can to use precedented clinical delivery.”
During the transcription of DNA into RNA, noncoding introns are usually removed, while exons that remain are spliced together to form messenger RNA (mRNA) that can be translated into protein. Mutations result in malformed proteins that cause disease.
Ascidian’s RNA exon editors are designed to bind to target pre-mRNA through what the company calls a highly specific binding domain. The editor molecules are delivered as a DNA construct and transcribed into mutation-free, exon-only RNA, designed with a highly specific binding domain.
Trans-splicing process
Through a binding process called pre-mRNA trans-splicing, exon editors replace disease-causing exons, leading to what Ascidian said is expression of wild-type mRNA and protein at proper levels, in the right cells at the right time.
The exon editors are designed to address large genes or genes with high mutational variance.
“There are other excellent targets which are dominant genes, where maybe you’re uncertain whether the disease-causing mutations are dominant because they’ve got a dominant toxic gain-of-function phenotype, or they’re dominant because it’s a haploinsufficiency. The nice thing about RNA exon editing is that it doesn’t really matter to us. We simply replace the sequence with wild type, so we don’t have to worry about whether you need allele-specific knockdown in those cases, or whether you are at risk of having a haploinsufficiency phenotype,” Ehlers explained.
The exon editing approach, Ascidian said, represents a sea change for RNA therapy, which has seen treatments incorporating antisense oligonucleotides, adenosine deaminase acting on RNA (ADAR)-mediated editing, and mRNA as applied in vaccines such as those for COVID-19, and in in vivo chimeric antigen receptor T-cell (CAR-T) therapies.
“RNA exon editing is really quite different, because you can target and dodge RNAs, and instead of editing one base at a time, you’re changing big swaths of sequence at a time, and unlike a lot of other forms of editing, whether DNA or RNA—not all, but for many—there’s no need to introduce exogenous enzymes or exogenous proteins to be able to conduct the editing,” Ehlers said. “That allows Ascidian to use RNA exon editing to go after a different set of diseases, a different set of disease genes, and potentially a larger patient population.”
In kidney disease, for example, more than 60 genetic diseases are known or suspected to affect the kidneys, with over 3.5 million Americans living with severe inherited kidney disease.
“I would not say all of them are treatable, but a reasonable portion of them are, and we’re prioritizing some that are clearly important, ones where RNA exon editing is particularly uniquely suited, we believe, to addressing the underlying genetic cause,” Ehlers said.
Undisclosed targets
Ascidian has granted Lilly exclusive, target-specific rights to Ascidian’s RNA exon editing technology for undisclosed kidney disease targets. The number of targets was also not disclosed. Ascidian has agreed to lead discovery and specified preclinical activities, with Lilly agreeing to oversee additional preclinical work, clinical development, manufacturing, and commercialization. Ascidian said it retains rights to pursue other kidney-focused targets, independently or with additional partners.
Ehlers said the Lilly collaboration resulted from conversations with the pharma giant held over several years that started with Ascidian discussing its research, and over time became more focused on the companies developing the research plan and programs that they agreed to work on.
“About a year and a half ago, I would say, we kind of got really quite a bit more specific about, well, what would be some interesting areas that might fit with Lilly’s strategic interests and capabilities, where Ascidian’s technology and know-how in RNA biology and splicing biology and using RNA exon editing could apply,” Ehlers recalled.
Genetic medicine expansion
Ascidian’s RNA research and technologies fit with Lilly’s commitment in recent years to expand in genetic medicines. Lilly launched the $700 million Institute for Genetic Medicine in 2021 in Boston’s Fort Point section as part of a strategy of advancing gene and gene editing therapies, and RNA- and other nucleic acid-based therapeutics. The Institute operates in Boston and New York City, where Lilly-owned neuroscience gene therapy developer Prevail Therapeutics is based. Prevail was acquired in 2021 for up to $1.04 billion.
This year, among its numerous acquisition and collaboration deals, Lilly announced plans in February to buy out circular RNA cell therapy developer Orna Therapeutics for up to $2.4 billion, targeting advancements in cell therapy, and last month acquired nonviral DNA delivery-focused drug developer Engage Biologics for up to $202 million cash.
In its latest collaboration with Ascidian, Lilly agreed to pay the biotech up to $1.9 billion, to consist of an undisclosed upfront payment and payments tied to achieving development and commercial milestones, as well as tiered royalties on global commercial sales.
Targeting Stargardt
Ascidian’s website discloses eight pipeline candidates, the most advanced of which is its sole clinical-phase candidate ACDN-01, a first-in-class RNA exon editing therapy designed to halt the progression of Stargardt disease or other ABCA4 retinopathies by targeting their genetic cause.
ACDN-01 contains a healthy copy of exons of ABCA4 RNA, designed to replace the sections of the ABCA4 RNA that contain mutations, thus creating healthy ABCA4 RNA in the retina. According to Ascidian, this is intended to produce normal ABCA4 protein that can then help clear the eye of toxic waste products. The FDA has granted ACDN-01 its Fast Track and Rare Pediatric Disease Designations.
“I anticipate this will be, by and large, the way that we will deliver exon editors. Although, in principle, it can be agnostic to the delivery method, it’s just whatever it takes to get that RNA exon editor into the cell, into the nucleus, effectively trans-splicing at the target.”
ACDN-01 is under study in the Phase I/II STELLAR trial (NCT06467344), an open-label, single ascending dose clinical study assessing the safety, tolerability, and preliminary efficacy of the treatment candidate when delivered subretinally in participants with ABCA4-related retinopathies. Last month, Ascidian said it had completed the adult dose escalation portion of the STELLAR trial and expanded the study to subjects over 12 years of age.
“We’re working as effectively as we can to get that up and going, so I’d say in the coming months,” Ehlers said when asked about the timing of the expansion.
Ascidian is also conducting an observational prescreening study called STARPATH (NCT06445322), which is designed to identify children ages 5+ and adults with Stargardt who may be eligible for future clinical trials evaluating ACDN-01.
ACDN-01 is among numerous candidates in clinical development to treat Stargardt. These candidates include genetic therapies such as:
SpliceBio’s SB-007, a dual AAV gene therapy designed to restore expression of a functional, full-length ABCA4 protein in the retina through a protein splicing intein platform using two AAV serotype 8 (AAV8) vectors to overcome the size limitations of conventional AAVs, reconstituting biologically active ABCA4 through protein trans-splicing in target photoreceptor cells.
VeonGen Therapeutics’ VG801, a dual AAV gene therapy enabled by the company’s vgAAV capsid and vgRNA REVeRT large-gene delivery platform, which delivers the full-length functional ABCA4 gene.
Single vector approach
Ehlers said ACDN-01 would stand out from the other genetic therapies because of its single vector approach to delivery: “I’d say the others, because the nature of the ABCA4 gene, it’s too large just for gene replacement in a single vector. All the others have to use dual vector technologies to try to address that.”
“You can imagine a single vector approach being potentially simpler and more technically feasible,” he added. “But of course, what matters is clinical data, and all these programs will play out in the clinic.”
Also in Ascidian’s pipeline: A second retinal program in lead identification phase; four neuro and neuromuscular programs in phase from lead identification to lead optimization; and two lead identification-phase programs in undisclosed “other areas.” Ascidian is also partnering with Roche to discover and develop RNA exon editing therapeutics against undisclosed neurological targets, through an up-to-$1.842 billion collaboration ($42 million paid initially) launched in 2024.
Following two years in stealth mode, Ascidian was formally launched in 2022 by venture capital firm Apple Tree Partners (ATP), which incubated the company and funded it with $50 million in Series A financing. Ehlers led that incubation as the company’s founding CEO, then chaired the company’s board while Romesh Subramanian, PhD, served as Ascidian’s president and CEO. After Subramanian left the company, Ehlers returned to Ascidian’s helm in 2023, when it closed on $40 million in Series A extension funding from ATP, with the goal of financing the development of ACDN-01 and other pipeline programs.
Since then, Ascidian has grown its workforce to about 40 people, Ehlers said.
“For a clinical stage editing company, to be in the clinic with $90 million in equity financing and have 40 people plus or minus is no small feat, and I think it has been accomplished by having the focus that we’ve had, and having just one of the best scientific teams that I’ve ever had the fortune of working with,” Ehlers said.
“We might have little bits of growth here and there to be able to support this [Lilly] collaboration, to be able to expand the technology, but I’m not anticipating substantial growth,” he added. “We’ve built the company to be efficient and focused, and we’re going to maintain that going forward.”
Lilly’s hot streak
The Ascidian collaboration continues a hot streak of collaboration and acquisition deals for the pharma giant, which is flush with cash from sales of its blockbuster glucagon-like peptide 1 (GLP-1) receptor agonist drug tirzepatide, marketed for type 2 diabetes as Mounjaro® and for obesity as Zepbound®.
So far this year, Lilly has either acquired or is acquiring 10 biotechs, most recently three privately-held developers of vaccines for infectious diseases purchased for a combined up to $3.83 billion cash—Vaccine Company for up to $1.55 billion, Curevo for up to $1.5 billion, and LimmaTech Biologics for up to $780 million.
The Ascidian collaboration is Lilly’s third partnership with a biotech, announced just this week. The other two, totaling a combined amount of up to $4.304 billion-plus, were announced with Asian partners.
Seoul-based Hanmi Pharmaceutical said Lilly had agreed to license from it the rights to develop, manufacture, and commercialize sonefpeglutide (LAPSGLP-2 analog), a Phase II glucagon-like peptide 2 (GLP-2) receptor agonist, worldwide excluding South Korea. Hanmi is now studying sonefpeglutide in a global Phase II trial (NCT04775706) in short bowel syndrome (SBS).
Lilly agreed to pay Hanmi $75 million upfront, and up to an additional $1.185 billion in payments tied to achieving clinical development, regulatory approval, and commercialization milestones, plus royalties on sales following product launch.
Beijing-based Haisco Pharmaceutical Group announced a licensing and research collaboration with Lilly to develop treatments across multiple undisclosed therapeutic areas. Haisco agreed to oversee discovery and identification of up to five “innovative target” programs, while Lilly agreed to lead IND-enabling studies, clinical development, and commercialization. Lilly will obtain exclusive global rights for some programs, as well as exclusive rights worldwide, excluding China, Hong Kong, Macau, and Taiwan, for the other programs.
Lilly agreed to pay Haisco up to $87 million in upfront and near-term payments, up to $2.967 billion in unspecified milestone payments, and single-digit tiered royalties on future product sales.
platform. Lilly also snapped up another gene therapy developer,