Radically different
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.”
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.
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.
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.”
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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]](https://www.genengnews.com/wp-content/uploads/2026/05/Low-Res_Fig-4H-002-300x300.jpg)
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.”
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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.
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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Bristol Myers Squibb (BMS) will partner with Hengrui Pharma to co-develop 13 early-stage programs in oncology, hematology, and immunology, the companies said today, through a collaboration that could generate more than $15.2 billion for the Chinese drug developer.
BMS and Hengrui have inked global strategic collaboration and license agreements covering the 13 candidates—consisting of four oncology/hematology assets from Hengrui, four immunology assets from BMS, and five “innovative” assets to be jointly discovered and developed by both companies.
The companies said their collaboration is intended to combine BMS’ research and discovery strengths, global clinical development capabilities, regulatory expertise, and commercial scale with Hengrui’s discovery engine, platform technologies, and efficient early-stage development expertise.
To that end, Hengrui has agreed to fully oversee early clinical development in order to accelerate clinical proof of concept for these programs. Hengrui has the option to co-develop select assets and the potential to conduct certain commercialization activities globally with BMS.
“By leveraging Hengrui’s growing R&D capabilities and proven efficiency in discovering and advancing innovative therapies, we are poised to advance the best of both pipelines,” Frank Jiang, MD, PhD, Hengrui’s executive vice president and chief strategy officer, said in a statement. “It also reflects Hengrui’s continued commitment to strengthen our global presence.
BMS will obtain exclusive worldwide rights to the Hengrui‑originated candidates outside China, Hong Kong Special Administrative Region (SAR), and Macau SAR—Hengrui’s territory of operation—while Hengrui will gain exclusive rights to the BMS‑originated assets within those areas, with BMS retaining rights for the rest of the world.
BMS has agreed to pay Hengrui up to $950 million over two years, to consist of a $600 million upfront payment, a $175 million first anniversary payment, and a second contingent anniversary payment of $175 million in 2028.
The approximately $15.2 billion value of the collaboration includes exercising available options for the joint discovery programs and achieving development, regulatory, and commercial milestones for all programs. Hengrui also is eligible to receive tiered royalties on net sales of products commercialized outside its territory.
The collaboration deal is expected to close in the third quarter, subject to review under the Hart‑Scott‑Rodino Antitrust Improvements Act and other customary closing conditions.
“This strategic collaboration reflects our commitment to advancing innovative science while maintaining a disciplined approach to portfolio management,” stated Robert Plenge, MD, PhD, BMS executive vice president and chief research officer. “By leveraging complementary capabilities across geographies, we aim to accelerate early clinical learning and make informed decisions that support driving top tier growth in the next decade and, ultimately, our mission to deliver medicines that help patients prevail over serious diseases.”
Behind that focus on top-tier growth for BMS, as with other pharma giants, is a quest to recoup the billions of dollars in sales it stands to lose as aging blockbuster drugs head for the proverbial “patent cliff” by losing exclusivity in the U.S. and other key markets.
Of the Top 20 Drugs Heading for the Patent Cliff through 2029—the subject of a GEN A-List last November—BMS had three marketed treatments: The cancer drug Revlimid® (lenalidomide), indicated for forms of multiple myeloma, myelodysplastic syndromes, and three forms of lymphoma, which lost U.S. exclusivity in January; and two drugs set to lose exclusivity in 2028: the cancer immunotherapy Opdivo® (nivolumab), and the factor Xa-inhibiting blood thinner Eliquis® (apixaban).
Eliquis generated $14.443 billion in product revenue last year plus another $4.137 billion in the first quarter. Opdivo made $10.049 billion in 2025 plus $2.146 billion in Q1, while Revlimid racked up $2.951 billion and $349 million.
BMS has laid groundwork for rebuilding its pipeline over the past year through a series of collaborations and acquisitions with companies that include:
BMS also outlicensed five pipeline assets to Beeline Medicines, an autoimmune and inflammatory drug developer formed in April with a $300 million Series A financing from Bain Capital. Beeline’s pipeline of BMS castoffs includes afimetoran, being developed for both cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), BMS-986326 (atopic dermatitis, CLE, and SLE); lomedeucitinib (formerly BMS-986322, plaque psoriasis), and two IND-stage next-generation biologics for unspecified diseases that target the IL-18 and IL-10 pathways.
Hengrui last September outlicensed its cardiac myosin inhibitor RS-1893 to Braveheart Bio ($65 million upfront, up to $1.013 billion in milestones); and two months earlier inked an up to $12.5 billion ($500 million upfront) partnership with GlaxoSmithKline (GSK) to develop to develop chronic obstructive pulmonary disease (COPD) candidate HRS-9821 and 11 additional programs across respiratory, immunology and inflammation, as well as oncology indications.
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A new study has shown that targeting ultrasound stimulation to brain regions involved in processing pain can induce long-lasting changes in brain activity, significantly reducing pain perception. Published in Nature Communications, these findings point at a novel non-invasive strategy to treat chronic pain.
“Our study represents an important first step in understanding how this technology can non-invasively stimulate deep brain regions involved in pain processing,” said Sam Hughes, PhD, senior lecturer in pain neuroscience at the University of Exeter. “We found that targeting a specific brain region involved in pain processing can alter how pain is perceived and change how this area communicates with other parts of the brain’s pain network. The next stage of our research will be to test whether this approach can help people living with chronic pain.”
Hughes and colleagues used transcranial ultrasound stimulation (TUS), a low-intensity neuromodulation technique, to target the dorsal anterior cingulate cortex (dACC), a brain region implicated in chronic pain. The study recruited a total of 32 healthy volunteers, who were treated either with TUS or a sham while putting their right hand in a cold gel to trigger pain due to the low temperature. All participants were asked to rate the severity of the pain they were feeling and underwent MRI and MRS scans to monitor the physiological changes caused by the treatment.
Results showed that, while TUS had no immediate effect on pain intensity, participants reported a significant reduction in pain from 28 to 55 minutes after the stimulation, suggesting it can trigger a delayed analgesic effect. At the physiological level, TUS was found to disrupt the relationship between temperature and pain intensity, increasing the connectivity between the dACC and other brain regions involved in pain modulation and changing the concentration of the GABA neurotransmitter within the dCC.
“The study aimed to characterize how transcranial ultrasound stimulation interacts with—and potentially also alters—the brain’s processing of pain,” said Sophie Clarke, PhD, postdoctoral research fellow at the University of Plymouth and lead author of the study. “Understanding these mechanisms will be very important to support the next steps in understanding whether the stimulation can be effective in helping patients with chronic pain.”
Previous research at the University of Plymouth had shown the potential benefits of TUS for psychiatric conditions including anxiety, depression, and addiction. This study shows these benefits could extend beyond neurological disorders and one day offer a non-invasive treatment option for those experiencing chronic pain due to conditions such as fibromyalgia, back pain, and arthritis, or recovering after cancer treatment.
“Having shown the use of ultrasound can yield positive results for people with a variety of neurological conditions, we wanted to explore what it could mean for those living with chronic pain,” said Elsa Fouragnan, PhD, director of the University of Plymouth’s Brain Research and Imaging Centre (BRIC) and Centre for Therapeutic Ultrasound (CENTUS). “Most of us know someone experiencing chronic pain, and there are very few treatments that deliver any form of long-term benefit. The findings of this new work are really promising, and we are already building on it to assess whether TUS could be a beneficial and non-invasive therapeutic treatment.”
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Scientists have developed a sensor platform that can monitor cerebrospinal fluid (CSF) in intensive care unit patients, overcoming major delays in diagnosis associated with current testing methods. A study published today in Science Translational Medicine reports that the NeuroSense platform can provide near real-time readings of four key biomarkers every 27 minutes, with results accurately reflecting standard clinical measurements.
In neurological intensive care units, external ventricular drainage (EVD) systems are routinely used to temporarily assist patients with drainage of excess CSF, manage postoperative complications and monitor intracranial pressure. However, the use of these devices carries a high infection risk, with rates reaching up to 20% of patients.
Delayed diagnosis of these infections can lead to severe meningitis, neural damage, cognitive impairment, permanent disability, or even death. However, current testing methods are labor-intensive and require sending samples to external laboratories for biomarker analysis and manual inspection. This limits testing to every one to two days, significantly delaying clinical decisions that can be critical for preventing severe complications.
“To address these limitations, we developed NeuroSense, a multiplexed sensing platform that integrates with standard external ventricular drainage systems to enable near real-time monitoring of key CSF biomarkers, including glucose, lactate, pH, and flow rate, that are essential for detecting infection and drain dysfunction,” write the study authors.
The NeuroSense platform employs aptamer-based biosensors to detect glucose and lactate levels in CSF, which are key markers of bacterial infections. These types of biosensors are more stable and have a longer shelf life than conventional enzymatic biosensors, ensuring the platform can consistently and accurately track these markers for the entire time EVD systems remain in place, typically between five to 10 days.
Furthermore, an impedance-based sensor measures CSF flow rate to monitor for potential catheter obstructions or incorrect EVD settings, while a polydopamine sensor keeps track of pH changes, which can indicate acidosis, hemorrhage, infection, or a disrupted blood-brain barrier.
The platform’s performance was evaluated in a small-scale study that recruited six patients with EVDs hospitalized in the intensive care unit. Every four hours, readings from the NeuroSense platform were compared with those from standard testing methods, revealing a strong correlation between the sensor platform and clinical reference measurements.
A survey of the healthcare providers and clinicians involved in the study further showed that most participants found the platform easy to use, as it integrates with standard EVD systems routinely used in the intensive care setting.
Going forward, the researchers plan on further improving the performance of the pH sensor and continue developing the platform to comply with regulatory requirements for running large-scale clinical studies and eventually making the platform available to healthcare providers.
“Beyond infection detection and EVD assessment, NeuroSense enables higher temporal-resolution tracking of CSF biomarkers and flow dynamics, supporting earlier recognition of evolving trends that may be missed with intermittent sampling,” write the researchers. “Although the current system measures glucose, lactate, pH, and flow, the platform is modular and can accommodate additional sensors in future iterations. By providing near-bedside, actionable insights into patients’ neurological health, NeuroSense has strong potential to enhance clinical decision-making and improve patient care.”
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President of the American Society of Gene and Cell Therapy (ASGCT), Terry Flotte, MD, is excited to host this year’s conference in his own backyard. It will be a short drive east on the Mass Turnpike from his office at UMass Chan Medical School in Worcester to the Menino Convention and Exhibition Center in Boston’s Seaport district. Flotte is hopeful that the 2026 conference will draw the largest attendance in the meeting’s history. His tenure as president ends this week on the last day of the conference, May 15.
In the run-up to this year’s conference, GEN spoke with Flotte, who is also Editor in Chief of GEN’s sister journal Human Gene Therapy, about the central themes and most anticipated sessions at this year’s conference. “I have a full dance card, let me tell you,” Flotte joked. The conference will highlight several themes of Flotte’s productive tenure.
(This interview has been edited for length and clarity.)
GEN: Terry, what’s the theme of this year’s ASGCT conference?
Terry Flotte: We’re working very hard on access for rare and ultra-rare conditions and have been for some time. You’ll see that in the presidential symposium. This is in the context of our mission to improve access to rare disease cell and gene therapy (CGT). This is the guiding principle of our strategic plan: we want to work for universal access to CGT. There are two orthogonal axes to this: I’m focusing on rare and ultra-rare diseases. ASGCT is going to continue to work in parallel on universal access in a more global context.
We have created a first-of-its-kind exchange for shelved CGTs. An increasing number of CGTs for rare and ultra-rare diseases are being discontinued or deprioritized after they reach the clinical stage—not because they lack clinical efficacy but because they lack market viability. We have partnered with Orphan Therapeutics Accelerator to create a new entity called CGTxchange. This collaborative venture is meeting the need of these promising clinical-stage CGTs that are not progressing. This entity will be an AI-enabled digital platform that will list the available clinical-stage CGT programs and generate AI-enhanced profiles, digest the data, score them for their level of advancement and the robustness of their responses, and essentially shorten the due diligence that investors normally have to do, enabling the connections to work faster.
I estimate there’s at least 50-100 of these programs. We had our own personal experience with Sio Gene Therapies [formerly Axovant] on both GM1 and GM2 gangliosidosis. This is part of a broader set of initiatives. Over the past few years, we created a taskforce in response to this increasing rate of discontinuation of these therapies. The two main outgrowths that the ASGCT board has endorsed are to create a consortium of CGT developers that might be able to offer non-profits less expensive manufacturing in a limited way but also work toward a drug master file sharing data for those who benefit from the less expensive vectors—in addition to the clearinghouse I just mentioned.
GEN: What else is new this year?
Flotte: A new thing for ASGCT is we’re having a patient advocate presenting. Terry Pirovolakis pioneered the CGT therapy for spastic paraplegia type 50 (SPG50) by developing his own company, Elpida Therapeutics, which has taken SPG50 to the clinic and now is doing that for other rare and ultra-rare diseases.
The second example is from Claire Booth, MBBS, PhD, (Great Ormond Street Children’s Hospital, London). Her team has received market authorization to be the
pseudo-commercial manufacturer of a fully licensed therapeutic for different forms of SCID.
Those are two direct examples of alternatives to get things to the clinic, other than getting a new commercial sponsor. [Hopefully] we can end up getting more of those picked up, whether through the CGTxchange or direct outreach. We’re also going to honor Timothy Yu, MD, PhD, with the Jerry Mendell Translational Research Award. He will be talking about the N=1 Collaborative with the parallel effort with oligonucleotide therapeutics. There is a purposeful theme to this meeting, aiming to make a big change in how things can get to the clinic and stay in the clinic.
GEN: Last year in New Orleans, the conference was dominated by the Baby KJ story. Will anything stand out in the same way this year?
Flotte: We are honoring the three primary authors of the Baby KJ story—Kiran Musunuru, MD, PhD, Rebecca Ahrens-Niklas, MD, PhD, and Fyodor Urnov, PhD.
I have also selected the work of Lindsey George, MD (Children’s Hospital of Philadelphia) as a presidential abstract. She is going to present the first case of an AAV-induced tumor—or at least an aggressive and autonomously growing malignancy…. This occurred in an MPS1 patient who received a high dose of AAV into the ventricles. It is not exactly a meningioma, but it’s arising from the neuroepithelial cells lining the ventricles. The tumor has AAV integrated with a strong promoter immediately upstream of a known oncogene. I put that into the presidential lecture, even though it’s not good news—but I’m not a [gene therapy] campaign manager here! I think this is a significant finding that we’ll have to pay attention to.
Lindsey is not saying that nobody should ever do this again. She’s going to point out aspects of this that were very manageable and how this patient overall has a dramatically better outcome than they would have without the therapy. In a way, [this is] somewhat like when those leukemia cases developed in Europe in the early SCID [gene therapy] trials. It is in a way parallel to that.
GEN: This will be your last conference as president of ASGCT!
Flotte: Yes, it ends on May 15th! We only get to be president for one year. I started the Rare Disease Task Force as vice president. This was my cause over the past three years [as an officer]. I’m very pleased we were able to stand this up.
We have an actual corporation, a joint venture, 50% owned by ASGCT. We set up this manufacturing consortium. Somewhat related, we set up our own charitable foundation, the ASGCT Foundation. We will have our first event—a gala at the conference. It will have a lot of time to grow. The foundation has just been incorporated as a subsidiary not-for-profit.
GEN: How do you view things at FDA currently?
Flotte: We will have a fireside chat with the new director of CBER, Katherine Szarama, PhD. We are very encouraged—she’s a very highly trained professional. We love that FDA is paying a lot of attention to rare diseases, but we need some scientific and evidence-based guidelines on how to do this consistently. We’re looking to someone who has regulatory experience.
GEN: What else has got you and your colleagues in the gene therapy space excited of late?
Flotte: I’m hoping we’re going to better understand high-dose AAV toxicity… I think what we’ve got is several different syndromes, but many of them may have a common link… We’ve been seeing with high-dose AAV a very broad distribution, but the doses are incredibly high and there have been deaths—the DMD patient deaths that occurred in the first two weeks are the best-known examples, but there have been other ones.
In my lab, we’re trying to figure out the primary pathogenesis. We have found a number of situations with unexpected vector expression in the endothelial cells and then seeing vascular leakage into some of these tissues causing tissue injury. So, in the post-mortem analysis we helped on, we saw high expression in the lungs and alveolar capillaries. They had diffuse leakage into the capillaries leading to a syndrome known as acute respiratory distress syndrome (ARDS). But in some of the others where they’re seeing some complement activation, we think that small vessel injury could be a convergent pathway. Now, where does this come into play in the broader sense?
One of the holy grails of recent AAV gene therapy is to design an AAV capsule that efficiently crosses the blood-brain barrier. Many diseases that are appropriate for AAV are diseases of the central nervous system (CNS). You can think of, for instance, the easiest cells to access in the CNS are the spinal motor neurons, hence the SMA1 treatment, Zolgensma. So, if you treat an SMA newborn, that is essentially solved or at least adequately solved. But in none of the diseases that affect the brain have we seen an IV gene therapy that is robustly efficacious—just giving an AAV at a high enough dose to get across the blood-brain barrier. Many different companies are trying to develop AAV capsids that will penetrate the blood-brain barrier, the first one that got to clinic was a vector designed by Capsida Biotherapeutics. But the first patient treated on the Capsida trial developed cerebral edema and died.
One of the important challenges for the field is to understand if we can separate a blood-brain barrier penetration from endothelial cell toxicity, because you could think perhaps a vector designed to get through the blood-brain barrier could cause injury as it crosses to the endothelial cells in the brain. I think there may be ways around this, but to me this is a central issue because the CNS is affected in so many single-gene disorders. The parents see a child who has a disability or degenerating, as in Tay-Sachs, and they want to be able to do an IV therapy. They don’t want to have to have a direct brain injection or some other invasive intervention. So that’s what I’m looking for at ASGCT 2026.
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