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May 1, 2026

Going Non-Viral: Gene Delivery Enters Its Translation Era

Kunwoo Ryan Lee, PhD, knew as early as 2012 that solving the delivery problem would be crucial in fulfilling the promise of the newly discovered CRISPR-Cas9 gene editing technology. He felt strongly that gene editing had potential to transform medicine by curing genetic disorders, but the viral and non-viral vectors available at the time had significant drawbacks. With the support of CRISPR pioneers Jennifer Doudna and Stanley Qi, Lee completed his doctoral thesis on a gold nanoparticle delivery system for Cas9 ribonucleoprotein. He went on to co-found BreezeBio, formerly GenEdit, in 2016 with the aim of creating the next generation of gene editing-based therapeutics. To realize that goal, Lee and his team looked beyond traditional viral gene delivery systems and instead invented a new technology from the ground up.

Most clinical gene therapy trials use viral vectors, including retroviruses, lentiviruses, adenoviruses, and adeno-associated viruses. However, viral vectors are limited in the size of the gene they can deliver. They also tend to trigger strong immune reactions and usually can’t be dosed more than once due to acquired immunity.

Non-viral vectors are an alternative technology that offer greater gene loading capacity, more straightforward preparation, and less likelihood of triggering problematic immune reactions. BreezeBio and other biotechnology companies are reimagining gene delivery through non-viral approaches like targeted LNPs, transposons, and novel chemistry.

Flow cytometry analysis of immune cells in BreezeBio’s laboratory. [BreezeBio]

BreezeBio’s hydrophilic nanoparticle (HNP) platform, NanoGalaxy, hearkens back to Lee’s doctoral work. Lee said he and his cofounders realized that a hydrophobic molecule was needed to deliver a gene payload into cells, because the cell membrane is a lipid bilayer. Lee also noted that the best molecule for targeting different cell types is an antibody, a hydrophilic molecule. Pairing these two elements introduced a complex manufacturing challenge that the company solved by using a polyamide as a backbone structure and conjugating a hydrophobic small molecule to that backbone for targeting, resulting in the hydrophilic HNP. The company then used artificial intelligence to optimize HNPs for different tissue types.

“Using the platform, we have demonstrated that we can deliver to the spleen, immune system, heart, and lung,” Lee said. The firm also developed a set of nanoparticles targeted to the central nervous system.

Based on those targeted delivery profiles, the Brisbane, California-based BreezeBio has worked with multiple partners to provide delivery solutions for their products, including a multiyear collaboration with Genentech, a member of the Roche Group, signed in 2024. Meanwhile, the company is also advancing its own pipeline of therapeutics built on the NanoGalaxy platform, including a lead candidate for type 1 diabetes, as well as investigational therapies for autoimmune disease and cancer.

Lee said a key advantage of the NanoGalaxy platform for their pipeline, which heavily leans toward autoimmune disease, is that, unlike a viral vector, the company’s studies have shown it does not activate the innate immune system. “That enabled us to use our technology for autoimmune applications and in more targeted oncology applications, as well,” Lee said.

Snug as a bug in a rug

The red flour beetle, a notorious scourge of grain and cereal stores, is the surprising source of Bio-Techne’s transposon-based, non-viral gene delivery system. The system, dubbed TcBuster for the beetle’s scientific name, Tribolium castaneum, was invented by B-MoGen, a spin-out of the University of Minnesota, which was acquired in 2019 by Minneapolis-based Bio-Techne. Researchers at B-MoGen and Bio-Techne developed a hyperactive version of the natural TcBuster transposon by creating a library of three million unique genetic variants and screening each in mammalian cells. In a proof-of-concept study, CAR NK cells engineered using TcBuster demonstrated in vitro functionality and improved survival in a preclinical model of Burkitt lymphoma with a single dose.¹

“The reason you want a hyperactive version is that wild-type transposon systems are fairly low activity,” said Miles Smith, PhD, a product manager for cell and gene therapy at Bio-Techne. “For generating a cell therapy, you want something that’s going to be comparable to the state of the field, and that’s lentivirus.”

TcBuster system illustration — The TcBuster system is electroporated into cells where its components are translated, and TcBuster transposes and excises genes of interest and inserts DNA cargo into the host cell genome. [Bio-Techne]

Smith said the TcBuster system, which comprises an mRNA encoding transposase and a DNA transposon, can be produced faster than a lentiviral vector. The system is also more scalable, more cost-effective, and has increased gene cargo capacity, according to Smith. TcBuster can deliver multiple genes in a single vector, and it can be multiplexed with other gene therapy tools. “If you wanted to use base editors or CRISPR-based knockout gene editing in conjunction with TcBuster, you could do that in one step, compared to multiple steps with a viral system,” Smith said.

Unlike other commercial transposon systems for gene delivery, like Sleeping Beauty and PiggyBac, Smith said TcBuster is not restricted by exclusive licensing. “The turnaround time for GMP material is just a couple of months,” Smith said. “Versus something that might take a lot longer if you have to go through licensing or create a viral batch.”

Gene therapy SORTed

ReCode Therapeutics is developing a pipeline of genetic medicines based on its selective organ targeting (SORT) LNP platform, which adds an additional lipid to the standard LNP formulation, allowing it to zero in on specific organs. Conventional LNPs comprise four lipids—cholesterol, a helper phospholipid, a PEGylated lipid, and an ionizable lipid—that encapsulate a therapeutic gene cassette. These traditional LNPs are primarily taken up by the liver after intravenous administration, limiting their usefulness for other organs and systems. ReCode engineered its SORT LNPs with a biochemically distinct fifth lipid that enables the body to direct the particle to the targeted organ, such as the lung or spleen, bypassing the liver, if necessary.

“Because mRNA in a cell has a relatively short half-life, maybe a day or so, in order to have constant protein production, you need to administer it relatively frequently,” Vladimir Kharitonov, PhD, senior vice president of CMC and pharmaceutical sciences at ReCode, said. “With viral delivery, you can’t really administer it repeatedly.”

Scientists conducting qualification of the semi-automated filling and stoppering machines at ReCode’s laboratory in Menlo Park. [ReCode]

The Menlo Park, California-based firm’s two clinical-stage therapies are given by inhalation using a nebulizer. SORT lipids enable targeting specific cell types in the lung epithelium.

In 2024, ReCode presented preclinical data from its cystic fibrosis program showing its mRNA-based therapeutic RCT2100 significantly restored CFTR function in human bronchial epithelial cells derived from patients with cystic fibrosis. In vivo studies using a ferret model demonstrated improvement in mucociliary clearance. ReCode launched the first clinical trial of RCT2100 later that year. The LNP for RCT2100 contains SORT lipids to fine-tune its delivery to the airway epithelial cell types that have a defective or mutated CFTR protein, causing cystic fibrosis. The company is also developing a second mRNA therapy delivered via SORT LNP, RCT1100, for primary ciliary dyskinesia, which targets different cell types in the lung epithelium.

From idea to therapy faster

Gene delivery is just one of many services offered by GenScript to support research from discovery through clinical testing, including gene synthesis, CRISPR reagents, antibodies, and more.

“Gene editing is entering a new era, and the focus has shifted from discovery to translation,” said Jianpeng Wang, PhD, senior director of nucleic acid and peptide R&D at GenScript. “Our goal at GenScript is to help scientists move from idea to therapy faster.”

When it comes to non-viral vectors, the firm offers off-the-shelf and bespoke solutions to fit the customer’s need for delivery of DNA, RNA, siRNA, peptides, and other molecules. Through its targeted LNP service, GenScript offers LNPs designed to enhance precision in directing genetic material to cells. GenScript’s ReadyEdit LNP solutions include Cas9 knock-in and knock-out, Cas12 knock-out, and base or prime editing tailored for the customer’s needs.

“In our ecosystem, we include all of the materials needed,” Wang said. “This integration can help scientists evaluate gene editing efficiency early, both ex vivo and in vivo.”

Wang said the choice of a vector is heavily dependent on the specific therapeutic program. “There isn’t a universally effective or better way to deliver a therapy, either viral or non-viral,” Wang said. He noted, for example, that viral vectors remain a good choice when long-term gene expression is desired. And for viral vectors, the manufacturing process might be more mature, easing transfer to a contract development and manufacturing organization.

However, Wang cautioned that viral vectors still present certain safety concerns. “In recent years, an increasing number of scientists and the FDA have recognized these risks,” he said, “leading to a surge in interest for non-viral delivery methods—particularly for in vivo CAR T therapy and gene editing.”

GenScript has provided LNP services to several customers globally. The most advanced of those is using GenScript’s GMP CRISPR materials (gRNA, HDR templates, and nuclease) alongside a customized LNP encapsulation recipe and is preparing an investigational new drug application.

Foundational LNP science

Vancouver-based Genevant traces its scientific lineage through a string of predecessor companies dating back to the early 2000s and controls foundational intellectual property for the field. Based on its scientists’ work at Protiva Biotherapeutics, the intellectual property comes to Genevant via Arbutus Biopharma, which acquired Protiva in 2015 and partnered with Roivant in 2018 to establish Genevant.

Unlike many companies developing nucleic acid delivery platforms that focus on a single payload modality, Genevant has applied its LNP to many payloads, including mRNA, siRNA, and gene editors in fields spanning antiviral, oncology, and metabolic disorders. The firm’s LNP platform is part of the first RNA-LNP product to achieve regulatory approval, Alnylam Pharmaceuticals’ Onpattro (patisiran), a treatment for polyneuropathy in people with hereditary transthyretin-mediated amyloidosis. Genevant’s LNP technology is also behind Moderna’s COVID-19 vaccines, which were confirmed earlier this month with the resolution of a longstanding patent dispute. An infringement case against Pfizer and BioNTech is pending. Genevant collaborated with Chula Vaccine Research Center and the University of Pennsylvania to develop a COVID vaccine for low- and middle-income countries in Southeast Asia during the pandemic. The program had success, demonstrating non-inferiority to Pfizer and BioNTech’s Comirnaty in clinical trials.

Some key differentiators for Genevant’s LNPs include strategies for optimized delivery in non-human primates instead of mice,² which has resulted in improved gene editing in the liver, and novel chemistries for biodegradable LNPs that prevent accumulation in tissue.³ The company has recently disclosed data showing targeted delivery to T cells for in vivo CAR T therapy, as well as hematopoietic stem and progenitor cells (HSPC) and hepatic stellate cells.

References

Skeate JG, Pomeroy EJ, Slipek NJ, et al. Evolution of the clinical-stage hyperactive TcBuster transposase as a platform for robust non-viral production of adoptive cellular therapies. Mol Ther. 2024;32(6):1817-1834. doi:10.1016/j.ymthe.2024.04.024
Lam K, Schreiner P, Leung A, et al. Optimizing lipid nanoparticles for delivery in primates. Adv Mater. Published online March 27, 2023. doi: 10.1002/adma.202211420
Holland, R, Lam K, Jeng S, et al. 2024. Silicon ether ionizable lipids enable potent MRNA lipid nanoparticles with rapid tissue clearance.” ACS Nano. 2024;18 (15): 10374–87. doi:10.1021/acsnano.3c09028.

The post Going Non-Viral: Gene Delivery Enters Its Translation Era appeared first on GEN – Genetic Engineering and Biotechnology News.

May 1, 2026

Breaking Through the Barrier

According to the American Brain Foundation, over one in three people around the world are affected by neurological conditions, the leading cause of illness and disability worldwide. This silent epidemic is not country-specific. Neurological conditions such as lysosomal storage disorders, rare enzyme deficiencies, and Alzheimer’s and Parkinson’s disease take their victims, regardless of age, race, or location.

For decades, scientists have struggled to deliver therapeutics to the brain, only to be thwarted by the highly protective blood-brain barrier (BBB). First-generation approaches demonstrated proof of principle but still require advancements to improve the ability to reach specific areas of the brain, or specific cell types, safely, and with sufficient dosage to enable meaningful therapeutic effects.

Although much remains unknown generally about brain biology and its defensive mechanisms, novel therapies for devastating neurological diseases are progressing into clinical trials. There is no magic bullet—no promises, no cures—but a gleaming light can be seen in this particular long and dark tunnel.

Dedicated scientists continue to work on gene therapies for the indications that most benefit from a once-and-done approach, in addition to neurological shuttles to address those disorders that require therapeutic tempering and dosage control.

Expanding platform technologies

In 2021, JCR Pharmaceuticals received regulatory approval for the first biotherapeutic, IZCARGO (pabinafusp alfa), designed to cross the BBB to deliver a therapeutic enzyme for the treatment of a lysosomal storage disorder called mucopolysaccharidosis type II (MPS II) or Hunter syndrome.

The platform technology has been expanded to exploit receptor-mediated transcytosis (RMT) to address other lysosomal storage and neurodegenerative diseases. Still, delivery to specific cells or parts of the brain remains challenging, along with efficient delivery of antisense oligonucleotides or siRNA.

“The issue is not delivery across the BBB, but the endosomal escape to efficiently suppress the target RNA,” said Hiroyuki Sonoda, PhD, representative director, president, and CSO, at JCR Pharmaceuticals. “Small molecule CNS delivery is related to physicochemical properties. The structural design needs to make them lipophilic, yet also able to evade typical transporter clearing mechanisms.”

blood-brain barrier penetration technology diagram — The first approved blood-brain barrier penetration technology was developed into the J-Brain Cargo platform that can help drugs cross the blood-brain barrier. [JCR Pharmaceuticals]

J‑Brain Cargo^® uses RMT, mainly focusing on the transferrin receptor (TfR). Other promising candidates target different receptors. “We have successfully transported enzymes, antibodies, peptides, decoy receptors, antisense oligos, and siRNA into the CNS,” commented Sonoda. J‑Brain Cargo is particularly suited for enzyme replacement therapies in lysosomal storage disorders and conditions where dose control, reversibility, and titration are important.

For gene therapies, JCR developed the JUST-AAV platform technology. Novel changes in the capsid almost completely eliminate liver tropism. The modified capsids express miniaturized antibodies on the capsid surface against receptors on selected tissues, organs, or the BBB, enhancing targeted delivery. JUST‑AAV is for diseases where continuous transgene expression is desired to achieve the optimal effect.

Several candidates are in global clinical trials, including JR-141 (pabinafusp alfa) for individuals with MPS II (also known as Hunter syndrome), JR-171 to treat MPS I (also known as Hurler, Hurler Scheie, or Scheie syndromes), and JR-441 for individuals with MPS IIIA (also known as Sanfilippo syndrome A).

Programs in collaboration with MEDIPAL HOLDINGS CORPORATION are in different stages of clinical and pre-clinical development for individuals with MPS IIIB (also known as Sanfilippo syndrome B), Fucosidosis, and GM2 gangliosidosis (including Tay-Sachs and Sandhoff disease).

Collaborating with leading pharmaceutical companies is core to JCR’s strategy to bring these platform technologies to broader application. “We enable our partner by turning their biologics into CNS-penetrating versions of their original molecule,” said Sonoda.

JCR manufactures most of its drug products in-house. Last year, they were selected for the Ministry of Economy, Trade and Industry’s “Regenerative CDMO Subsidy” to expand biomanufacturing capacity for regenerative, cell, and gene therapies.

Optimizing BBB transport

“Protein engineering architecture differentiates our delivery technology along with its optimization for efficacy, safety, and tolerability,” said Ryan Watts, PhD, co-founder and CEO of Denali Therapeutics.

The TransportVehicle (TV) technology has the RMT binding site integrated directly into the constant domain (Fc) of an antibody for optimal properties and modularity. This allows the same TV sequences to transport a range of large molecule biotherapeutics such as enzymes, oligonucleotides, and antibodies for systemic administration. The engineered Fc domains bind to specific natural transport receptors expressed at the BBB, such as TfR.

Transport Vehicle technology illustration — The integration of the receptor-mediated transcytosis binding site into the TransportVehicle (TV) technology allows the same TV sequences to transport a range of large molecule biotherapeutics, such as enzymes, oligonucleotides, and antibodies, for systemic administration. [Denali Therapeutics]

“Our research recently demonstrated that a TV platform-enabled anti-Ab antibody improved distribution in the brain and significantly reduced risk of Amyloid-Related Imaging Abnormalities (ARIA) in a mouse model of Alzheimer’s disease, when compared with a conventional anti-Ab antibody.¹ The study provides the first mechanistic insight for mitigating the risk of ARIA,” detailed Watts.

The Enzyme TransportVehicle (ETV) contains a fusion of a therapeutic enzyme. The Fc portion of the fusion molecule binds the apical surface of the TfR to avoid interference with normal iron transport.

In March 2026, Denali’s lead ETV program, Avlayah (tividenofusp alfa-eknm), received FDA accelerated approval for the pediatric treatment of the lysosomal storage disorder MPS II. Avlayah is the foundation for their broader ETV franchise, addressing other lysosomal storage disorders such as MPS IIIA. Results from the open-label Phase I/II clinical trial are available.²

Their Oligonucleotide TransportVehicle (OTV) platform is an engineered TV conjugated to an oligonucleotide for the systemic delivery of genetic medicines to the brain. Extensive characterization and research demonstrate the ability of OTV to elicit broad biodistribution of oligonucleotide therapies throughout the CNS following systemic exposure.

“For example, our investigational therapy DNL628 for the treatment of Alzheimer’s disease is designed to cross the BBB and reduce the tau protein by targeting the MAPT gene that encodes for tau,” explained Watts.

Lastly, the Antibody TransportVehicle (ATV) platform is designed to enable brain delivery of antibodies capable of selective immune activation and a targeted therapeutic approach after intravenous administration. The investigational anti-Ab antibody therapy DNL921, for example, is designed to reduce amyloid plaques and avoid ARIA.

The TV-enabled clinical development portfolio also includes candidates for frontotemporal dementia-granulin and Pompe disease.

Advancing clinical options

“It is exciting to begin to see that delivery through the BBB is possible using gene therapy or shuttle approaches,” said Todd Carter, PhD, CSO at Voyager Therapeutics. Although first-generation therapeutics are demonstrating meaningful levels of delivery, optimization, and improvement of the functionality, exposure duration, and therapeutic effects are still needed.

“For some diseases, gene therapy is the preferred treatment modality, as both the capsid and the payload can be modified to perform a specific job,” said Carter. But viral vector delivery for gene therapy has had problems with liver-based toxicity.

For the best human translation opportunities, Voyager developed a model in non-human primates (NHPs) requiring cross-species activity across multiple NHP species. This strategy resulted in the company’s TRACER (Tropism Redirection of AAV by Cell-type-specific Expression of RNA) technology, used to screen tens of millions of vector variants using barcoded libraries in which capsids were modified with slight insertions of seven to nine amino acids.

TRACER, Voyager’s unbiased capsid and receptor discovery engine, identified ALPL as a broadly enabling brain delivery receptor. [Voyager Therapeutics]

Successful expression in neurons demonstrated that the capsids crossing the BBB worked. Directed evolution improved them. “Next, we needed to determine the mechanism—the receptors they were targeting,” said Carter. This led to the identification of the receptor, alkaline phosphatase (ALPL), tissue nonspecific.

Now, Voyager has multiple families of capsids that mediate delivery into the brain, are detargeted from the liver, and, for the most advanced, have improved the capsid’s ability to target the brain using ALPL. “Using the ALPL receptor elevates delivery to the brain and allows us to substantially reduce dosage,” said Carter.

“I would not have picked ALPL just on face value,” added Mihalis Kariolis, PhD, vice president of non-viral therapeutics at Voyager Therapeutics. “It highlights the power of the unbiased TRACER approach. Expanding the number of brain delivery receptors provides highly differentiated options to reduce side effects and expand the diversity of treatment modalities.”

Both gene therapy and shuttle approaches have opportunities in different indications. Once-and-done gene therapy is not tweakable, whereas shuttle-based dosing is. “In our APOE gene therapy program, we want to reduce existing APOE4 and replace it with APOE2 permanently,” said Carter. “The shuttle has advantages in situations where permanent ongoing delivery is not required.”

Voyager’s most advanced program (VY7523) is a tau monoclonal antibody that is exquisitely specific for pathological tau. Data will be available in the second half of the year. A gene therapy (VY1706) moving into the clinic this year is designed to knock down tau mRNA and protein intracellularly. A collaboration with Neurocrine Biosciences focuses on Friedreich’s ataxia (FA) and is also expected to enter the clinic this year.

Combining transport receptors

The protective BBB is crucial for maintaining homeostasis and ensuring proper neurological function. Comprised of both cellular and acellular components, this sophisticated structure tightly regulates information flow between the periphery and the brain. According to Tanya Wallace, PhD, vice president of neuroscience discovery research at AbbVie, despite the BBB’s importance, many seemingly basic biological questions remain unanswered, fueling additional global research.

The complexity of the BBB also represents a significant bottleneck for advancing therapeutics targeting brain-related disorders. Historically, achieving therapeutically relevant levels of drugs in the brain has been a major challenge in treating serious diseases such as Alzheimer’s and Parkinson’s diseases. “A notable success story is the development of L-DOPA, a prodrug that leverages existing transport mechanisms to cross the BBB,” said Wallace. Once in the brain, L-DOPA is metabolized into dopamine, offering a key symptomatic treatment for Parkinson’s disease.

Breakthroughs in delivery now allow scientists to leverage more technologies that can bring not only small molecules but also complex biologics into the brain. The Modular Delivery (MODEL^TM) platform exemplifies this progress. The platform enables engineering of bispecific antibodies, capable of targeting naturally expressed BBB receptors such as TfR and CD98. TfR and CD98 are well-characterized at the BBB, and, together, they offer distinct advantages for increasing brain exposure to therapeutics.

“By engaging these transport pathways, the platform can enhance the uptake of a variety of therapeutics, including antibodies and oligonucleotides,” highlighted Wallace. “This multi-receptor strategy provides flexibility to optimize the balance of uptake, release, and distribution in the brain, paving the way for potentially more effective treatments across neurological disease areas.”

This platform technology facilitated the development of ABBV-1758, which is progressing in clinical development. ABBV-1758 utilizes TfR to transport a 3pE-Ab antibody across the BBB to enable the removal of amyloid beta plaques, a pathological hallmark of Alzheimer’s disease.

As scientists aspire to further refine delivery strategies, ongoing research is exploring additional receptors and innovative approaches, including insulin-like growth factor 1 receptor (IGF-1R) and brain cell-type-specific targeting. The field is rapidly evolving to advance more precise, personalized interventions for challenging neuroscience conditions.

“Successful brain delivery requires more than just advances in transport technology; it demands interdisciplinary collaboration, novel preclinical models, and thoughtful clinical translation,” Wallace pointed out. Continued biological research and investment into innovative discovery platforms will be crucial for bringing transformative therapies to patients with the greatest unmet needs.

References

Pizzo ME, Plowey ED, Khoury N et al. Transferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA. Science. 2025 Aug 7;389(6760):eads3204. doi: 10.1126/science.ads3204.
Muenzer J, Burton BK, Harmatz P et al. An intravenous brain-penetrant enzyme therapy for mucopolysaccharidosis II. N Engl J Med. 2026 Jan 1;394(1):39-50. doi: 10.1056/NEJMoa2508681.

The post Breaking Through the Barrier appeared first on GEN – Genetic Engineering and Biotechnology News.

May 1, 2026

Gene Editing at Scale, Clinic Seeks Generalizable Therapies

Ajay Gannerkote, president of Integrated DNA Technologies (IDT), says what’s most exciting about CRISPR is its potential to shift medicine from managing disease to directly correcting its root cause. “For patients with severe genetic conditions, especially those with no existing treatment options, that represents a fundamental change in what’s possible,” he said.

IDT played a pivotal role in manufacturing the personalized gene editing therapy given to baby KJ Muldoon to treat his rare metabolic disorder. Today, KJ is free from the toxic ammonia buildup that drives a 50% mortality rate for his condition in infancy. While his story highlights the life-changing potential of gene editing, the field now wrestles with the next challenge: expanding these therapies to benefit broader patient populations.

In contrast to KJ’s urea cycle disorder, which stemmed from a single disease-causing mutation that could be precisely targeted, many genetic disorders arise from numerous mutations scattered across a gene where individualized corrections are too resource-intensive to scale.

Gannerkote says turning powerful gene editing tools into broadly accessible clinical therapies requires progress across multiple fronts. Many CRISPR therapies are still bespoke, with manufacturing processes that are not yet standardized or easily repeatable, leading to long timelines and high costs. In regulation, therapy developers and government regulators face a learning curve when evaluating new modalities, particularly when speed is critical for patients with life-threatening conditions.

Today’s gene editing companies reflect on what’s required to scale personalized CRISPR therapies for maximized impact in the clinic.

End-to-end

Sadik Kassim, PhD, CTO of Genomic Medicines at Danaher, explains that personalized therapies do not naturally lend themselves to traditional drug-development models. Gene editing companies are now seeking “platformization,” where common manufacturing processes are standardized, and limited elements, such as guide RNAs, are customized for each patient to reduce costs and speed timelines.

“Baby KJ’s treatment succeeded because multiple elements aligned simultaneously,” explained Kassim. The foundational science, which achieved successful gene corrections in animal models of phenylketonuria (PKU), an inherited metabolic disorder caused by mutations in the PAH gene that impair the enzyme responsible for breaking down phenylalanine, had already been developed in the academic labs led by Children’s Hospital of Philadelphia (CHOP) physician scientists, Rebecca Ahrens-Nicklas, MD, PhD, and Kiran Musunuru, MD, PhD. Teams were then able to move quickly when the clinical need became clear.

Regulatory engagement was also critical. Danaher teams worked directly with the FDA to streamline the treatment approval process without compromising patient safety. That collaboration compressed a timeline that would normally take 18–24 months down to roughly six months.

“Replicating this for future patients will require moving away from one‑off efforts and toward repeatable platforms with established processes, validated assays, and clearer regulatory precedents, so that speed becomes the norm rather than the exception,” Kassim said.

Amy Pooler, PhD, CSO of ElevateBio, agrees that the transition steps between therapy design and manufacturing are often where the greatest delays occur. ElevateBio seeks to address this bottleneck by building an end-to-end genetic medicine platform.

“A critical driver for the company is making sure we have a clear line of sight into manufacturing from the very beginning,” Pooler said. “One reason Baby KJ’s case was successful is that Danaher managed the handoffs smoothly.”

Pooler also describes developing genetic medicines as “building the plane while you’re flying it.” The field still lacks enough data to reliably predict patient outcomes. Every clinical trial readout provides a valuable lesson for the field.

“I’m excited about the clinical evidence that’s starting to accumulate, showing gene editing can be transformative for patients, which we didn’t have five to ten years ago,” she said.

Large gene, generalizable therapy

ElevateBio’s expanding CRISPR toolbox includes base, prime, and epigenetic editing. Notably, the Durham-based company’s AI platform generates novel recombinases for targeted gene insertion, an approach that holds promise as a generalizable medicine that could treat patients regardless of their underlying disease-causing mutation.

Using AI-guided design, ElevateBio explores entirely new regions of protein space to discover potent and highly specific recombinases that expand the range of diseases amenable to gene editing. These engineered enzymes, which possess 50% or less homology to known proteins, can access novel genomic regions that remain difficult to target with existing CRISPR technologies.

Ben Kleinstiver, PhD, associate investigator at Massachusetts General Hospital (MGH) and co-author of the NEJM study describing KJ’s case, says the FDA’s Plausible Mechanisms Pathway has helped address some of the regulatory challenges to streamline the path to the clinic. Yet, there remains a major motivation for pan-mutation approaches that are more widely applied across patients.

Kleinstiver’s research group, in collaboration with Full Circles Therapeutics, recently developed a circular single-stranded DNA donor (ssDNA) that enables safer kilobase-scale integration for human cells.¹The technology provides an alternative to double-stranded DNA (dsDNA) donors that evoke harmful immune responses yet are required for recognition by the diverse suite of genome editing enzymes. Notably, the new circular donor maintains recombinase compatibility by attaching a short region of dsDNA that can go undetected by the cytosolic DNA sensor and immune system activator, cGAS.

Patients now

While the gene editing field often concentrates on large indications driven by a single common mutation, Edward Kaye, MD, CEO and director of Aurora Therapeutics, aims to extend these technologies beyond the “lucky few” who share the same mutation.

Aurora’s leadership team, from left: Morgan Maeder, PhD, Edward Kaye, MD, and David Litvak, MBA [Aurora]

Co-founded by Jennifer Doudna, PhD, CRISPR Nobel Laureate, and Fyodor Urnov, PhD, scientific director of the Innovative Genomics Institute, Aurora launched in January to build a sustainable pipeline to scale rare disease treatments. Traditionally, developing therapies for these ultra-rare or N-of-1 conditions can require several million dollars for a single patient.

Aurora is pursuing an “umbrella IND” strategy that allows multiple guide RNAs to be evaluated within a single clinical trial. The company’s initial focus is on PKU.

PKU offers several advantages for early clinical development. Patients are routinely identified through newborn screening programs shortly after birth, which facilitates trial participant identification and enrollment. The condition also benefits from a clear regulatory precedent: reductions in phenylalanine levels are an established clinical endpoint used to move therapies toward approval.

“What we learn from PKU will be used for many other diseases because we have the systems in place,” said Kaye. “It expands gene editing into many more patients, by going after one disease first.”

Kaye also stresses the importance of engaging patient communities, whose input can ensure studies and regulatory processes are not overly burdensome for patients and families.

Maher Masoud, CEO of MaxCyte, emphasizes putting patients at the forefront. He adds that most gene-editing therapies in the clinic require significant patient conditioning, which can lead to lengthy treatment cycles and clinical trial timelines. Yet he sees these barriers to scale being eroded over the near term. As an example, modalities, such as allogeneic cell therapies, require far less patient conditioning and easier dosing regimens to support cheaper therapies.

In 2013, MaxCyte partnered with CRISPR Therapeutics on early work that led to the first FDA-approved therapy based on CRISPR-Cas9, Casgevy, with MaxCyte’s ExPERT electroporation platform enabling the efficient delivery of gene editing machinery into cells.

More than a decade later, the company has developed more than 1,000 applications and protocols. The broad engineering platform can repeatedly engineer batches of at least 20 billion cells using CRISPR-Cas9 in addition to base and prime editing.

Masoud says low-significant gene editing commercial success has been a bottleneck to scaling personalized therapies. Yet, he reiterates that CRISPR and other gene editing technologies were discovered a short 12 years ago.

“With CRISPR, we are finally seeing cures, Casgevy, LYFGENIA, and baby KJ are proof of that,” he says. “This is just the beginning.”

References

Tou, C.J., Xie, K., Ferreira da Silva, J., et al. Invasive DNA donors and recombinases license kilobase-scale writing. Nature. 2026. DOI: 10.1038/s41586-026-10241-z.

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May 1, 2026

Rewriting the Rules of CAR T Delivery

Why ProBio’s tLVV platform stands out

ProBio is advancing the field with a purpose-built LVV platform designed specifically for in vivo CAR T applications, “known as tLVV—a T cell binder present on the LVV envelope, which serves as a ‘T cell specifically targeting LVVs’ or ‘T cell re-targeting LVVs’.” says Huang. “Our tLVV platform optimizes membrane fusion capability, which leads to higher functional titers and maximized transduction efficacy.” The system integrates a proprietary transfer plasmid backbone with customer-provided binders and fusogens. The binder acts as a targeting mechanism, directing where the viral particle attaches, while the fusogen enables entry into the desired cell. This modular approach allows developers to tailor targeting strategies while leveraging ProBio’s optimized backbone and supporting plasmid systems.

Importantly, ProBio’s platform is engineered to address a key concern in in vivo delivery: off-target effects. By incorporating a proprietary backbone designed to silence unintended CAR expression, the system helps reduce the risk of incorrect binding and antigen masking—issues that can compromise efficacy or lead to resistance. This design focus supports more controlled and efficient transduction in vivo.

LVVs also offer a significant advantage in terms of acceptance by regulators. “From a regulatory perspective, LVV is more mature,” says Jingyuan Zhang, PhD, content marketing specialist at ProBio. “So, there’s less barrier when applying it to in vivo approaches.”

Because LVVs are already widely used in ex vivo CAR T therapies, they come with an established safety and manufacturing track record. This familiarity can help streamline regulatory pathways, allowing developers to focus innovation on delivery and targeting rather than introducing entirely new vector systems.

From design to scaled delivery

Once administered, the LVV delivers CAR genes directly into T cells, initiating an immune response against disease targets. However, achieving reliable performance in vivo requires overcoming challenges such as envelope protein variability, vector aggregation, and binding inefficiencies.

ProBio addresses these issues through optimized plasmid design, refined manufacturing workflows, and integrated development services that support consistency from early-stage research through clinical production. The company’s new facility in Hopewell, New Jersey, further strengthens this capability, providing scalable viral-vector manufacturing tailored to in vivo CAR T and gene therapy applications. This facility can also manufacture non-viral versions of gene therapy.

Combined with end-to-end support—from construct design to CMC and GMP production—ProBio’s tLVV platform positions developers to move more efficiently from concept to clinic. As in vivo CAR T continues to evolve, such integrated solutions may play a crucial role in translating promise into practical, accessible therapies.

Explore More: www.probiocdmo.com/webinars/gene-cell-therapy-categories

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May 1, 2026

Molecular Testing System for Rapid Mycoplasma Detection

bioMérieux has introduced the BIOFIRE^® SPOTFIRE^® system for rapid mycoplasma testing in pharmaceutical manufacturing. The instrument provides automated sample processing and delivers molecular results in under one hour, helping quality control teams detect mycoplasma contamination during biologics, vaccine, and cell and gene therapy production. The system includes touchscreen operation, integrated barcode scanning, and stackable modules for scalable capacity, and it is compatible with the existing BIOFIRE Mycoplasma panel used in bioprocessing environments.

bioMérieux

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May 1, 2026

Agitator Platform

Alfa Laval has introduced the EnSaLine agitator platform for mixing in hygienic production environments such as pharmaceutical manufacturing. The system incorporates a cartridge based seal and bearing assembly designed for easier maintenance and uses EnSaFoil impellers to support efficient mixing and gentle product handling. The agitators are built for clean in place operation, include options for side and bottom mounted configurations, and are equipped with sensors that enable condition monitoring for predictive maintenance workflows.

Alfa Laval

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May 1, 2026

Automated Fill and Finish System

Thermo Fisher Scientific has introduced the Gibco CTS Compleo Fill and Finish System, an automated, functionally closed instrument designed to support formulation and filling steps in cell therapy manufacturing. The system helps reduce manual handling of patient derived cells by providing a compact, sterile, closed workflow for preparing small volume cell therapy batches. It is intended for use in autologous and other cell therapy processes, where maintaining dose accuracy, sterility, and batch to batch consistency is critical.

Thermo Fisher Scientific

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May 1, 2026

3D Light Sheet Microscope

Leica Microsystems has introduced the Viventis SCAPE light sheet microscope, a system designed for rapid 3D imaging of live biological samples. The instrument uses SCAPE technology to capture fast volumetric images under gentle conditions, allowing researchers to follow time critical cellular and tissue processes without compromising specimen viability. Because it is compatible with standard sample carriers, the system supports consistent handling and makes experiments easier to repeat and compare across conditions.

Leica Microsystems

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May 1, 2026

Inexpensive seafloor-hopping submersibles could stoke deep-sea science—and mining

Smack dab between Australia and South America, the US National Oceanic and Atmospheric Administration (NOAA) research vessel Rainier is currently on a mission to map more than 8,000 square nautical miles of the Pacific seafloor in search of critical mineral deposits. But it isn’t doing it alone; for a month starting this week, it will deploy two oblong neon submersibles as the project’s special agents, sending them nearly 6,000 meters down to hop along the seafloor.

The submersibles, built by the young company Orpheus Ocean, are designed to explore just this environment: a squelchy substrate that teems with life of all kinds, from tiny microbes to worms and snails, along with egg-size “nodules” of metals—such as copper, cobalt, nickel, and manganese—that are crucial for technologies worldwide.

Scientists and companies have long sought to probe the deep sea and bring such treasures to the surface. Orpheus, which spun off from the Woods Hole Oceanographic Institution (WHOI) in 2024, could be well positioned to make those possibilities a lot more economical. The company has designed its vehicles on a simple philosophy: “deep for cheap,” says Jake Russell, Orpheus’s cofounder and CEO, who is a chemist by training. The vehicles cost a couple of hundred thousand dollars each to build, whereas existing options can range from $5 million to $10 million. And unlike most autonomous ocean vehicles, they can push into the seafloor and capture cores of sediment—and the creatures within.

Orpheus’s engineers have been tinkering with their deep-sea designs for years, much of the work taking place at WHOI and in collaboration with NOAA and the National Aeronautics and Space Administration. Its prototype vehicles were rated capable of diving to 11,000 meters—the deepest part of the Mariana Trench. They’ve completed two commercial deployments, but this new expedition marks the submersibles’ biggest test yet: operating over large ranges for multiple weeks and with multiple instruments at play. Using Rainier as their home base on the ocean’s surface, the vehicles will swim out for 10 kilometers at a time, taking one high-resolution image every second and up to eight physical samples from the seafloor apiece.

If all goes well, the test could help establish the vehicles as a tool for government agencies, scientists, and companies that hope to probe the vastly understudied deep sea and the resources it holds. And while they’re not the only option on the market, Orpheus hopes their size and low building cost will soon make them one of the most accessible.

At present, to reach these depths scientists must wait for time on a limited and expensive set of submersibles owned by government agencies and research institutes. That formula lends itself better to capturing snapshots of the deep sea than it does to probing its interconnected ecological and biogeochemical systems. “A lot of this region that we’re surveying … has really never been explored in any kind of detail,” says Russell. “Anything we see is going to be new to NOAA and new to science.”

A sediment specialist

The Orpheus subs are classified as autonomous underwater vehicles (AUVs), which operate on a mix of preprogrammed commands and live decision-making and without being tethered to a ship. But unlike traditional AUVs engineered for long-distance, high-speed gliding, these submersibles are short and stout with little legs—better for making soft landings on the seafloor and then pushing into the mud to suck out sediment cores for scientists. When they do land, the submersibles can lift off the surface, thrust a few feet, and settle once more in a “hopping” fashion.

Their bodies are made mostly of a buoyant material known as syntactic foam, with the important electronics encased in a thick sphere of glass. The same kind of foam, which is interspersed with hollow microspheres of glass to prevent it from collapsing under high pressures, went to the deep in the vehicle that carried the filmmaker James Cameron to the Mariana Trench in 2012; he even donated leftover material for use in earlier Orpheus prototypes.

At less than two meters in length and under 600 pounds (270 kilograms), Russell says the Orpheus robots are the smallest—and correspondingly the least expensive—ocean vehicles on the market capable of descending to 6,000 meters. They’re designed to populate future fleets of robotic explorers.

The approach stems from a fundamental challenge, says Victoria Orphan, a geobiologist at the California Institute of Technology, who has previously worked with an Orpheus vehicle on a science campaign: “Anytime you do things in the deep ocean, you always run this risk, when you put something over the side [of a ship], that it might not come back.” With existing fleets of large, expensive vessels operated by groups like NOAA, WHOI, and the Monterey Bay Aquarium Research Institute (MBARI), losing a vehicle can be disastrous, not least because scientists must already compete for their limited time.

In the spring of 2024, Orphan and her colleagues put an Orpheus sub through its paces during an expedition to study deep-sea methane seeps off the coast of Alaska’s Aleutian Islands. They hoped to use the vehicle to create maps of the area before the team sent down a human-crewed submersible called Alvin to study specific areas—and the microorganisms and animals that live there—in more detail.

But as with any sort of new type of technology, “there’s always growing pains,” recalls Orphan. Frigid temperatures and steep topography added unseen challenges, and it took the full three weeks for the sub to get high-resolution photographs of the seeps.

The setback didn’t dull Orphan’s excitement about the potential of these machines. “There’s a lot of real, unknown science right at that interface between the sediment and the ocean surface,” she says. “The Orpheus-type class of instrument, with the right kinds of sensors and samplers, could be a very enabling tool.”

Russell envisions pairing the vehicles with specially designed payloads that can sense the heat of chemical seeps and detect plumes of sediment, DNA shed from ocean life-forms, or the magnetic tug of buried cables.

The vehicles are the “the best of both worlds,” says Andrew Sweetman, a deep-sea ecologist at the Scottish Association for Marine Science, who has not worked with Orpheus. While they can roam large areas like an AUV, they can also carry out precise sampling maneuvers like a remotely operated vehicle (ROV), a robot connected to a ship via cables that fulfills real-time human commands.

In addition to the low price tag, says Sweetman, the small size of the vessels means they don’t require a large research vessel to ferry them out to sea. That might make exploration more accessible for smaller or poorer countries without such ships, he says: “It will, in a way, help democratize deep-sea science.” He imagines using the sediment cores the submersibles gather to probe how seafloor-dwelling animals cycle nutrients—a crucial element of the ocean’s role as a carbon sink.

The mining push

As much as smaller, cheaper ocean vehicles have caught scientists’ eye, they have also piqued the interest of companies. Russell says inquiries come in weekly from businesses involved in deep-sea mining, defense, offshore wind, telecommunication, and oil and gas. He notes that Orpheus is merely a “service provider,” helping collect data where needed but not making decisions about how to use the seafloor. And he says that better data—such as information on the shape of the seafloor, the sediment quality, and the presence of life—also “raises the bars” that governments and regulators are only beginning to set.

But many scientists are far from eager about the growing push for seabed mining, which an executive order from President Donald Trump stoked further last week by mandating that the US government rapidly develop mineral exploration and processing. And earlier last month, the administration announced the creation of a new government office: the Marine Minerals Administration.

the Orpheus from below with flare from its two lower lights — A view of an Orpheus vehicle from below.

Given the current dearth of information on the deep sea, says Sweetman, “I think the push for deep-sea mining is happening way too fast.” And deep-sea communities are “probably the most stable environment on our planet,” adds Orphan. “The organisms that live there are really not adapted to a lot of disturbance, and it takes a really, really long time for them to recover, if at all.”

One mining method that governments and companies propose involves a machine that essentially operates like a giant bulldozer, trawling the seafloor, sucking up a trail of material, and leaving scar marks and sediment plumes in its wake. Brett Hobson, an ocean engineer at MBARI, says that Orpheus-like technology might enable companies to “take samples in a more surgical way, instead of just grossly scooping everything up off the seafloor and filtering through it.”

Hobson, who has run MBARI’s work on ocean vehicles for decades, also notes that Orpheus submersibles won’t be the only option available. Companies and government agencies—including those in Norway, France, Japan, China, and the UK—are developing similar deep-sea vehicles, he says: “What we really need [as] a society is just more of these systems out there.”

As Orpheus’s neon vehicles plunge into the Pacific over the next few weeks, their readiness for future scientific and resource surveys should become clearer. Each time they dive, they will get a little bit more data—“just the smallest of postage stamps of our planet,” says Orphan. “There’s still so much to learn.”

May 1, 2026

A new US phone network for Christians aims to block porn and gender-related content

A new US-wide cell phone network marketed to Christians is set to launch next week. It blocks porn, which experts in network security say marks the first time a US cell plan has used network-level blocking for such content that can’t be turned off even by adult account owners. It’s also rolling out a filter on sexual content aimed at blocking material related to gender and trans issues, which will be optional but turned on by default across all plans.

The network, which is currently being tested ahead of its May 5 launch date, will be run by Radiant Mobile, a newly launched mobile virtual network operator (MVNO). These operators don’t own cell towers but buy bandwidth from the big providers (in this case, T-Mobile) and sell to specific demographics (President Trump announced his own MVNO last year called Trump Mobile; CREDOMobile sends donations to progressive causes).

“We are going to create—and we think we have every right to do so—an environment that is Jesus-centric, that is void of pornography, void of LGBT, void of trans,” Radiant Mobile’s founder, Paul Fisher, told MIT Technology Review. A representative for T-Mobile did not comment on whether these content blocks violate any of its policies. In a statement, the representative added that T-Mobile does not have a direct relationship with Radiant Mobile but instead works through the MVNO manager CompaxDigital.

Fisher says he’s recruited a mix of Christian influencers to advertise the plan and has also done outreach to thousands of churches around the country, offering a way to have Radiant donate a portion of congregants’ $30-per-month subscription fee to their church. Fisher has ambitions to market it beyond the US in other countries with significant Christian populations, like South Korea and Mexico.

At least one piece of Radiant’s pitch will sound familiar: the idea that the internet is awash in toxic sludge. It’s powered by content and algorithms that are making us more sad, hateful, and detached. A number of efforts aim to fix that, including contentious age verification laws and a coming wave of lawsuits alleging that social media companies knowingly got young users hooked on their platforms.

Fisher is pursuing the nuclear option. He says Radiant is working with the Israeli cybersecurity company Allot to block categories of content, such as material about violence or self-harm. Some categories are banned by default and cannot be allowed even for adult users.

This includes pornography. Chris Klimis, a minister in Orlando who was recruited to be the company’s chief operating officer, says part of the reason he got involved was to offer Christians a real way to “do something” about what he sees as a pornography crisis in the faith. He was appalled by a recent survey showing that 67% of pastors have a “personal history” with porn use. And he worries his six children will come across porn on their devices, even if only inadvertently.

“We’ve got to figure out some way to close the door to the digital space,” he says. “That’s what we’re trying to do.”

The technology to do this blocking is a blunt instrument: Allot groups website domains into more than a hundred categories, which include pornography but also violence, malware, gaming, and in Radiant Mobile’s case “sects,” which includes websites about Satanism. If one of its users tries to visit a website that belongs to a blocked category, the page won’t load. That’s harsher than app-based content blockers like Covenant Eyes, a Christian porn-quitting app that sends notifications to your friends or family if you slip up; those can be worked around or deleted.

“Blocking in the network is certainly not new,” says David Choffnes, a computer science professor and executive director of Northeastern University’s Cybersecurity and Privacy Institute. Such blocking is the backbone of censorship efforts by authoritarian governments, for example. But there are more benign ways it’s used too. US telecoms block particular domains known to be spreading malware and offer optional network-level controls to block adult content on kids’ phones. What is new is a US cell plan instituting network-level blocks that can’t be removed, even by adults.

The trouble is that most websites don’t fit neatly into one category, leaving Fisher with enormous and subjective control over which are allowed or banned. This is most apparent in his effort to block content related to gender identity.

Anthony Re, a sales director at Allot, says the company does not have a category specific to gender but that “LGBT content” tends to fall into its sexuality category, which is described on Radiant Mobile’s website as “sites that provide information on sex, sex and teenagers, and sexual education, without pornographic content.” This category is blocked by default for all phones, a setting that can be changed by adult account owners.

But if a news site starts hosting enough gender-related content, Fisher might not just label it as “press,” which is allowed, but also “sexuality,” thus blocking the whole domain to any phone with that category blocked.

Fisher illustrates the subjectivity of such decisions with a recent example involving Yale University. Its general website, www.yale.edu, is categorized by Allot as education. “But they have a subsection of one of their websites that’s totally focused on, you know, trans equality,” Fisher says, referring to lgbtq.yale.edu. Because it’s a distinct domain, Radiant Mobile is able to place it in the sexuality category and block it.

Yale’s main website remains unblocked, for now. “If we see [the LGBTQ content] on the front pages consistently of Yale University, we’ll block them too,” Fisher says.

Managing website block lists is a professional pivot for Fisher, who spent his career not in telecoms but in fashion; he was an agent for supermodels like Naomi Campbell and members of the Hilton and Getty families, and he later hosted a reality show in which he found people in rehab facilities and homeless shelters and tried to turn them into models. He ultimately left the industry and now says he regrets the role he played in it: “Am I proud that I spent 35 years creating star models or star influencers? Not at all.”

Last year, his friend and fellow fashion mogul Bernt Ullmann suggested he look at what Ryan Reynolds had built with his cell network Mint Mobile: It made buying a cell plan feel less like dealing with a utility and more like choosing a brand, and it had been acquired by T-Mobile in 2023 for $1.3 billion. Fisher liked the business model but didn’t have an audience in mind. Then came a late-night revelation. “God is talking to me,” Fisher recalls. “Do something in the faith-based industry.” He set out to build the first cell network that would let in only content deemed compatible with Christianity.

Fisher says the company has received $17.5 million in investment from Compax Ventures, part of the company serving as the technical middleman between Radiant and T-Mobile. Roger Bringmann, a vice president at Nvidia, is Radiant Mobile’s lead investor and silent partner (Bringmann recently funded a new complex at Austin Christian University in Texas, which bills itself as “the university for Christian entrepreneurs”).

To fill the gap left by all the sites being blocked, the company intends to offer access to a library of religious content, including AI-generated Bible videos. It plans to use characters like Cinderella, Tinker Bell, and others (it has obtained rights from the entertainment and media company Elf Labs, which has been amassing rights to hundreds of children’s characters). “Those characters were originally constructed with a conservative perspective,” Klimis says. They’ll be used in AI-generated content alongside testimonials and devotionals.

Choffnes has technical doubts that the plan’s firewall will be as effective as promised, not least because “it’s really hard to come up with a list of every website you think is problematic.” But beyond that, he sees the internet, frustrating as it can be, as better open than closed. “I do believe in an open internet,” he says. “I also believe that a lot of the internet is toxic, but I don’t believe that this sledgehammer approach of blocking content is the right answer.”