ASGCT takeaways

Donatas Staniulis, Head of Business Development, Caszyme:
One of the most widely discussed themes this year was the increasing use of lipid nanoparticles (LNPs) for the delivery of nucleic acid and mRNA-based therapeutics. While LNPs are not replacing adeno-associated viruses (AAVs), they are emerging as a strong alternative and competitor in the field of gene delivery.

Artificial intelligence continued to gain confidence, with growing interest in its applications across multiple areas, including protein engineering (e.g., nucleases and deaminases), viral vector design, DNA integration analysis, off-target prediction, and mRNA sequence optimization. The diversity and expanding use of AI were evident throughout numerous sessions.

And of course — CRISPR. At this therapeutics-focused conference, there were fewer talks centered on CRISPR development itself. Instead, CRISPR has become a standard tool applied across a wide range of therapeutic contexts. For example, CAR-T cell therapy remains a major area of focus, with many new CRISPR-edited CAR-T therapies currently in development.

A highlight of the conference was the keynote presentation by Dr. Kiran Musunuru, who shared an inspiring case study on a patient-specific in vivo CRISPR gene therapy developed and delivered to a newborn with a rare genetic disease — within just six months. This remarkable achievement underscores the potential of close collaboration between research institutions and hospitals to accelerate the development of personalized treatments for patients with severe conditions.

Elizabeth Figueroa, Ph.D., Senior Consultant, Dark Horse Consulting:
One of the biggest splashes of the conference centered LNPs: the N-of-1 personalized base editing therapy for baby KJ Muldoon via an LNP delivery vector. Dr. Kiran Musunuru (University of Pennsylvania School of Medicine) and Dr. Rebecca Ahrens-Nicklas (Children's Hospital of Philadelphia) provided ASGCT attendees with a one-two punch, walking us through their groundbreaking work in two sessions. The sheer speed with which this therapy was developed, screened, optimized, and manufactured was hugely encouraging to behold, a testament to the possibilities available when multiple academic, industry, and regulatory agency stakeholders collaborate efficiently towards a common goal. It also belies the benefits of non-viral vectors relative to their viral counterparts; I truly do not think this would have been possible in the same timeframe with a viral vector due to the complexity and duration of viral vector manufacturing processes.

I also appreciated the messaging that Musunuru and Ahrens-Nicklas provided around mutational discrimination: The idea that developing personalized gene therapies for patients is not possible in many parts of the world due to the extensive uncatalogued variants for most patients worldwide. While it is true that the manufacturing cost, complexity, and cold chain make LNPs well suited for global reach, mutational discrimination is a hurdle we must overcome in order to truly globalize the reach of non-viral gene therapies.

Carl Schoellhammer, Partner, Life Science/Biopharma Strategy Consulting, DeciBio: 
Targeted lipid nanoparticles (LNPs) appear to be firmly establishing themselves as a leading strategy for achieving extra-hepatic delivery. Notably, Editas presented compelling data on in vivo hematopoietic stem cell (HSC) editing with liver de-targeting. Multiple companies such as including Beam, CRISPR Therapeutics, and Tessera are actively pursuing this approach for indications such as sickle cell disease and beta thalassemia. While preclinical studies in animal models and non-human primates have demonstrated therapeutically meaningful levels of editing, no programs have yet entered the clinic, raising questions as to what is holding this field back.

Another key takeaway relates to the role of adeno-associated virus (AAV) vectors. It’s fair to say that AAV is far from obsolete and continues to provide meaningful utility as a well-characterized delivery vehicle. Unlike many other advanced modalities, AAV has already undergone its post-pandemic market correction and now appears to be stabilizing. There are several late-stage assets in pivotal studies, including RegenxBio’s program for wet age-related macular degeneration and a broader pipeline targeting indications where the value proposition is clear and compelling.

Kim Benton, Ph.D., Master Principal and Head of Regulatory, Dark Horse Consulting:
The session “FDA’s START Pilot Program in Action: Insights from Year One” provided a nice overview of this FDA initiative to accelerate the development of rare disease therapeutics. Representatives from Neurogene, Moderna, and Myrtelle, three of four companies with CGT rare disease programs selected for the START pilot, spoke about their experiences.

The intent of the START pilot was to facilitate more efficient development of potentially life-saving therapies for rare disease indications and generation of high-quality compelling data to support a future marketing application. The pilot aims to achieve this goal via enhanced communication between FDA and the selected pilot participants. The speakers described a regular cadence of meetings with the FDA review team, prospectively scheduled on a quarterly basis. The logistics of these meetings sounded typical of formal meetings with FDA, in that the sponsor prepared and submitted a briefing package, FDA provided preliminary responses in advance of the meeting, and based on these responses the Sponsor could select the key issues to prioritize for discussion at the meetings. While the speakers did not provide specifics of their FDA meetings, they did note that topics included clinical study design, appropriate control group and patient population, statistical analysis, product characterization and other CMC topics, and overall discussion of flexible approaches that could be taken in development.

The pilot participants noted that FDA was receptive to ad hoc teleconferences and email exchanges as needed between the quarterly meetings. It was mentioned that the communication was a two-way street, with FDA communicating questions to the sponsors as they arose during review. The resource commitment was also noted to be two-way. The speakers characterized the START pilot as constructive, efficient, and an overall well-run program. They expressed hope that the program will be continued and expanded for all rare disease therapeutic development.

Charles St. James, Manager, Inside Sales & Business Development, Made Scientific:
Scalability, speed, expense — the three horsemen plaguing CGT manufacturing and ultimately patient access. Could in vivo cell therapy be the answer to CGT global access? In vivo cell therapies stole the spotlight at ASGCT, showcasing their potential to turn the human body into the cell therapy manufacturing site — bypassing the complexity and costs associated with ex vivo cell production.

ASGCT posters from Capstan, Interius, and Ensoma highlighted the transformative potential of in vivo cell therapy: 90% in vivo T-cell engineering with target cell depletion, HSC-based in vivo approaches achieving tumor control, and a landmark first-in-human phase 1 trial demonstrating in vivo CARs for B-cell malignancies — all pointing to a new era in cell therapy.

In vivo cell therapy’s remarkable progress comes with its own set of unique challenges — target specificity, regulatory uncertainty, and therapeutic durability. Some argue these challenges are minor compared to ex vivo CAR-T, which reaches only 20–30% of eligible U.S. patients.

So… in vivo or ex vivo for CGT global access? Hard to tell — but ASGCT certainly showcased the tailwinds and innovations of in vivo cell therapy, and its potential to democratize cell therapy.

Philipp Beck, Ph.D., Team Lead Formulation Development, Ascend Advanced Therapies:
My three favorite talks from this year’s ASGCT conference fall into two broad themes: vector tropism (talks 1 and 2) and clinical translation (talk 3).

1. LNP tropism in non-human primates
In Wednesday morning’s LNP session, James Dahlman presented an elegant study on lipid nanoparticle (LNP) tropism in non-human primates (NHPs). His team ethically used barcoded LNP libraries in NHPs that were due to be euthanized for unrelated medical reasons (e.g., cancer or heart failure). The animals were administered the LNP libraries intravenously a day prior to euthanasia, allowing for detailed tissue analysis post-mortem.

The results were striking: LNP distribution patterns observed in cultured cells and mice failed to predict behavior in primates. In fact, some LNPs that performed poorly in mice showed strong tropism in NHPs — and vice versa. It’s a sobering reminder of the limits of traditional preclinical models in guiding delivery platform development.

2. AAV tropism mapping in humans
Jude Samulski — an AAV pioneer — presented a landmark study that could reshape the field for years to come. His team conducted a tropism study in humans, using AAV vectors administered to individuals who were confirmed brain dead and had consented to donate their bodies to research. These individuals were not eligible for organ donation (due to conditions like cancer), but their contribution enabled the first human-wide AAV biodistribution study of its kind.

Post-mortem tissue sampling allowed for an unprecedented look at real human AAV tropism. The resulting atlas will likely become a key reference for rational AAV capsid design and route-of-administration strategies.

3. RNA editing meets gene delivery in DMD
A standout clinical update came from Pengfei Yuan (Edigene), who presented first-in-human data for an RNA editing therapy delivered via AAV in boys with Duchenne muscular dystrophy. Even at the lower dose level (2E13 vg/kg), early efficacy signals were observed, including improvements in NSAA scores and the six-minute walk test.

The work is a compelling example of how sophisticated editing technologies and mature delivery platforms are finally converging in the clinic.

David Peritt, Ph.D., Founder and CSO, Lupagen: 
1. T-cell exhaustion in cancer therapy is a huge issue for endogenous cancer reactive cells, TIL and CAR-T therapies. Checkpoint inhibitors solve for a portion of these patients. But more is needed.

2. In vivo CAR-T is finally moving to the clinic. If it works, it will be a HUGE boon for cost and access.

3. HSC editing in vivo was always a dream for a great many diseases. Early studies seem promising. Bluebird certainly showed us we can cure diseases with HSC editing, but the market will not pay the prices they were asking (hence the bankruptcy). 

Ry Leahy, VP of Research & Strategic Partnerships, Phacilitate:
ASGCT is one of the most important meetings of the year to get a lay-of-the-land for the research and early-stage progress for the field of gene therapy, and to help identify the key trends going into the next decade of development for advanced therapies.

A stand-out for me was an early workshop at ASGCT was "The Business of Advocates Advancing CGTs" was designed to empower patient advocacy organizations (PAOs) by providing them with the tools and knowledge to effectively navigate the evolving landscape of advanced therapies. The session aimed to address the business aspects of advocacy, focusing on strategies for sustainability, growth, and impactful engagement. I left the session with practical knowledge and resources to enhance an organizations' impact in the CGT landscape.

Read the ISCT 2025 takeaways