Introduction: Expanding the Promise of Gene Editing

A recent conference held by the American Society of Gene and Cell Therapy (ASGCT) focused on in vivo gene editing. Gene editing can refer to an array of new technologies, many using clustered regularly interspaced short palindromic repeats (CRISPR) based approaches, capable of making flexible, modular, and precise changes to chromosomes in target cells. In vivo means that the gene editing machinery is delivered directly to cells in the patient (by, for example, injection or infusion) without an intervening ex vivo step for modification of cells in the lab. In general, compared to ex vivo drug products that involve very complex supply chain and manufacturing requirements, drug products for in vivo gene editing may be manufactured, distributed, stored, and administered in a manner more comparable to traditional medicines, such as small molecules and antibodies. This broadens the promise of interventional genomics beyond rare disease and traditional academic medical centers, enhancing accessibility for more patients, potentially including low-income countries and the developing world.

Health leaders globally showed increasing attention to the potential for these technologies in 2025. A June horizon scanning report from the European Commission listed in vivo gene therapy as a top priority.1 In the United States (US) in September 2025, the Advanced Research Projects Agency for Health (ARPA-H) agency announced a new funding program in in vivo precision genetic medicines.2 In November, FDA leadership published a preview of a new Plausible Mechanism pathway for marketing approval of rare disease medicines, with special reference to recent advances in in vivo gene editing.3

Conference Overview: Themes and Therapeutic Areas

The recent ASGCT Breakthroughs in In Vivo Gene Editing conference (Nov. 21-22, San Diego, CA) highlighted promises and challenges of bringing novel interventional genomics to the clinic.4 Presentations at this conference addressed the potential for gene editing to offer new therapies across therapeutic areas. The therapeutic areas included rare diseases with no treatments available and common conditions, such as hyperlipidemia, for which effective but suboptimal treatments are already frequently used. 

A major challenge with any in vivo therapy is delivering the drug product to the correct cells in the correct tissue. The easiest tissue to target is the liver and initial important successes have involved liver-targeted therapies. To investigate ways to expand on these successes, the conference agenda was divided into sessions according to target tissue: hematopoietic (blood) stem cells, muscle, immune cells, central nervous system (CNS), and liver.

Many of the concepts raised throughout the T conference converged in a presentation by Dr. Sonia Vallabh. Dr. Vallabh co-leads initiatives researching therapies for inherited prion disease at the Broad Institute. Dr. Vallabh’s story is especially compelling and urgent, as she described the case of her own mother’s death due to sudden onset dementia resulting from prion disease. Subsequently, Dr. Vallabh discovered that she also inherited the genetic variant that predisposes her to suffer from the same condition. While the underlying biology of prion disease is quite unusual compared to the majority of therapeutic areas, the challenges and opportunities presented by Dr. Vallabh brought together several themes introduced by other speakers.

Prion disease is caused by misfolded proteins in nervous tissue, in this case due to inheritance of a genetic variant that predisposes an individual to sudden onset of this terminal CNS disease. Dr. Vallabh explained how her search for effective treatments involves a broad range of genetic and nongenetic modalities. Her presentation emphasized the fact that very recent developments over the last year have made delivery of gene editing medicines to all parts of the human brain a plausible approach for treatment of CNS diseases. Her lab is now actively pursuing development of a gene editing modality to correct the underlying genetic cause of inherited prion disease in affected individuals.

The potential to access cellular targets throughout the brain was emphasized in a presentation by Yong-Hui Jiang from Yale University, who is developing a gene-editing delivery technology, based on Stimuli-responsive Traceless Engineering Platform-RiboNucleo Proteins (STEP-RNPs). Because they are smaller (at about 10-15 nm) than commonly used viral vector particles, STEP-RNP particles are capable of broader dispersal to more cellular targets inside the brain. Dr. Jiang is working on proof of concept approaches for Angelman syndrome and H1-4 syndrome.

To approach inherited and acquired diseases of the blood, speakers presented several promising approaches. Cecilia Cotta-Ramusino, from Tessera Therapeutics, addressed the delivery of GeneWriter drug products to blood stem cells via lipid nanoparticles (LNPs) optimized to “de-target” the liver and reach long-term hematopoietic stem cells (LT-HSC). Chan Li, from University of Washington (UW), presented work on a new generation of adenoviral vectors to deliver base editing and prime editing machinery to stem cells in vivo. Both the Tessera Therapeutics and UW programs are proposed for treatments of sickle-cell disease. In addition, Dr. Li presented preclinical data supporting in vivo gene editing for treatment of HIV (Human Immunodeficiency Virus, the causative agent of AIDS) infection by preventing expression of the CCR5 HIV coreceptor on T cells.

CAR-T cell manufactured ex vivo have provided enormous clinical benefits for patients with B cell malignancies and show great promise in other therapeutic areas, such as autoimmune diseases. However, it requires significant time and resources to produce autologous ex vivo products, and this limits global access to these treatments. Jenny Hamilton, from Azalea Therapeutics, presented preclinical progress on Azalea’s Enveloped Delivery Vehicles (EDV) platform in combination with a viral vector for in vivo generation of CAR-T cells for treatment of liquid and solid tumors.

The most advanced clinical programs presented were those involving the liver. Rebecca Ahrens-Nicklas, with the Children’s Hospital of Philadelphia (CHOP), presented an update on personalized gene therapy for metabolic diseases. This included an update on Baby KJ, treated earlier this year with a bespoke gene editing product for an inherited urea cycle disorder,5 who was doing well per the presentation. It also included a summary of regulatory innovation that Dr. Ahrens-Nicklas’ team hopes to harness for platform approvals of new therapies for rare disease.6 Amy Simon, with Beam Therapeutics, presented progress on the BEAM-302 clinical trial of LNP-delivered gene editing therapy for Alpha-1 Antitrypsin Deficiency (AATD)-associated diseases. Dr. Simon reported that initial reportable dose escalation resulted in rapid total increase of Alpha-1 Antitrypsin to therapeutic levels, with no serious adverse events and with further escalation planned.

Multiple speakers presented opportunities to apply these technologies beyond rare disease, including in indications with high prevalence, such as, atherosclerotic cardiovascular disease secondary to elevated LDL cholesterol (LDL-C) levels. Preclinical information on the EDIT-401 program (EDITAS Medicine) was presented. Inspired by a natural human variant in the LDLR gene associated with extremely low LDL-C, EDIT-401 aims to increase expression of the LDLR protein to treat hyperlipidemia. This is an area of research with active programs at multiple companies mentioned during the sessions.

In a concluding session, a panel of speakers addressed the future of targeted in vivo gene editing. Kiran Musunuru, with University of Pennsylvania, remarked that if the meeting had been held a year ago, “it would not have been this exciting.” Dr. Vallabh highlighted the challenges of working in a “memory-less system” for clinical development, with a need for increased transparency among drug developers.

Members of the audience seemed to agree that this was a great meeting for concentrated and exciting content, with a lot of enthusiasm for a future installment in this rapidly developing space.

Conclusion

The ASGCT Breakthroughs in In Vivo Gene Editing conference underscored the rapid evolution of gene editing technologies and their potential to transform medicine. From rare genetic disorders to widespread conditions like hyperlipidemia, the field is moving toward scalable, accessible solutions. While challenges remain, particularly in delivery and regulatory pathways, the enthusiasm and progress showcased at this meeting signal a future where precision genetic medicines could become mainstream. Continued collaboration, transparency, and innovation will be key to realizing this promise.

References:

  1.  JRC Publications Repository – Healing the Future – Horizon scanning for emerging technologies and breakthrough innovations in the field of cell and gene therapies
  2. ARPA-H unveils programs to develop custom gene editing therapies
  3. FDA’s New Plausible Mechanism Pathway | New England Journal of Medicine
  4. Breakthroughs in Targeted In Vivo Gene Editing | ASGCT
  5. World’s First Patient Treated with Personalized CRISPR Gene Editing Therapy at Children’s Hospital of Philadelphia | Children’s Hospital of Philadelphia
  6. How to create personalized gene editing platforms: Next steps toward interventional genetics – ScienceDirect