Acuitas Therapeutics and CHOP Pioneer Personalized CRISPR Therapy for Infant with Urea Cycle Disorder
核心洞察
Acuitas Therapeutics (搜索), Children's Hospital of Philadelphia, and University of Pennsylvania successfully delivered the world's first personalized LNP-delivered CRISPR (搜索) gene-editing therapy to an infant with urea cycle disorder (搜索), with no adverse events reported.
The groundbreaking therapy was developed, manufactured, and delivered in just six months, establishing a new model for rapid development of personalized gene therapies through cross-functional partnerships.
Acuitas also presented advances in targeted LNP delivery, including DARPin-conjugated formulations achieving up to 98% binding and 90% expression in human CD8+ T cells (搜索), expanding therapeutic applications beyond the liver.
Acuitas Therapeutics (搜索), in collaboration with the Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania, has successfully delivered the world's first personalized lipid nanoparticle (LNP)-delivered CRISPR (搜索) gene-editing therapy to an infant with urea cycle disorder (搜索) (UCD). The landmark achievement was presented at the 2025 American Society of Gene & Cell Therapy (ASGCT) annual meeting in New Orleans, alongside Acuitas' latest advances in LNP delivery technology.
The personalized CRISPR (搜索) therapy, recently published in The New England Journal of Medicine, was administered to an infant patient with severe UCD—a genetic condition that impairs the body's ability to process protein properly, leading to dangerous ammonia accumulation in the blood. The therapy consisted of mRNA encoding a CRISPR enzyme and guide RNA, encapsulated in Acuitas' LNP formulation using ionizable lipid ALC-0307™ and PEG-lipid ALC-0159™.
In a remarkable demonstration of rapid therapeutic development, the treatment was created, manufactured, and delivered to the patient in just six months. The therapy was administered at three separate timepoints with no adverse effects reported, validating the safety profile of Acuitas' LNP platform for gene-editing applications.
"What made this collaboration exceptional wasn't just the science—it was the shared commitment to transforming how patients receive care," said Dr. Thomas Madden, President & CEO of Acuitas Therapeutics (搜索). "Working alongside Children's Hospital of Philadelphia, University of Pennsylvania, Aldevron (搜索), and IDT, we aligned our capabilities to deliver a personalized CRISPR (搜索) therapy in an impressive six months. This model of cross-functional partnerships establishes a blueprint for how future personalized therapies can be co-developed efficiently, safely, and with direct patient impact in mind."
Expanding LNP Applications Beyond the Liver
At ASGCT, Acuitas also presented significant advances in expanding the targeting capabilities of their LNP technology. The company evaluated an "active" targeting approach using Athebody® designed ankyrin repeat proteins (DARPins)—antibody mimetic proteins that function as high-affinity and high-specificity ligands for delivery to specific target cells.
The results demonstrated remarkable targeting efficiency:
- Non-targeting LNP formulations showed less than 2% engagement in murine lymphocytes
- DARPin-conjugated LNP achieved up to 86% binding and 59% transgene expression in murine CD8+ T cells
- In human CD8+ T-cell samples, the DARPin-conjugated LNP achieved approximately 98% binding with 46% to 90% expression
"These results represent a significant step forward in enhancing the precision of LNP therapeutics," said Dr. Ying Tam, CSO of Acuitas Therapeutics (搜索). "By utilizing targeting ligands such as Athebody DARPin in our LNP formulations, we've enabled targeted mRNA delivery to specific target cells such as CD8+ T cells (搜索). This research sets the stage for new therapeutic strategies for many other potential beyond-the-liver indications."
Improved Preclinical Models for LNP Development
Acuitas also presented findings from studies using improved preclinical models for LNP delivery assessment. In a nonhuman primate (NHP) study, three lead LNP formulations were administered intravenously at 0.5 or 1.5 mg/kg monthly for three months. The formulations demonstrated high activity with two different mRNA payloads and exhibited consistent pharmacodynamic, pharmacokinetic, and toxicity profiles with repeated administration.
Histopathology revealed only mild, non-adverse, and predictable effects in the liver, spleen, and adrenal glands, supporting the feasibility and safety of the LNP platform for repeated dosing—a critical factor for many therapeutic applications.
To address species-specific limitations in current models, Acuitas evaluated PXB-mice, a humanized liver model, for their predictive utility in mRNA-LNP delivery and development. Three LNP candidates were assessed, with LNP13 showing the greatest activity and excellent tolerability at doses up to 5.0 mg/kg. The studies revealed broad liver distribution and slightly delayed mRNA expression in human hepatocytes, reinforcing the model's value in studying human-specific responses to LNP-based therapies.
Implications for Future Gene Therapies
The successful delivery of a personalized CRISPR (搜索) therapy for UCD represents a significant milestone in the field of gene editing. UCD affects approximately 1 in 35,000 births in the United States and can be fatal if not treated promptly. Traditional management includes dietary protein restriction, medications, and in severe cases, liver transplantation.
This personalized approach to genetic medicine demonstrates the potential for tailored therapies that address the specific genetic mutations of individual patients. The rapid development timeline—six months from concept to patient administration—also highlights the potential for accelerated therapeutic development when multiple partners collaborate effectively.
Acuitas' LNP technology has already been clinically validated in approved products, including the Pfizer-BioNTech COVID-19 vaccine (COMIRNATY®) and Alnylam Pharmaceuticals' ONPATTRO® for the treatment of transthyretin amyloidosis. The company continues to focus on enhancing LNP formulations to expand targeting beyond the liver, enable safe repeat dosing, and support a broad range of therapeutic programs.
The advances in targeted delivery to T cells could have particularly significant implications for immunotherapy applications, potentially enabling more precise and effective cell-specific therapies for cancer and other conditions where immune cell targeting is beneficial.
As personalized medicine continues to evolve, the collaborative model demonstrated by Acuitas, CHOP, and their partners provides a template for how complex genetic therapies can be developed and delivered efficiently, potentially transforming treatment paradigms for patients with rare genetic disorders.