Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we report interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. As of 31 May 2023, 16 participants were enrolled across 5 dose cohorts. Twelve of the 16 participants completed the dose-optimization study and enrolled in the extension study. A total of 346 intravenous doses of mRNA-3927 were administered over a total of 15.69 person-years of treatment. No dose-limiting toxicities occurred. Treatment-emergent adverse events were reported in 15 out of the 16 (93.8%) participants. Preliminary analysis suggests an increase in the exposure to mRNA-3927 with dose escalation, and a 70% reduction in the risk of metabolic decompensation events among 8 participants who reported them in the 12-month pretreatment period.

Significance: Systemically administered lipid nanoparticles (LNPs) targeting the liver were able to express the cytoplasmic enzyme arginase 1 (ARG1) in a conditional knockout model of ARG1 deficiency. Metabolically, this resulted in maintaining normal plasma ammonia and arginine, preventing the build-up of excessive hepatic arginine, and obviated the development of guanidino compounds, a hallmark of this enzyme deficiency. Unlike controls, repeat dosing of LNPs encapsulating human codon-optimized ARG1 messenger RNA led to long-term survival without evidence of toxicity, restoration of ureagenesis, and the ability to handle toxic ammonia loading. These findings have implications for therapy of ARG1 deficiency, which is presently inadequately treated and leads to progressive neurological decline.

Adeno-associated viruses (AAVs) are being increasingly used as gene therapy vectors in clinical studies especially targeting central nervous system (CNS) disorders. Correspondingly, host immune responses to the AAV capsid or the transgene-encoded protein have been observed in various clinical and preclinical studies. Such immune responses may adversely impact patients' health, prevent viral transduction, prevent repeated dosing strategies, eliminate transduced cells, and pose a significant barrier to the potential effectiveness of AAV gene therapy. Consequently, multiple immunomodulatory strategies have been used in attempts to limit immune-mediated responses to the vector, enable readministration of AAV gene therapy, prevent end-organ toxicity, and increase the duration of transgene-encoded protein expression. Herein we review the innate and adaptive immune responses that may occur during CNS-targeted AAV gene therapy as well as host- and treatment-specific factors that could impact the immune response. We also summarize the available preclinical and clinical data on immune responses specifically to CNS-targeted AAV gene therapy and discuss potential strategies for incorporating prophylactic immunosuppression regimens to circumvent adverse immune responses.

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas that over time leads to irreversible fibrosis and loss of function. Such repeated and progressive injury commonly manifests with intractable pain, malabsorption, and diabetes mellitus.^1,2 During a period of decades, the risk of malignant conversion is up to 50 times greater in patients with CP than in the general population, particularly among those with a history of smoking or hereditary etiology.³ For many, the debilitating abdominal pain often leads to a diminished quality of life due to multiple hospitalizations, invasive interventions, and potential narcotic dependency.