👤 Madelyn Landis

The development of nucleic acid therapeutics using non-viral delivery systems requires efficient payload delivery to target organs for higher potency and tolerability. While lipid nanoparticle (LNP) formulations influence biodistribution, cellular uptake, and therapeutic efficacy, underlying mechanisms remain incompletely understood. This study develops potent mRNA-LNP formulations and investigates determinants of liver tropism using ornithine transcarbamylase (OTC) deficiency as a protein replacement therapy model. Systematic screening of ionizable and helper lipids, optimization of composition and process, and biophysical characterization identify a liver-tropic helper lipid-1,2-dierucoyl-sn-glycero-3-phosphoethanolamine (DEPE) that modulates LNP structure and apolipoprotein E (ApoE) binding, enhancing liver-specific delivery. Analysis of ionizable lipid chemistry reveals its role in cellular uptake mechanisms, leading to the identification of a novel ionizable lipid designed with N-(2-Hydroxyethyl)piperazine-N'-(4-butanesulfonic acid) (HEPBS) core that enables efficient delivery independent of the low-density lipoprotein receptor (LDLR) pathway. The optimized formulation achieves robust dose responsiveness, sustained therapeutic expression, and favorable tolerability in preclinical models. Therapeutic levels of OTC protein expression are observed with minimal toxicity, as indicated by stable liver function markers and cytokine levels. These findings provide mechanistic insights and establish a platform for mRNA-based protein replacement therapies, supporting broader applications in rare genetic diseases requiring hepatic gene expression. Show less

Branched-chain amino acid (BCAA) metabolism is perturbed in patients with pancreatic cancer, but the contribution of systemic or pancreas-intrinsic BCAA catabolism to pancreatic carcinogenesis is unclear. We show here that pancreas-specific loss of DBT, the E2 subunit of the branched-chain keto-acid dehydrogenase (BCKDH) complex required for BCAA oxidation, strikingly exacerbates premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in KC ( Show less

Background Chromosomal microarray analysis (CMA) provides an opportunity to understand genetic causes of congenital heart disease (CHD). The methods for describing cardiac phenotypes in patients with CMA abnormalities have been inconsistent, which may complicate clinical interpretation of abnormal testing results and hinder a more complete understanding of genotype-phenotype relationships. Methods and Results Patients with CHD and abnormal clinical CMA were accrued from 9 pediatric cardiac centers. Highly detailed cardiac phenotypes were systematically classified and analyzed for their association with CMA abnormality. Hierarchical classification of each patient into 1 CHD category facilitated broad analyses. Inclusive classification allowing multiple CHD types per patient provided sensitive descriptions. In 1363 registry patients, 28% had genomic disorders with well-recognized CHD association, 67% had clinically reported copy number variants (CNVs) with rare or no prior CHD association, and 5% had regions of homozygosity without CNV. Hierarchical classification identified expected CHD categories in genomic disorders, as well as uncharacteristic CHDs. Inclusive phenotyping provided sensitive descriptions of patients with multiple CHD types, which occurred commonly. Among CNVs with rare or no prior CHD association, submicroscopic CNVs were enriched for more complex types of CHD compared with large CNVs. The submicroscopic CNVs that contained a curated CHD gene were enriched for left ventricular obstruction or septal defects, whereas CNVs containing a single gene were enriched for conotruncal defects. Neuronal-related pathways were over-represented in single-gene CNVs, including top candidate causative genes Show less

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion ( Show less