Biology subjects

Reznik, B.

Publications and source records attributed to Reznik, B..

3 recordsLinked to original sources

bioRxiv2026

LNP Delivery of Prime Editors Enables Durable Correction of PAH R408W in Phenylketonuria Models

Phenylketonuria (PKU) is a monogenic metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, the most common of which is c.1222C>T (p.R408W). Current treatment options, including dietary restriction and enzyme substitution, can be effective but are often challenging for patients to maintain and do not address the underlying genetic defect. Gene editing represents a compelling one-time treatment approach for PKU. Herein, we demonstrate mRNA:LNP-mediated delivery of prime editors that enable therapeutically-relevant levels of correction of the R408W mutation in both in vitro and in vivo model systems. Further, we found that co-delivery of the DNA repair modulator RAD18 and engineering of the prime editor protein, enabled 2-fold and 3-fold increases in prime editing relative to PE3 respectively, resulting in ~50% correction efficiency in a humanized PKU mouse model. Collectively, this work identifies novel potential approaches to enhancing prime editing and establishes LNP-delivered prime editing as a mutation-specific, non-viral therapeutic strategy for PKU, as well as providing a framework for extending prime editing to other inherited liver diseases.

pharmacology and toxicology↗

bioRxiv2025

Cardioprotective effects of AMPK activation in H1N1 influenza virus infection

Cardiac complications are among the most common and severe extrapulmonary manifestations of influenza virus infection, yet they are rarely recapitulated in mouse models without immunodeficiency. We found that influenza virus A/California/04/2009 (H1N1) carrying a mouse-adaptive amino acid substitution in the PB2 protein (E158A) disseminates to the heart in WT C57BL/6 mice, where it induces inflammation, electrical dysfunction, and fibrotic remodeling. Influenza virus-infected heart tissue was significantly altered in mitochondrial metabolism, extracellular matrix, circadian rhythm, and immunity pathways. Particularly striking was activation of gene expression downstream of the mitochondrial biogenesis-promoting AMPK/PGC-1 axis, which occurred late in infection but failed to reverse the repression of mitochondria-associated genes, suggesting an insufficient or delayed compensatory response. Accordingly, we administered AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) early in infection and observed restoration of mitochondria-associated gene levels, amelioration of cardiac electrical dysfunction and fibrosis, and improvement in survival without overt effects on lung function. Overall, the advent of an immunocompetent model for severe influenza-associated cardiac dysfunction revealed activation of AMPK signaling as a host-targeted metabolic intervention for mitigating virus-induced heart pathologies

microbiology↗

bioRxiv2018

Heterogeneity of transposon expression and activation of the repressive network in human fetal germ cells

Epigenetic resetting in germ cells during development leads to the de-repression of transposable elements (TEs). piRNAs protect fetal germ cells from potentially harmful TEs by targeted destruction of mRNA and deposition of repressive epigenetic marks. Here we provide the first evidence for an active piRNA pathway and TE repression in germ cells of human fetal testis. We identify pre-pachytene piRNAs with features of secondary amplification that map most abundantly to L1 family TEs. We find that L1-ORF1p expression is heterogeneous in fetal germ cells, peaks at mid-gestation and declines concomitantly with increasing levels of piRNAs and H3K9me3, as well as nuclear localization of HIWI2. Surprisingly, following this decline, the same cells with accumulation of L1-ORF1p display highest levels of HIWI2 and H3K9me3, whereas L1-ORF1p low cells are also low in HIWI2 and H3K9me3. Conversely, earlier in development, the germ cells lacking L1-ORF1p express high levels of the chaperone HSP90a. We propose that a subset of HSP90a-armed germ cells resists L1 expression, whereas only those vulnerable L1-expressing germ cells activate the PIWI-piRNA repression pathway which leads to epigenetic silencing of L1 via H3K9me3.

developmental biology↗