Inhalation of Rhodococcus equi causes severe pneumonia in humans and animals worldwide, most commonly affecting horse foals. The standard for preventing R. equi pneumonia in foals is transfusion of hyperimmune plasma, which is expensive and carries the risk of adverse effects. Our goal was to passively immunize foals against R. equi by nebulizing mRNA encoding an equine monoclonal antibody (mAb) against

TAR DNA binding protein-43 (TDP-43)-mediated pathology is a hallmark of devastating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Thus, monoclonal antibodies (mAbs) are being developed to target the pathological forms of this protein. To improve mAb exposure within the central nervous system, a potent anti-TDP-43 mAb, ACI-5891, was generated

Covalently closed-end adeno-associated virus vector (cceAAV) is a new generation of self-complementary vector (scAAV) which does not utilize a mutant ITR for vector production. Importantly, packaged genomes of these cceAAV vectors are markedly more intact than traditional scAAVs, which typically contain a large fraction of incomplete genomes, including many that lost their self-complementary configuration

Hutchinson-Gilford progeria syndrome (HGPS), an extremely rare progressive genetic disorder, is caused by a point mutation in LMNA that induces progerin production, which disrupts cellular function and triggers premature aging and mortality. Despite extensive efforts, HPGS remains incurable. We successfully implemented a strategy using RfxCas13d to selectively target progerin mRNA at specific junction

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder involving ventricular arrhythmias, cardiac dysfunction, and fibrofatty myocardial replacement. Current treatments are largely palliative, with heart transplantation as the only definitive option for advanced ACM. Here we show that, building upon our previous identification of a patient with a PNPLA2c.G245A/c.G245A mutation, we developed a

Adenine base editors (ABEs) and cytosine base editors (CBEs) are prominent tools for precise genome editing but are hindered by limited editing activity at positions proximal to the protospacer adjacent motif (PAM). This study investigates the potential of enhancing base editors editing activity by fusing them with RNA-DNA hybrid binding domains (RHBDs). Specifically, fusing ABE8e with the RHBD of

Phenylketonuria (PKU) is a genetic defect caused by lack of liver enzyme phenylalanine hydroxylase (PAH). This deficiency results in elevated blood Phenylalanine (Phe) levels and neurotoxicity which is manifested by reduced brain size, lower neurotransmitter levels, and reduced myelination. The goal of this study was to investigate brain myelination defects and their reversibility upon blood Phe lowering

Epilepsy affects approximately 50 million people worldwide, and over 30% of patients are considered treatment-resistant to currently available anti-seizure drugs. Neuropeptide Y (NPY) has been shown to inhibit excitatory synaptic transmission in hippocampal slices from human epilepsy patients via Y2 receptors (Y2R), and overexpression of NPY and/or Y2R in the hippocampus reduces seizures in rodent

Glycoengineering of IgG, particularly Fc glycosylation, holds significant promise for treating autoimmune diseases by modulating antibody effector functions. However, methods that precisely control IgG glycosylation profiles in vivo are still lacking. In this study, by delivering mRNAs encoding the glycosyltransferases B4GALT1 and ST6GAL1 intravenously, we successfully expressed functional enzymes

Adenosine-to-inosine (A-to-I) RNA editing, and N6 methyladenosine (m6A) are among the most abundant modifications in eukaryotic messenger RNA, affecting various aspects of RNA metabolism and cellular function, including proliferation, differentiation, responses to stressors, and cell death. Recent preclinical evidence suggests that both modifications play a significant role in multiple disorders, including

Natural killer cells are innate lymphocytes equipped with the ability to rapidly identify and eliminate cancer cells. However, cancer cells release nanosized extracellular vesicles that can induce an immunosuppressive tumor microenvironment, subsequently hindering natural killer cell immunosurveillance. Studies have reported that extracellular vesicles derived from different cancers, such as acute

Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal malignancies, highlighting the critical need for innovative therapeutic strategies. In this study, we examined the roles of nicotinamide adenine dinucleotide (NAD) synthesis pathway in PDAC. Targeting the NAD synthesis pathway significantly mitigated lethality in a Drosophila model that recapitulated the PDAC genotype. Within this

Adenosine deaminase severe combined immunodeficiency (ADA-SCID) is a monogenic disorder caused by mutations in the ADA gene. Gene therapy using γ-retroviral and lentiviral vector gene addition approaches have shown curative results. We sequenced the ADA transgene in transduced CD3+ T cells, and in peripheral blood cells from patients treated with autologous CD34+ cells transduced with either a γ-retroviral

T cell receptor (TCR)-engineered T cell therapy holds great promise for treating solid tumors, but the overall clinical efficacy remains limited. The vital challenge lies in the loss of TCR-targeted antigens and poor T cell persistence. Here, we demonstrate a novel approach to enhance TCR-T cell therapy and reject antigen-heterogeneous tumors through a multi-engineered T cell vaccine (Multi-Tvac).

Podocyte injury contributes to the progression of glomerular disease and aging; however, causative molecular/physiological pathways are poorly defined, and there are few therapies to improve kidney outcomes. We previously reported that free fatty acid receptor 4 (FFAR4) agonist TUG891 improved podocyte injury to alleviate renal inflammation and fibrosis in diabetic nephropathy. However, the role of

CD117 is a cell-surface receptor expressed on hematopoietic stem and progenitor cells and acute myeloid leukemia (AML), and thus CD117-targeting chimeric antigen receptor T cells (CART117) can function as both conditioning for hematopoietic stem cell transplantation and a therapy for AML. We developed human and mouse CART117s to evaluate the safety and feasibility of targeting CD117 in preclinical

Colorectal cancer (CRC) is a major cause of cancer deaths, with poor outcomes in advanced stages. CD47, overexpressed in CRC, helps tumors evade immune detection by blocking macrophage phagocytosis, while CD47 blockade has shown limited efficacy in CRC. Our study showed that dual blockade of CD47 and TNFR2 demonstrated synergistic antitumor effects in murine CRC models. Since TNFR2 was highly expressed

The adaptive immune protection elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has been proven to control the severity of novel coronavirus disease 2019 (COVID-19). However, the contributions of innate lymphoid cells formed from immunization are poorly defined in vaccine evaluation. Here, we highlight how the natural killer (NK) and macrophage (Mϕ) cells’ response

Chimeric antigen receptor (CAR) T cell therapies have shown clinical success in treating hematologic malignancies. However, heterogeneous target antigen expression can impair the durability of response. Combining CAR and T cell engagers (TCEs) targeting additional tumor antigens can address tumor heterogeneity and antigen escape. In allogeneic settings, eliminating the T cell receptor (TCR) of the

The development of mucosal mRNA vaccines is promising but extremely challenging. Major efforts have been focused on optimizing delivery systems, but it is still unknown whether the intrinsic quality of mRNA components significantly impacts the potency of airway-inoculated mRNA vaccines. Here, we systematically demonstrate that mucosal mRNA vaccine requires higher standards of purification and a tailor-designed

Significant breakthroughs have been made in translation of adeno-associated virus (AAV) vectors for hearing disorders targeting auditory hair cells (HCs). In addition to HCs, spiral ganglion neurons (SGNs) are also impacted in a large number of sensorineural hearing loss cases in adults. However when administered directly into the cochlea in rodents aged older than P1–P3, AAV-mediated SGN transduction

Chronic pain remains a global health challenge, often resistant to available treatments with socioeconomic and psychological burdens. All chronic pain is believed due to neuronal signaling imbalances, resulting in increased excitability. Gene therapy represents a promising molecular therapy targeting molecular pain processing pathways, by offering precise, localized, long-lasting neuromodulation while

Focal cortical dysplasia type II (FCDII) is a leading cause of refractory epilepsy in children, yet treatment options remain limited. The most frequent genetic cause of FCDII is mosaic and somatic variants in genes of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, leading to hyperactivation of mTOR signaling. The presence of dysmorphic

Peritoneal metastasis (PM) is a prevalent mode of metastasis in colorectal cancer (CRC) with rapid disease progression and limited treatment options. Locoregional infusion of immune cells have been explored in different types of solid tumors, but the feasibility and safety of locoregional chimeric antigen receptor-natural killer (CAR-NK) cells in treating CRC-PM is still unknown. We report the results

Poor tumor trafficking and the immunosuppressive tumor microenvironment (TME) limit chimeric antigen receptor (CAR) T cell efficacy in solid tumors, such as neuroblastoma. We previously optimized GPC2 CARs in human neuroblastoma xenografts leading to clinical translation; however, there have not been preclinical studies using immunocompetent models. Thus, here we generated murine GPC2 CAR T cells using

There remain several unmet clinical needs in Parkinson’s disease (PD) including waning and incomplete efficacy of symptomatic therapies, development of medication side effects (i.e., levodopa-induced dyskinesias [LID]) and unfettered disease progression. CaV1.3 calcium channels are therapeutic targets of intense interest in PD. We developed an RNA interference (RNAi)-based vector approach utilizing

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication depends on the NSP12-NSP8-NSP7 complex, which plays a critical role in enhancing RNA-dependent RNA polymerase (RdRp) activity. NSP8 is particularly essential, stabilizing the RdRp complex and supporting viral replication across diverse variants. To disrupt this crucial interaction, we designed four NSP8-derived peptides—N8-Pepα

Inherited retinal degenerations (IRDs) cause progressive photoreceptor loss, leading to vision impairment. Gene therapy using adeno-associated viral (AAV) vectors holds immense promise for treating these conditions. However, achieving optimal gene expression at mid to late stages of retinal degeneration remains challenging due to scarcity of efficient photoreceptor-specific promoters expressed at these

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2%–3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene suppression a promising approach, supported by preclinical data and the 2023 Federal Drug Administration (FDA) approval of the GapmeR ASO targeting

Glaucoma is a neurodegenerative disease manifested by retinal ganglion cell (RGC) death and irreversible blindness. We have identified apolipoprotein A-I binding protein (AIBP) that controls excessive cholesterol accumulation and neuroinflammation in the retina by upregulating the cholesterol transporter ABCA1 and reducing TLR4 signaling and mitochondrial dysfunction. Here, we demonstrated that AIBP

De novo heterozygous variants in the neuronal STXBP1 gene cause severe, early-onset developmental and epileptic encephalopathy. Adeno-associated virus (AAV)-based gene replacement therapy offers the potential for a one-time, disease-modifying approach for STXBP1-related disorders. However, off-target overexpression in the liver and in the dorsal root ganglion (DRG) are known potential toxicities of

Acute kidney injury (AKI) encompasses a spectrum of conditions, varying from mild and self-limiting to severe cases that can lead to chronic kidney disease (CKD). Macrophages are crucial in the progression from AKI to CKD, yet the diversity of macrophage subsets complicates the identification of key functional types. We established a detailed single-cell atlas of mononuclear macrophages from the onset

Delivery of systemically administered therapeutics to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB). Bioengineered adeno-associated virus (AAV) capsids have been shown to penetrate the BBB with great efficacy in mouse and non-human primate models, but their translational potential is often limited by species selectivity and undefined mechanisms of action. Here, we

Renal fibrosis serves as a critical pathological mechanism driving the progression of chronic kidney disease (CKD). However, the pathogenesis and therapeutic targets involved in this process remain unclear. Interestingly, we currently found that IGFBP7 is highly expressed in tubular epithelial cells (TECs) from the fibrotic kidneys of human patients and animal models. However, their functional roles

The field of adoptive T cell immunotherapy has been dominated by a chimeric antigen receptor (CAR) design that combines antigen recognition through antibody-derived domains and signaling into a single polypeptide. This conventional design redirects the immense cytotoxic potential of T cells toward tumors, and it is the core of several commercially marketed CAR-T cell products. Recent research in the

Molecular tether-mediated extracellular targeted protein degradation (eTPD) presents an innovative technology and underlies a promising drug modality. However, to precisely implement eTPD within specific cell compartments remains a significant challenge. As eTPD depends on the degrader molecule expression and activity, we first seek to expand the panel of potential eTPD degraders. To this end, more

This study investigates key microscopic regions involved in colorectal cancer liver metastasis (CRLM), focusing on the crucial role of cancer-associated fibroblasts (CAFs) in promoting tumor progression and providing molecular- and metabolism-level insights for its diagnosis and treatment using multi-omics. We followed 12 fresh surgical samples from 2 untreated CRLM patients. Among these, 4 samples

Gaucher disease type 1 (GD1) is caused by mutations in the GBA1 gene, which result in deficient enzyme β-glucocerebrosidase (GCase) activity and production with the harmful accumulation of the lipid substrate glucocerebroside. Replacement of GCase is current standard of care for GD1; however, GCase has a relatively short active half-life at both physiological and lysosomal pH and biweekly intravenous

Duchenne muscular dystrophy (DMD) poses challenges in therapy design due to dystrophin’s complex role in maintaining muscle function since the restoration of truncated protein products has failed to completely address the disease’s pathophysiology in clinical trials. As ∼70% of patients harbor deletions, strategies enabling targeted DNA insertion to restore full-length dystrophin protein are essential

The emergence of mRNA vaccines for infectious diseases has heralded development for a slew of other indications, including cancer. Lipid particle delivery vehicles can protect RNA from degradation and promote delivery to intended targets in vivo. In this mini-review, we discuss mRNA vaccine mechanisms and capacity for enhancement followed by progress to date in the clinical development of mRNA cancer

NOTCH2 is a widely expressed protein that plays a crucial role in the normal development and function of various tissues, including skeletal muscle. This study focused on a pedigree with centronuclear myopathy, primarily characterized by muscle weakness and centralized nuclei, and identified the autosomal recessive NOTCH2p.I1689F mutation through whole-exome sequencing. Using a homologous mutant mouse

Hypokalemia is a prevalent complication of COVID-19 patients with acute kidney injury (AKI); however, mechanisms have yet to be fully understood. By single-nucleus RNA sequencing, we found that COVID-19 patients with AKI were associated with a marked upregulation of the epithelial sodium channel (ENaC) in the renal tubular epithelial cells (TECs). By using a mouse model of AKI induced by kidney-specific

Currently, there are an estimated 8,000 genetic disorders that cumulatively affect approximately 10% of the population. Even among the 5% of patients with genetic disease that have treatment options, these therapeutics rarely address the underlying cause of disease but rather focus on managing or modifying symptoms and typically require recurrent, lifelong therapy. A therapeutic approach to genetic

Casitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase critical for negatively regulating receptor protein tyrosine kinases (RTKs). Deleterious CBL mutants lose E3 activity, but act as adaptors that gain function to cause myeloproliferative neoplasms. Currently, there is no targeted treatment available for patients with CBL mutant-dependent disorders. By combining phage-display technology and structure-based

Despite the notable success of chimeric antigen receptor (CAR) T cell therapies in hematological malignancies, clinical outcomes remain variable, making it critical to understand how manufacturing influences product composition and function. We developed a 36-marker spectral flow cytometry panel enabling integrated profiling of phenotypic, metabolic, and functional attributes across CAR T cell production

Four exon-skipping antisense oligonucleotides (ASOs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy (DMD), including eteplirsen, golodirsen, viltolarsen, and casimersen. Current data from long-term real-world usage of these ASOs suggests a broad safety profile and a delay in muscle deterioration. Nevertheless, the exon-skipping efficacy

Autonomous “living drug” chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer medicine. However, concerns about on-target off-tumor T cell activation and resulting toxicities require advanced precise regulatory control systems for CAR-T. Here, we present a novel strategy using a genetic “AND” gate that integrates chemically induced proximity (CIP) and tumor-activated prodrug approaches

Centronuclear myopathies (CNMs) are severe genetic disorders characterized by generalized muscle weakness associated with organelle mispositioning in myofibers. Most CNM cases are caused by mutations in proteins involved in membrane remodeling, including amphiphysin 2 (BIN1). There is no treatment, and the pathological mechanisms are not understood. Here, we aimed to cure the Bin1-CNM mouse model (Bin1mck−/−)

There are no effective therapies for patients with dry age-related macular degeneration (AMD) or C3 glomerulonephritis (C3G). Unfortunately, past efforts to treat C3G using exogenous human complement factor H (CFH) found limited success due to immune rejection of a foreign protein response. AMD research has also faced myriad challenges, including the absence of an ideal therapeutic target and difficulties