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 (FCD II) is a leading cause of refractory epilepsy in children, yet treatment options remain limited. The most frequent genetic cause of FCD II is mosaic and somatic variants in genes of the PI3K-AKT-mTOR pathway, leading to hyperactivation of mTOR signaling. The presence of dysmorphic neurons (DNs) resulting from hyperactive mTOR signaling is critical for the development

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 CAR-NK cells in treating CRC-PM is still unknown. We report the results of a phase I dose-escalation clinical trial

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

Mucolipidosis II (MLII) is a lysosomal storage disorder (LSD) caused by mutations in GNPTAB and loss of mannose 6-phosphate-dependent targeting of lysosomal enzymes. Affected children exhibit cognitive deficits, skeletal dysplasia, and cardiopulmonary disease, with death typically occurring before age 10. A naturally occurring feline model of MLII results from a nonsense mutation in GNPTAB; cats develop

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, cartilage damage, and bone erosion. Despite improvements with the introduction of biological disease-modifying anti-rheumatic drugs (DMARDs), RA remains an incurable life-long disease. Advancements in peptide-based vaccination may open new avenues for treating autoimmune diseases, including RA, by inducing

Hematopoietic stem cell (HSC)-based gene therapies have seen extraordinary progress since their initial conception, now fundamentally transforming the treatment paradigms for various inherited hematologic, immunologic, and metabolic conditions—with additional use cases under exploration. Decades worth of work with advances in viral vector technologies and cell manufacturing have paved the way for HSC

The immune checkpoint protein, CD112 receptor (CD112R, also known as PVRIG), suppresses T and natural killer (NK) cell activation upon binding to tumor-expressed CD112 (Nectin-2) ligands. Here, we determine the structure of the CD112-CD112R complex and use it to guide the engineering of multiple CD112-targeting immunotherapy candidates. The 2.2 Å-resolution crystal structure reveals an antiparallel

Chimeric antigen receptor-engineered NK cells hold promise for adoptive cancer immunotherapy. In one such approach, the ErbB2 (HER2)-specific CAR-NK cell line NK-92/5.28.z is under investigation as an off-the-shelf therapy in a phase I trial in glioblastoma patients. To evaluate activity of NK-92/5.28.z cells against ErbB2-positive breast cancer, here we developed an organoid model derived from CKP

Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) has demonstrated great potential for patients with treatment-refractory metastatic melanoma. However, the need for interleukin-2 (IL-2) co-administration during TIL cell therapy limits patient eligibility and restricts treatment to intensive care units due to the risk of severe side effects. Instead, engineering TIL with membrane-bound

Adeno-associated virus-based vector (AAV)-based gene therapy has been used to treat thousands of patients, but a limitation can be inefficient transgene expression from AAV vectors. AAV transduction can be affected by the small ubiquitin-like modifier (SUMO) system, in which SUMO proteins are attached to proteins after translation, thereby modulating their function and stability. However, to date,

Recombinant adeno-associated viruses (AAVs) are leading vectors for in vivo human gene therapy. An integral vector element is promoters, which control transgene expression in either a ubiquitous or cell-type-selective manner. Identifying optimal capsid-promoter combinations is challenging, especially when considering on- versus off-target expression. Here, we report a pipeline for in vivo promoter

Histone deacetylases (HDACs) have emerged as key regulators in the pathogenesis of various kidney diseases. This review explores recent advancements in HDAC research, focusing on their role in kidney development and their critical involvement in the progression of chronic kidney disease (CKD), acute kidney injury (AKI), autosomal dominant polycystic kidney disease (ADPKD), and diabetic kidney disease

Hemophilia, a congenital bleeding disorder, can cause arthropathy, impaired mobility, pain, and life-threatening hemorrhage events, significantly impacting quality of life for patients and caregivers. Current therapies, although effective, necessitate costly lifelong treatment, often in specialized settings. However, as a monogenic disorder caused by loss-of-function genetic variants, hemophilia is

Advances in nucleic acid delivery have positioned the liver as a key target for gene therapy, with adeno-associated virus vectors showing long-term effectiveness in treating hemophilia. Steatotic liver disease (SLD), the most common liver condition globally, primarily results from metabolic dysfunction-associated and alcohol-associated liver diseases. In some individuals, SLD progresses from simple

Human induced pluripotent stem cell (hiPSC)-derived insulin-producing β cell therapy shows promise in treating type 1 diabetes and potentially type 2 diabetes. Understanding the genetic factors controlling hiPSC differentiation could optimize this therapy. In this study, we investigated the role of glucose-regulated protein 94 (GRP94) in human β cell development by generating HSP90B1/GRP94 knockout

Base editing offers high potential for treating genetic diseases, particularly those with limited treatment options. Retinoschisis, an X-linked retinal disease causing progressive vision loss, currently lacks effective therapies. We identified the c.422G>A (p.Arg141His) variant of the RS1 gene in six male patients with retinoschisis and generated a humanized mouse model harboring this variant, which

Pericytes are contractile cells of the microcirculation that participate in wound healing after spinal cord injury (SCI). Thus far, the extent to which pericytes cause or contribute to axon growth and regeneration failure after SCI remains controversial. Here, we found that SCI leads to profound changes in vasculature architecture and pericyte coverage. We demonstrated that pericytes constrain sensory

Chimeric antigen receptor T (CAR-T) cells targeting B cell maturation antigen (BCMA) have changed the treatment landscape for patients with relapsed and refractory multiple myeloma. However, T cell dysfunction associated with progressive disease and multiple prior lines of therapy (PLOT) raises concerns about the feasibility of consistently manufacturing effective CAR-T cells. We investigated the practicality

Intramuscular injection of donaperminogene seltoplasmid (recombinant human hepatocyte growth factor plasmids) represents a gene therapy that treats patients with chronic limb-threatening ischemia (CLTI). The HOPE CLTI-2 trial was a phase 3, multicenter, double-blind, placebo-controlled study aimed to evaluate the efficacy and safety of seltoplasmid in patients with Rutherford class 5 CLTI. This study

While mRNA vaccines have been effective in combating SARS-CoV-2, the waning of vaccine-induced antibody responses and lack of vaccine-induced respiratory tract immunity contribute to ongoing infection and transmission. In this work, we compare and contrast intranasal (i.n.) and intramuscular (i.m.) administration of a SARS-CoV-2 replicon vaccine delivered by a nanostructured lipid carrier (NLC). Both

Immunotherapy has revolutionized cancer treatment and complements traditional therapies, including surgery, chemotherapy, radiation therapy, and targeted therapies. Immunotherapy redirects the patient’s immune system against tumors via several immune-mediated approaches. Over the past few years, therapeutic immunization, which enable the patient’s T cells to better recognize and kill tumors, have been