A5004211070- Virus-based gene therapy research
- Herpesvirus Infections and Treatments
- Viral Infectious Diseases and Gene Expression in Insects
- Toxin Mechanisms and Immunotoxins
- RNA Interference and Gene Delivery
- Cancer Research and Treatments
- RNA modifications and cancer
- Ion channel regulation and function
- Extracellular vesicles in disease
- Neuroscience and Neuropharmacology Research
- Pain Mechanisms and Treatments
- Cytomegalovirus and herpesvirus research
- Viral gastroenteritis research and epidemiology
- Viral Infections and Immunology Research
- CAR-T cell therapy research
- Cancer-related gene regulation
- RNA Research and Splicing
- interferon and immune responses
- Nerve injury and regeneration
- Healthcare and Venom Research
- RNA and protein synthesis mechanisms
- Genomics and Chromatin Dynamics
- Microtubule and mitosis dynamics
- CRISPR and Genetic Engineering
- Glioma Diagnosis and Treatment
University of Pittsburgh
2010-2024
Casa Sollievo della Sofferenza
2009
Istituti di Ricovero e Cura a Carattere Scientifico
2009
Glioblastoma multiforme (GBM) remains an untreatable human brain malignancy. Despite promising preclinical studies using oncolytic herpes simplex virus (oHSV) vectors, efficacy in patients has been limited by inefficient replication tumor cells. This disappointing outcome can be attributed part to attenuating mutations engineered into these viruses prevent normal Alternatively, retargeting of fully replication-competent HSV tumor-associated receptors the potential achieve specificity without...
Glioblastoma multiforme (GBM) is an aggressive brain cancer for which there no effective treatment. Oncolytic HSV vectors (oHSVs) are attenuated lytic viruses that have shown promise in the treatment of human GBM models animals, but their efficacy early phase patient trials has been limited. Instead attenuating virus with mutations virulence genes, we engineered four copies recognition sequence miR-124 into 3'UTR essential ICP4 gene to protect healthy tissue against replication; expressed...
The use of mutant strains oncolytic herpes simplex virus (oHSV) in early-phase human clinical trials for the treatment glioblastoma multiforme (GBM) has proven safe, but limited efficacy suggests that more potent vector designs are required effective GBM therapy. Inadequate performance may derive from poor intratumoral replication and spread to uninfected cells. Vector be impaired by mutagenesis strategies achieve safety, hampered entrapment tumor-specific extracellular matrix (ECM) is...
Chronic pain is common and inadequately treated, making the development of safe effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition neuronal ER inositol trisphosphate receptor-1 (ITPR1) subsequent decrease calcium release reduction cytoplasmic free calcium, essential to regulation excitability. This study tested hypothesis novel JDNI8 replication-defective herpes simplex-1...
Pol32 is an accessory subunit of the replicative DNA Polymerase δ and translesion ζ. involved in replication, recombination repair. Pol32's participation high- low-fidelity processes, together with phenotypes arising from its disruption, imply multiple roles for this within eukaryotic cells, not all which have been fully elucidated. Using pol32 null mutants two partial loss-of-function alleles pol32rd1 pol32rds Drosophila melanogaster, we show that plays essential role promoting genome...
Transductional targeting of herpes simplex virus (HSV)-based gene therapy vectors offers the potential for improved tissue-specific delivery and can be achieved by modification viral entry machinery to incorporate ligands that bind desired cell surface proteins. The interaction nerve growth factor (NGF) with tropomyosin receptor kinase A (TrkA) is essential survival sensory neurons during development involved in chronic pain signaling. We targeted HSV infection TrkA-bearing cells replacing...
There are many well‐studied examples of human phenotypes resulting from nonsense or frameshift mutations that modulated by Nonsense‐Mediated mRNA Decay (NMD), a process typically degrades transcripts containing premature termination codons (PTCs) in order to prevent translation unnecessary aberrant transcripts. Different types germline the VHL gene cause von Hippel‐Lindau disease, dominantly inherited familial cancer syndrome with marked phenotypic variability and age‐dependent penetrance....
Recognition sequences for microRNAs (miRs) that are down-regulated in tumor cells have recently been used to render lytic viruses tumor-specific. Since different types down-regulate miRs, this strategy requires virus customization the target tumor. We explored a feature is shared by many types, up-regulation of miR-21, as means generate an oncolytic herpes simplex (HSV) applicable broad range cancers.We assembled expression construct dominant-negative (dn) form essential HSV replication...
Deletion analysis of mouse DNMT1, the primary maintenance methyltransferase in mammals, showed that most N-terminal regulatory domain (amino acid residues 412–1112) is required for its enzymatic activity. Although deletion mutants helps to identify regions a protein sequence particular activity, amino deletions can have drastic effects on structure and/or stability. Alternative approaches represented by rational design and directed evolution are resource demanding, require high-throughput...
Oncolytic herpes simplex viruses (oHSVs) have demonstrated efficient lytic replication in human glioblastoma tumors using immunodeficient mouse models, but early-phase clinical trials reported few complete responses. Potential reasons for the lack of efficacy are limited vector potency and suppressive glioma tumor microenvironment (TME). Here we compare oncolytic activity two HSV-1 vectors, a KOS-strain derivative KG4:T124 an F-strain rQNestin34.5v.1, CT2A GL261N4 murine syngeneic models....
Chronic pain is common in our population, and most of these patients are inadequately treated, making the development safer analgesics a high priority. Knee osteoarthritis ( OA ) primary cause chronic disability worldwide, lower extremity major contributor to loss quality-adjusted life-years. In this study we tested hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vector rdHSV incorporating modified carbonic anhydrase-8 transgene CA8* produces analgesia treats...
Abstract Glioblastoma Multiforme (GBM) is an aggressive brain cancer for which there no effective treatment. Oncolytic HSV vectors (oHSV) are attenuated lytic viruses that have shown promise in the treatment of human GBM models animals. Although proven safe patients, oHSVs efficacy has been limited, a consequence poor intra-tumoral virus replication and spread. To counter these limitations, we developed whose selective cells does not rely on defective genes. This was accomplished by (i) full...
Glioblastoma Multiforme (GBM) is an aggressive brain cancer for which there no effective treatment. Oncolytic HSV vectors (oHSV) are attenuated lytic viruses that have shown promise in the treatment of human GBM models animals. Although proven safe patients, oHSVs efficacy has been limited, a consequence poor intra-tumoral virus replication and spread. To counter these limitations, we developed whose selective cells does not rely on defective genes. This was accomplished by (i) full...
Abstract Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment GBM, but efficacy has been limited. Impediments to oHSV therapy include poor spread due part tumor extracellular matrix, and insufficient replication cells as a result attenuating mutations. Thus, central goal this project is improve vector delivery, while maintaining safety specificity. We already developed new class two stage targeted...
Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment GBM, but efficacy has been limited. Impediments to oHSV therapy include poor spread due part tumor extracellular matrix, and insufficient replication cells as a result attenuating mutations. Thus, central goal this project is improve vector delivery, while maintaining safety specificity. We already developed new class two stage targeted combining (i)...
Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment glioblastoma multiforme, but efficacy has been limited. Impediments to oHSV therapy include poor spread due part tumor extracellular matrix, and insufficient replication cells as a result attenuating mutations. Thus, our central goal was improve vector delivery, replication, while maintaining safety specificity. We had already developed new class two...
Gene therapy often requires selective gene delivery to specific cellular subpopulations provide the most effective therapeutic outcome and avoid off-target effects. This can be accomplished by viral vector targeting involving replacement of natural virus-cell interactions that trigger virus entry, with novel cell-specific interactions, thereby permitting transgenes cell types. Strategies for full retargeting HSV require (i) mutagenesis-mediated detargeting from its cognate receptors (HVEM...
Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment GBM, but efficacy has been limited. Impediments to oHSV therapy include poor spread due part tumor extracellular matrix, and insufficient replication cells as a result attenuating mutations. Thus, central goal this project is improve vector delivery, while maintaining safety specificity. We already developed new class two stage targeted combining (i)...
Gene therapy approaches to treat chronic pain have been limited by short-term duration, the inability turn off therapeutic gene expression avoid unwanted side-effects or tolerance. To overcome this, we employed replication-defective herpes simplex virus (rdHSV) vectors expressing glycine receptor alpha-1 (GlyRa1) subunit silence pain-signaling neurons in a variety of models upon addition glyine. However, window was small since centrally occurring GlyR spinal cord were activated at higher...
Chronic pain represents a major cause of morbidity and effective therapy remains significant unmet medical need. The standard care relies primarily on systemic drug therapies that do not target the site sensation. These often have limited effectiveness, deleterious side effects, ,induce tolerance. Herpes simplex viruses (HSV)-based gene vectors offer an attractive alternative to since therapeutic genes can be delivered sensory nerve afferents where is arising. Our goal develop...