31 research outputs found
Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses
Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can “cloak” the vector from inducing unwanted immune responses in multiple, but not all, models. This “coupled immunomodulation” strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods
Platelet-rich plasma (PRP): an adjuvant to hasten hamstring muscle recovery. A randomized controlled trial protocol (ISCRTN66528592)
Analysis method for PCBs in reclaimed oil using a fast-GC triple stage quadrupole mass spectrometer with the 13-component quantitation method
Sexual Health Counselor Preferences of African American and European American Women: A Brief Report
Moderate tidal volumes and oxygen exposure during initiation of ventilation in preterm fetal sheep
Heroin intoxication in a dog
peer reviewedAn 11-month-old intact male boxer cross was presented unconscious following oral heroin consumption. At home, intramuscular naloxone given by the owner showed no obvious improvements. Intravenous naloxone given in the hospital quickly reversed the clinical signs. The owners were not able to afford hospitalisation and the animal was discharged against medical advice. No signs of rebound opioid toxicity were reported. This case report describes the clinical presentation and treatment of a case of heroin intoxication in a dog