Validation of Anti-Adeno Associated Virus Serotype rh10 (AAVrh.10) Total and Neutralizing Antibody Immunogenicity Assays.

Immunogenicity assessment of Adeno-Associated Virus (AAV) vectors is a critical part of gene therapy drug development. Whether the assays are used for inclusion/exclusion criteria or to monitor the safety and efficacy of the gene therapy, they are critical bioanalytical assessments. While total anti-AAV assays are perceived as easier to develop and implement than neutralizing anti-AAV assays, the gene therapy field is still nascent, and it is not yet clear which of the assays should be implemented at what stage of drug development. Recently AAVrh.10 has gained interest for use in gene therapies targeting cardiac, neurological, and other diseases due to its enhanced transduction efficiency. There is limited information on anti-AAVrh.10 antibodies and their clinical impact; thus, the information presented herein documents the validation of both a total antibody assay (TAb) and a neutralizing antibody (NAb) assay for anti-AAVrh.10 antibodies. In this manuscript, the validation was performed in accordance with the 2019 FDA immunogenicity guidance with additional evaluations to comply with CLIA where applicable. The AAVrh.10 TAb and NAb assays were compared in terms of sensitivity, drug tolerance, and precision, along with a concordance analysis using the same individual serum samples. This comparison gave insight into the utility of each format as a screening assay for inclusion into clinical studies.

Impaired consciousness, hypokalaemia and renal tubular acidosis in sustained Nurofen Plus abuse.

Ibuprofen-induced renal tubular acidosis is a rare but important diagnosis which should be considered in patients presenting with hypokalaemia and metabolic acidosis. This case report details the case of a 33-year-old woman presenting with reduced conscious state, metabolic acidosis and profound hypokalaemia without an obvious cause. With correction of the patient's electrolyte and acid-base disturbance, her conscious state improved allowing disclosure of her use of Nurofen Plus for its euphoric opiate effects. The diagnosis of renal tubular acidosis had been considered and subsequent disclosure of excessive chronic ingestion of ibuprofen suggested this to be the underlying cause. The striking feature of our patient was the insidious development of the problem and delayed accurate drug history. An important safety message arising from our case is the composite risk of dependence on the opiate component of over the counter analgesics, such as Nurofen Plus, and adverse events related to the ibuprofen component.

Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model.

BACKGROUND: Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. METHODOLOGY/PRINCIPLE FINDINGS: EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). CONCLUSIONS/SIGNIFICANCE: Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma.

A case report of an 80 year old man with mesenteric panniculitis, a raised lactate and hyperglycaemia.

INTRODUCTION: Mesenteric panniculitis is a rare condition which presents as abdominal pain. It involves benign inflammatory or fibrotic changes affecting the mesentery of the bowel. PRESENTATION OF CASE: An 80 year old man presented with severe abdominal pain of acute onset. He was found to have a high lactate and high blood glucose. He was not a known diabetic. A computed tomography (CT) scan revealed a diagnosis of mesenteric panniculitis, and the patient rapidly responded to steroid treatment. DISCUSSION: Mesenteric panniculitis has been known to present as an acute abdomen. However, an associated high lactate and hyperglycaemia is hitherto unreported in the literature. With no obvious precipitant for an increased lactate, we propose it is potentially caused by the subsequent fat necrosis and regional ischaemia associated with mesenteric panniculitis. CONCLUSION: This case report underlines the importance of further research into the relationship between mesenteric panniculitis, a high lactate, and diabetes. In addition, short term steroid treatment (one month) seemed to confer the same benefit as long term steroid treatment.