Association of a protease with polytene chromosomes of Drosophila melanogaster

Incubation of Drosophila salivary glands with radioactive diisopropyl fluorophosphate results in the uniform labeling of polytene chromosomes. Extensive labeling is seen only when chromosome squashes are prepared by a formaldehyde fixation procedure and not by standard acetic acid techniques. The labeling is inhibited in the presence of tosylphenylalanine chloromethyl ketone and phenylmethane sulfonylfluoride but not by tosyllysine chloromethyl ketone, suggesting that a chymotrypsin-like serine protease is associated with the chromosomes. Protease inhibitors show no apparent effect on heat-shock specific puffing

Not reinventing the wheel – applying 3Rs concepts to viral vector gene therapy biodistribution studies

In pharmaceutical drug development, information on where a drug distributes within the body is helpful in understanding the overall chemical and/or biological characteristics of the compound. This is typically assessed preclinically in relevant animal species that are often used for the formal safety studies (toxicology, pharmacokinetics and drug metabolism. One accepted principle of animal studies is the application of the “3 R’s concept” (replacement, refinement and reduction http://www.nc3rs.org.uk/) to reduce animal use as far as makes sense. The focus of this article is to suggest that, for gene therapy biodistribution studies, reductions in animal use could be rationally achieved with no increase in clinical risk

Pre-clinical Specificity and Safety of UC-961, a First-In-Class Monoclonal Antibody Targeting ROR1.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen. Because of its expression on the cell surface of leukemia cells from patients with chronic lymphocytic leukemia (CLL), but not on normal B-cells or other postpartum tissues, ROR1 is an attractive candidate for targeted therapies. UC-961 is a first-in-class humanized monoclonal antibody that binds the extracellular domain of ROR1. In this article we outline some of the preclinical studies leading to an investigational new drug designation, enabling clinical studies in patients with CLL

Clinical Expert Panel on Monitoring Potential Lung Toxicity of Inhaled Oligonucleotides: Consensus Points and Recommendations

Oligonucleotides (ONs) are an emerging class of drugs being developed for the treatment of a wide variety of diseases including the treatment of respiratory diseases by the inhalation route. As a class, their toxicity on human lungs has not been fully characterized, and predictive toxicity biomarkers have not been identified. To that end, identification of sensitive methods and biomarkers that can detect toxicity in humans before any long term and/or irreversible side effects occur would be helpful. In light of the public's greater interests, the Inhalation Subcommittee of the Oligonucleotide Safety Working Group (OSWG) held expert panel discussions focusing on the potential toxicity of inhaled ONs and assessing the strengths and weaknesses of different monitoring techniques for use during the clinical evaluation of inhaled ON candidates. This white paper summarizes the key discussions and captures the panelists' perspectives and recommendations which, we propose, could be used as a framework to guide both industry and regulatory scientists in future clinical research to characterize and monitor the short and long term lung response to inhaled ONs