Considerations in the Design of Non-Clinical Development Programmes to Support Non-Viral Genetically Modified Mesenchymal Stromal Cell Therapies.

Due to their immune suppressive pharmacology, regenerative capacity, and immune privileged status, mesenchymal stromal cells (MSCs) are an attractive cell type to treat a variety of diseases. Genetically engineered MSCs are currently in non-clinical and clinical development for a wide range of applications including the delivery of pro-drugs and therapeutic proteins or modified to enhance their regenerative potential. Unmodified MSCs have been shown to have good safety profiles in clinical development.

A rapid, reproducible, noninvasive predictor of liver graft survival.

Background: Clinical and laboratory criteria are not reliable predictors of deceased donor liver graft quality. Intraoperative assessment of experienced surgeons is the gold standard. Standardizing and quantifying this assessment is especially needed now that regional sharing is the rule.

Assessment of hepatic steatosis by transplant surgeon and expert pathologist: a prospective, double-blind evaluation of 201 donor livers.

An accurate clinical assessment of hepatic steatosis before transplantation is critical for successful outcomes after liver transplantation, especially if a pathologist is not available at the time of procurement. This prospective study investigated the surgeon's accuracy in predicting hepatic steatosis and organ quality in 201 adult donor livers. A steatosis assessment by a blinded expert pathologist served as the reference gold standard.

Activation of cyclic adenosine monophosphate-dependent protein kinase a signaling prevents liver ischemia/reperfusion injury in mice.

Hepatic ischemia/reperfusion injury (IRI) occurs in multiple clinical settings, including liver transplantation. The cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway inhibits hepatocellular apoptosis and regulates toll-like receptor 4-triggered inflammation responses in vitro. Here we examined the function and therapeutic potential of cAMP-PKA activation in a murine (C57/BL6) model of liver warm ischemia (90 minutes) followed by reperfusion.

In vitro cytokine release assays: reducing the risk of adverse events in man.

The induction of cytokine release is a common consequence of the administration of therapeutic antibodies and in most cases is either tolerated by the patient or can be managed clinically by the administration of corticosteroids. However, in 2006, the administration of TGN1412 to six patients in a Phase I trial resulted in a unprecedentedly high level of cytokine release, systemic organ failure and the hospitalization of the subjects. Whilst the path to failure in this incident was multifactorial, at least one contributing factor was the lack of a robust in vitro model that would allow the prediction of the in vivo activity of a therapeutic antibody.

The design of chronic toxicology studies of monoclonal antibodies: implications for the reduction in use of non-human primates.

The changing environment of monoclonal antibody (mAb) development is impacting on the cost of drug development and the use of experimental animals, particularly non-human primates (NHPs). The drive to reduce these costs is huge and involves rethinking and improving nonclinical studies to make them more efficient and more predictive of man. While NHP use might be unavoidable in many cases because of the exquisite specificity and consequent species selectivity of mAbs, our increasing knowledge base can be used to improve drug development and maximise the output of experimental data.

Preclinical development of monoclonal antibodies: considerations for the use of non-human primates.

The development of mAbs remains high on the therapeutic agenda for the majority of pharmaceutical and biotechnology companies. Often, the only relevant species for preclinical safety assessment of mAbs are non-human primates (NHPs), and this raises important scientific, ethical and economic issues. To investigate evidence-based opportunities to minimize the use of NHPs, an expert working group with representatives from leading pharmaceutical and biotechnology companies, contract research organizations and institutes from Europe and the USA, has shared and analyzed data on mAbs for a range of therapeutic areas.