How Clinical Development Can, and Should, Inform Translational Science

Abstract

There is an urgent need for preclinical translational efforts to be realized as breakthroughs in therapy for the many patients with life-altering conditions affecting the CNS. Despite intensive efforts, few transformative therapies have emerged, and many new potential therapies that looked promising in preclinical development have failed in the clinic. In this Perspective, we suggest that if preclinical scientists partner early with clinical scientists, they can begin to envision the pathway forward for their work through clinical trials. Options might include determining the populations to be treated, issues of dose selection, timing of intervention, duration of intervention, and the availability of biomarkers. In addition, understanding other factors that impact the likelihood that a proof-of-concept trial can be performed, as well as other critical issues, will altogether increase the attractiveness of the project to investors and partners and will also increase the likelihood that the intervention will succeed in the clinic.

Evaluating an Etiologically Relevant Platform for Therapy Development for Temporal Lobe Epilepsy: Effects of Carbamazepine and Valproic Acid on Acute Seizures and Chronic Behavioral Comorbidities in the Theiler’s Murine Encephalomyelitis Virus Mouse Model

“…However, the present results suggest that the TMEV model has the potential to identify compounds possessing both acute seizure-suppressive effects and long-term disease-modifying potential. It is difficult to evaluate an antiepileptogenic effect of ASD treatment in post-traumatic or infection-induced epilepsy in clinical trials due to the low incidence of acquired epilepsy (Annegers et al, 1988(Annegers et al, , 1998Barker-Haliski et al, 2014a), most likely a cause of many clinical failures of antiepileptogenesis trials (Mani et al, 2011). Moreover, prior attempts at antiepileptogenesis with ASDs have come with considerable adverse effects on cognition and general health outcomes that have limited the complete evaluation of any antiepileptic effect (Dikmen et al, 1991).…”

“…Additionally, the long-term effects of acute therapeutic intervention on associated anxiety-like behavior (Umpierre et al, 2014) and neuropathology (Stewart et al, 2010a,b) known to develop after the acute viral infection were evaluated. Novel and symptom-specific models are of high value to translational research endeavors (Barker-Haliski et al, 2014a); therefore, characterizing the pharmacological profile of these models with known ASDs is necessary before any novel therapy is likely to advance to the clinic. The TMEV model of viral encephalitis-induced epilepsy thus provides an etiologically relevant platform to evaluate compounds with the potential for acute seizure-suppressive, and possibly disease-modifying, effects.…”

Potent Anti-seizure Effects of Locked Nucleic Acid Antagomirs Targeting miR-134 in Multiple Mouse and Rat Models of Epilepsy

“…Anti-epileptic drugs (AEDs) are effective at controlling seizures in many patients, acting through a range of neuronal targets, including ion channels, neurotransmitter release, and receptor mechanisms 1, 2. However, a third of patients with epilepsy fail to achieve seizure freedom, and current AEDs do not show disease-modifying properties.…”

“…However, a third of patients with epilepsy fail to achieve seizure freedom, and current AEDs do not show disease-modifying properties. Future treatments for epilepsy need to differentiate from currently marketed drugs, for example, by having a novel mechanism(s) of action or providing disease-modifying effects 1, 2…”

“…There are also barriers to antisense-based approaches and there has been some disengagement of industry from pursuing such efforts 25 . This is likely to be a problem for any new therapy for epilepsy, particularly one that is not based on traditional small molecule chemistry 1, 2. Pre-clinical development of an miR-134-based treatment for epilepsy might be more attractive if additional important questions are answered.…”