Armin Curt
Title:
Translational research: are neural stemcells safe in human SCI?
The translation of preclinical knowledge into the therapeutic application in humans is inherently challenged by many unpredictable interactions and effects. Safety issues reside
but are not limited to toxicological effects, an area where pharmacology has rather well
established pathways to estimate adverse events (like the therapeutic index defined as
the LD 50/ED50 (LD=letal dose; ED=effective dose)). The latter are related to organ specific
or systemic effects while reference values (i.e. levels of confidence) can be employed
from various established animal models. However safety aspects related to the mode of
application (like surgical procedures) are less established and common landmarks of safety are not yet well understood. Measures of efficacy as applied in human studies are even
less related or predictable based on outcome measures gained in animal studies (like the
BBB score in rats). There are no established relations between observed changes of
(sensori-)motor functions in animals (like ambulation or upper limb function) to potential
effects in humans (true not only for rodents but also non-human primates). This is even
more complicated when the potential magnitude of improvement (beneficial expectation)
needs to be balanced against safety concerns (risk of adverse events) to consider the
initiation of a clinical trial. Nevertheless these challenges don’t argue per se against the
initiation of clinical trials but ask for the introduction of rigorous trial protocols that are positioned to discern both subtle aspects of safety and efficacy. The obvious challenges in
translational research can be only overcome by a consorted interaction of basic and clinical research with the application of innovative trial protocols that are beyond rather basic
outcome measures (like ASIA scores).
Session
Cellular Therapy Clinical Trials in SCI: Which Cell? Which Patients? Which Outcomes?
Title:
Development of appropriate stratification and outcome algorithms in clinical SCI trials
Research discoveries and their translation into clinical applications are predominantly hypothesis driven with the assumption that detailed and rather specific drug or cell effects
might be achieved that eventually translate into a changed (obviously improved) outcome
in patients. Therefore, clinical trial protocols need to meet these specific requirements to
allow for a best stratification of patients (patients that will most likely respond successfully
to the intervention) and identification of outcome measures that are most sensitive to reveal changes (i.e. improvements) which are considered to be amendable by the specific
mode of action. So far most SCI trials apply rather unspecific outcome measures (like
ASIA scores) that although are of clinical relevance (albeit MCID issues are not yet resolved) are not able to reveal underlying mechanisms of recovery in SCI. This creates a
dilemma where the considered interventions are rather specific (it has to be admitted that
in many interventions the main mode of action is at best hypothesized and not necessarily
proven) but clinical trial protocols fail to monitor the mode of actions (both in the sense of
drug/cell activity and specific consequences in body function). This remains the field in the
unfortunate situation that translational information gained in clinical trials mirrored back to
basic research are rather weak (if any) and the potential reasons in failures of interventions (like complete failure or insufficient induction of drug/cell activity etc.) can not be discerned which is a requirement to modify interventions for an improved efficacy. In this
aspect SCI research falls behind other areas in neuroscience (like MS research) where
also surrogates have been successfully introduced to overcome the above mentioned
shortcomings.