Project Background
A biotech research team was investigating TDP-43‒related pathology in ALS, aiming to identify therapeutic strategies with translational potential.
Their initial plan followed a standard workflow: in vitro screening → in vivo validation
However, given the complexity of ALS, this approach carried a high risk of late-stage failure.
Challenge
ALS is not a single-cell-type disease. It involves:
- Motor neuron degeneration
- Glial cell-mediated neuroinflammation
- Neuromuscular junction dysfunction
This created three critical risks in a cell-first strategy:
- False positives: compounds effective in isolated neurons but not in vivo
- Poor translation: inability to cross the blood-brain barrier (BBB)
- Misaligned endpoints: reduction of aggregation without functional benefit
In short: strong cell data does not guarantee functional efficacy
Our Strategy
We restructured the study into an outcome-driven workflow, prioritizing early in vivo decision-making.
Step 1 — Early Functional Screening (In Vivo)
Instead of starting from cell models, we initiated short-term intervention studies in a TDP-43 transgenic mouse model.
Key endpoints included:
- Motor function (rotarod, grip strength)
- Survival trend (early signal)
- Neuroinflammatory markers
Goal: rapidly identify compounds with real disease-modifying signals
Step 2 — Mechanism Elucidation (In Vitro Back-Translation)
Only compounds showing in vivo efficacy were advanced into mechanistic studies.
We designed targeted in vitro systems to answer:
- Which cell types are involved (neurons vs glial cells)?
- What is the mechanism of action?
- TDP-43 localization
- Autophagy modulation
- What are the dose and timing dependencies?
Platforms used:
- Primary neuron cultures
- Astrocyte co-culture systems
- iPSC-derived motor neurons
Results & Impact
This strategy enabled a more efficient and decision-oriented workflow:
- Earlier go/no-go decisions based on functional endpoints
- Reduced time spent on non-translatable candidates (~30‒40% estimated reduction in screening cycles)
- Improved alignment between preclinical signals and disease biology
Outcome: higher confidence in candidate selection before advancing
Key Takeaway
For complex neurodegenerative diseases like ALS:
- In vitro models explain mechanism (“why”)
- In vivo models validate effect (“does it work”)
Starting from functional outcomes significantly improves translational relevance
How We Support Similar Projects
We provide integrated support across:
- disease models (including neurodegenerative models)
- Functional efficacy evaluation platforms
- Mechanistic in vitro systems
- Study design tailored to decision milestones
Designed to help teams move from data generation → decision making
Call to Action
Not sure whether to start with in vitro or in vivo? We can help you design a study aligned with your project stage and decision goals.