CNS Drug Discovery

Question 1

What is Translational Science (TS)?

Answer 1

The process of converting scientific discoveries into clinical interventions that benefit patients.

Question 2

Phases of Translational Science

Answer 2

1. Preclinical Phase – Lab research to identify potential targets.
2. Proof of Mechanism (PoM) – Demonstrating molecular activity.
3. Proof of Principle (PoP) – Testing in animal models.
4. Proof of Concept (PoC) – Small-scale human trials.
5. Clinical Trials – Large-scale human testing.

Question 3

Factors Affecting Drug Discovery Success

Answer 3

1. Strong link between drug target and disease pathway.
2. Identifying the right patient population.
3. Clear path from research to clinical development.
4. Early identification of potential risks.

Question 4

Genetic diseases (e.g., oncology, rare diseases) have high success rates because

Answer 4

o Disease drivers are known (mutations in specific genes).
o Target ID is straightforward.

Question 5

CNS disorders (e.g., Alzheimer’s, schizophrenia) are much harder:

Answer 5

o Complex pathophysiology.
o Multiple contributing factors.
o Lack of clear genetic targets.

Question 6

Challenges in CNS Drug Discovery - Neurological Disorder

Answer 6

• Leading cause of disability-adjusted life years (DALYs).
• 2nd leading cause of death globally (~9 million deaths/year).
• Examples:
  o Neurodegenerative diseases (Alzheimer’s, Parkinson’s).
  o Psychiatric disorders (Schizophrenia, Depression).
  o Epilepsy, Stroke, Multiple Sclerosis.

Question 7

The “Valley of Death” in CNS Drug Development

Answer 7

• CNS drugs have the highest failure rate (~50% fail in Phase II/III clinical trials).
• Reasons for failure:
  o Poor understanding of disease mechanisms.
  o Inadequate drug delivery across the blood-brain barrier (BBB).
  o High variability in patient responses.
  o Lack of predictive animal models.

Question 8

How can we escape the Valley of Death?

Answer 8

1. Improve Target Identification and Validation.
2. Use advanced screening techniques.
3. Develop better biomarkers for patient selection.

Question 9

Genetic Approaches

Answer 9

• Genome-Wide Association Studies (GWAS):
  o Identifies common genetic variants associated with disease.
  o Example: Over 100 schizophrenia-related mutations found.
  o Limitation: Many have low disease association.
• Rare Variant Analysis:
  o Identifies mutations with strong disease effects.
  o Example: Alpha-1 antitrypsin deficiency (lung disease).
• Epigenetics:
  o Investigates how environmental factors modify gene expression.
  o Example: DNA methylation changes in Alzheimer’s Disease.

Question 10

2. Big Data & Single-Cell Sequencing

Answer 10

• Single-cell RNA sequencing (scRNA-seq):
  o Identifies cell-specific gene expression changes.
  o Helps map cellular pathways in CNS disorders.
• AI & Machine Learning:
  o Used for target mining.
  o Integrates data from genetics, proteomics, and metabolomics.

Question 11

3. Tissue-Based Target Validation

Answer 11

• Immunohistochemistry (IHC):
  o Identifies protein expression in tissues.
  o Issue: Low antibody specificity can limit findings.
• Lumbar Puncture (CSF Sampling):
  o Used for biomarker discovery.
  o Issue: Highly invasive, data can be variable.

Question 12

4. Phenotypic Screening

Answer 12

• Targets disease-relevant phenotypes without assuming mechanism.
• Example:
  o Ketamine was discovered as an antidepressant through phenotypic screening, not target-based methods.
• CRISPR/Cas9 & RNAi screening:
  o Gene knockouts for high-throughput drug target validation.

Question 13

How to Improve CNS Drug Discovery?

Answer 13

1. Understand disease pathology better.
2. Use multiple approaches for Target ID & Validation.
3. Leverage big data and AI.
4. Develop better biomarkers and patient selection strategies.
5. Move away from single-target approaches for complex CNS disorders.