Neurotrophic Factor Therapy in PD

Question 1

What are neurotrophic factors (NTFs)?

Answer 1

Endogenous proteins critical for normal brain development, also present throughout life, support brain function

Question 2

What is the aim of NTF therapy?

Answer 2

To utilise these nurturing, maturation-inducing proteins (NTFs) in adult Parkinson’s brain in order to stimulate development/ survival/ function of neurons
- Intervene while neurons are still there

Question 3

Main region of degeneration in Parkinson’s Disease

Answer 3

Nigrostriatal pathway of dopaminergic neurons

projecting from substantia nigra pars compacta in midbrain to forebrain, primarily caudate & putamen

Question 4

Issues with translation of NFTs

Answer 4

1. Do not cross BBB
   - Large proteins
   - Need to be injected directly into the brain - intracerebral injection
   - Invasive surgery for elderly, vulnerable patients
2. Rapidly metabolised
   - By enzymes in the brain
3. High impact of placebo effect on Parkinson’s patients
   - Possibly related to dysregulation of dopamine systems
   - Hope of a cure activates the dopamine-based reward pathway

Question 5

Animal models of NFTs

Answer 5

• 6-hydroxydopamine-lesioned rat (6-OHDA-lesioned): unilateral impairment of movement
• MPTP-lesion in monkeys: bilateral impairment

Question 6

Which NTF works best for cholinergic neurons?

Answer 6

GDNF

Question 7

Potential explanations for lack of preclinical to clinical translation

Answer 7

• Insufficient dosage
• Inadequate targeting of the putamen
• Patients enrolled are at advanced disease stages
• Pathological changes in the Parkinson’s brain not observed in preclinical models