CNS Drug Targets

Question 1

Whats the hardest thing about developing drugs for the CNS?

Answer 1

Finding targets and modelling pathologies in the brain

Question 2

What needs to be known to generate CNS drug targets?

Answer 2

• How pathological events affect cell survival/ disease progression
• Pathogenesis
• Molecular and cellular events
• Identification of molecular events i.e the genes responsible for huntingtons disease

Lots of stuff to be learnt for CNS pathology

Question 3

If molecular events are indentified, then what can this allow?

Answer 3

• Halt/ prevention of disease

- protect cells from dying (inflammation, bystander affect)

Question 4

Whats an example of a CNS disease we want to treat?

Answer 4

Huntingtons

Question 5

What is huntingtons?

Answer 5

• Movement disorder
• selective loss of GABA spiny mdeium interneurons in the striatum / basal ganglia.
• Due to expanded CAG section in DNA normal 20 repeats, instead 36+
• Produces mutant huntingtin (Hh)
• Autosomal dominant
• Depression and psychiatric affects

Question 6

What role does BDNF play in HD?

Answer 6

Transport of BDNF is impaired in HD
- Due to mutant Htt
BDNF supports and protects GABA medium spiny interneurons, Htt mutation can no longer transport BDNF from cortex to striatum and MSN die from excitotoxicity

Question 7

This lack of BDNF means what?

Answer 7

BDNF may be a replacement target therapy option.

Question 8

How is HD modeled?

Answer 8

IPS cells from HD patients used.
- Differentiate in MSNs
(in vitro disease model)

Removal of BDNF during MSN development leads to fast rate of neuronal death during HD disease.

Question 9

In the HD disease model did replacement BDNF help?

Answer 9

yes it did

Question 10

How did they model HD initially in vivo?

Answer 10

Using normal rats, they injected quinilonic acid, to create a lesion model of HD (selectively kills MSN) (QA is formed in HD)

They then administered BDNF

Question 11

How was BDNF administered?

Answer 11

Cant cross the BBB therefore they injected directly into the model or used viral vectors. (AAV-BDNF)

Question 12

How did they know the rats had HD in the normal rat model?

Answer 12

3 weeks post unilateral QA lesion, the rats performed a test and favored one paw and tested sensorimotor function for 8 weeks

(One subset of mice received BDNF from viral vector at 3 weeks, after they knew they had HD)

Question 13

What was observed in the HD rats, between no BDNF and BDNF receiving rats?

Answer 13

BDNF protected MSN and prevented QA induced sensorimotor function impairment compared to the untreated rats, therefore from 3 weeks on those rats with BDNF suffered far less further HD associated degeneration.

Question 14

What was the next step in experimentation once they had used normal rats but induced QA lesions to model huntingtons?

Answer 14

The use of Transgenic HD rats

Question 15

Whats special about transgenic HD rats?

Answer 15

They were genetically bred to carry 51 CAG repeats
- therefore they will have progressive sensorimotor symptoms and cell loss starting around 6 months since birth.

(behavioral impairment first though)

Question 16

What was the timeline for transgenic HD rats to recieve treatment?

Answer 16

At 3 months, presymptoms, some rats received the AAV-BDNF

Then till 18 months all rats were made to to sensorimotor function tests to observe differences.

(both male and female rats were used)

Question 17

What was observed from the transgenic HD rats?

Answer 17

• AAV-BDNF prevented and reduced sensorimotor function impairment and the progressive loss of MSNs in tgHD rats
• Female rats had less sensorimotor loss and performed behavioral tests better. Also improved significantly better.

Question 18

So what is the summery of these experiments for HD?

Answer 18

BDNF is a potential therapy.
tgHD rats have better validity in this instance
The next step is safety profile of this treatment

Question 19

What is ms?

Answer 19

An autoimmune disease that results in brain degeneration

Question 20

What is currently used to treat MS?

Answer 20

Anti-psychotic agents i.e clozapine as they have antinflammatory properties. (known as a dirty drug as works on a range of receptors)

Question 21

Whats an in-vivo model of MS?

Answer 21

EAE model

• progressive degeneration of WMT
• paralysis

Question 22

What does clozapine do to the in vivo model?

Answer 22

Reduces disease progression and number of lesions

Question 23

What in vitro model was used for MS?

Answer 23

Primary human cells. = LPS stimulated macrophages.

Question 24

What was done in the in vitro model?

Answer 24

LPS stimulated macrophages produced IL-12 a proinflam marker. Modulates the immune system. Clozapine and respiradole reduced IL12 and increase IL10 (anti-inflam)

Question 25

Based on invitro models what antipsychotic agent is being used in clinical trials in NZ?

Answer 25

Clozapine

Question 26

Whats the benefit of examining current durugs for new uses?

Answer 26

Known safety profile

Fast tracked for approval if it works.