L9: Regenerative strategies after injury

Question 1

List 7 molecular methods for nerve regeneration?

NCCPRGT

Answer 1

1. Anti-NOGO antibodies.
2. Chondroitinase (reduces scar)
3. cAMP analogues (growth cone remodelling)
4. Phosphodiesterase (increase cAMP)
5. Rho-GTPase
6. Gene therapy
7. Taxol

Question 2

How do Anti-NOGO antibodies and Taxol work?

Answer 2

Anti-Nogo-A: Block axon growth inhibitino. Sprouting axons seen in rodents.

Taxol: Stabilises microtubules and therefore interferes with microtubule breakdown. (actin dynamics in growth cone wont collapse)
Reduced glial scar size and foot slips in mice.

Question 3

One more method, and its findings in research?

Answer 3

Stem cells.
Transplantation improved motor performance in rat contusion.
Later, labelled with GFP and formed long dense fibres leading to significant motor improvements.

Question 4

What was the first study to modulate an intrinsic signalling pathway in the endogenous CST?

Answer 4

PTEN deletion. Activated mTOR caused abundant axon sprouting.

Question 5

Give 2 examples of when overexpression of transcription factors was used.

Answer 5

VP16-KLF7: Promotes CST sprouting and regeneration. THis did not lead to functional improvements however.

SOX11: Overexpression reduced net retraction of centrally injured axons.

Question 6

2 other non molecular methods for rehabilitation?

Answer 6

Electrical stimulation

Dopaminergic/Serotinergic stimulation.

Question 7

Describe how brain machine interface works?

Answer 7

Implant electrodes in cortex to record activity. Connected to implanted impulse generator, which is implanted past the lesion site. Motor cortex sends signals to stimulators, inducing movements and muscle contraction.

Question 8

How may CNS axon regrowth be switched off?

Answer 8

Epigenetics. Histones around axonal growth genes become condensed during development, and cells locked into dormant gene expression state. Epigenetic modifying programming could be therapeutic.

Question 9

How does PCAF work?

Answer 9

Promotes acetylation. This causes histone hyperacetylation and chromatin relaxation, promoting regeneration.

Question 10

List some signals that are switched off in the CNS but on in the PNS.

Answer 10

H3K9Ac
GAP43
Galanin
BDNF

Question 11

List some combinatorial approaches to regeneration.

Answer 11

Biomaterials (scaffolds?)
Cell transplantation
tissue transplantation
Pharmacology

Question 12

What are critical factors to be considered for SCI treatment using gene therapy?

Answer 12

• Route of administration
• Duration of effect
• Level of expression
• Off/On switching
• Toxicity
• Inflammatory reaction
• Specificity to cell populations
• Infectivity
• Stability of transgene
• Regulatory issues

Question 13

Criteria for drug therapies?

Answer 13

-Therapeutic window not restrictive
-Improves structural and functional outcomes
-Clinically relevant
Improvements seen in multiple animal models, clinically relevant end points.
-Major findings in peer reviewed journal