M2+3 Therapeutic appraoches

Question 1

Therapeutic appraoches

*Gary Anderson Makes GFs In My Farm*

Answer 1

1. GCS
2. Anabolic agents (b-agonists/anabolic steroids)
3. Myostatin inhibitors
4. GF (IGF1)
5. IL15
6. Membrane sealants
7. Anti-fibrotic agents

Question 2

1) GC (catabolic)

Answer 2

• Maintain/↓ muscle fibre sizeSmall muscle fibre’s relationship to damage
  
  • Small fibre size could ↓ongoing damage to dystrophic muscles
    
    • May upregulate utrophin or modify muscle fibre phenotype
    • Counter chronic inflammation → may ↑/preservation of strength
• Mech:
  
  • Anti-inflam/immunosuppression of cytotoxic cells

Question 3

SE of GCs

Answer 3

• Weight gain, high BP, ulcers, growth inhibition
• But still ‘gold standard’ treatment

Question 4

VBP15

Answer 4

• novel anti-inflam and membrane-stabiliser → improves DMD without SE
• May ↓SE of prednisolone when used in conjunction

Question 5

2) Anabolic agents

Answer 5

• Grows muscle fibres and ↓inflammation
  
  • But may become more susceptible to contraction-mediated injury (hypothesis - which is shown to be false by b-agonists)

Question 6

B-agonists

Answer 6

• ↑muscle mass and size
• Transition from slow to fast muscle fibres (more glycolytic)
• Shows that ↑muscle size DOES NOT ↑susceptibility to contraction-induced injury → and actually shows better protection
• Preliminary trials:
  
  • Not very effective (but are using rather weak b-agonists)

Question 7

3) Myostatin inhibitors

Answer 7

• Myostatin acts to increase differentiation of muscles, which decreases muscle size
  
  • Anabolic (myostatin KO mice → 3x increase muscle mass)
• Genetic manipulation
• Neutralising AB

Question 8

4) GF (IGF1)

Answer 8

• Endogenous growth factor → for muscle growth and repair
• Improves muscle function in laminin deficiency Improves diaphragm function as well
• ↑ fibre size and number and ↓ fibrosis
• Improve oxidative capacity of the diaphragm

Question 9

SE of GF

Answer 9

• Effects on tumour growth (new/existing)

Question 10

5) IL15

Answer 10

• Myokine naturally released by muscles
• ↑ myoblast differentiation, ↓protein degradation, ↑protein syn, ↓protein BD
• Improve function of diaphragm in mdx mice
  
  • Due to ↓fibrosis

Question 11

6) Membrane sealant

Answer 11

• Poloxamer-188
• Plug holes in torn membrane → ↓in collagen

Question 12

7) Anti-fibrotic agents

Answer 12

• TGF-b inhibitors
• ↓fibrosis of diaphragm of mdx mice → but did not translate to improved force
• May potentially require co-therapies

Question 13

Effects of exercise training on DMD

Answer 13

• Needs to be very personalised → overworking causes more damage than benefits
• Mdx mice showed exercise avoidance behaviour
  
  • But exercise → improves function and fatigue
  • Also need to avoid eccentric contractions
• Diaphragm training → improve ventilation strength and endurance

Question 14

Effects of suspension

Answer 14

• Suspension → exacerbates pathology

Question 15

Results of inactivation of SERCA pumps in dystrophic muscles

Answer 15

• → overload of Ca → damage
• SERCA function also affected in dko mice
• ∴↑SERCA ameoliorate DMD

Question 16

Hsp72

Answer 16

• Induced by Hsp70
• Improves protein folding
• Interacts with SERCA and protects its structure and function
  
  • Protects against the thermal inactivation of SERCA
• Hsp72 overexpression ameliorates dystrophic pathology in mdx mcie
• Mech:
  
  • Potential contribution to improved myoproteostasis in DMD

Question 17

Pharmacological induction of Hsp72

Answer 17

• BGP-15 (more significant effect) & heat therapy → ↑Hsp72
• ∴BGP-15 improves pathology and survival even in dko mice
• Early intervention → ↓fibrotic infiltraion also in hearts of DMD mice

Question 18

What happens when Hsp70 is introduced at a later stage (older)

Answer 18

• Still have Hsp 72 induction from Hsp70, but no improvement in kyphosis of dko mice → pathlogy has already been established and is hard to modify
• Do still ↓fibroti infiltraion in hearts of DMD mice