week 11 part 2 Flashcards
Why are clinical trials necessary?
- Spontaneous recovery
- Placebo effect
- Safety
What is spontaneous recovery?
- Complete paralysis often occur immediately after SCI, but after time, spontaneous recovery can occur
- Rate of recovery greatest at 1st 3 months, but can continue for over a year
Placebo effect
- Patients with SCI are often desperate for recovery
2. Patients treated with placebo often report an improvement
What is the safety of the clinical trials?
- danger that treatment do not work effectively
2. Danger that treatment can be harmful (tumour, syingomyelia)
Phase 0
- Pharmacokinetics and toxicity of IND*
2. Very small number (~10 healthy individually)
Phase I
- Safety
2. Small number (20-100) of patients provided with treatment
Phase II
- Positive effect
2. Compare patients treated vs control in a larger cohort (100-300)
Phase III
- Positive effect in large cohort
2. Compared patients treated vs control in a large cohort (300-3,000)
What is the purpose of AIS?
- Standardize careful, detailed documentation of spinal cord injuries
- Guide further radiographic assessment and treatment
- Determine whether injuries are complete or incomplete
- Help predict recovery of autonomic function such as bowel, bladder, cardiovascular, respiratory and reproductive function
What does AIS consist of?
- Myotomal-based motor examination
- Dermatomal based sensory examination
- Anorectal examination
What does the sensory examination of AIS evaluate?
- 28 specific dermatomes bilaterally for light touch (generally a piece of cotton) and pinprick (generally a clean safety pin) sensation
What are the different grades for AIS?
- A grade of 0 - absent sensation
- A grade of 1 - impaired or altered sensation
- A grade of 2 - normal sensation
What does the motor examination consist of?
- Grading 5 specific muscle groups in the upper extremities and 5 specific muscle groups in the lower extremities
What is a complete spinal cord injury defined as?
- The absence of all motor and sensory function
2. Designated as being Grade A on the AIS
What is incomplete injury defined as?
- Some degree of retained motor or sensory function below the site of injury
Patients with AIS grade B injuries
- Some sensory function
2. No motor function
Patients with AIS grade C injuries
- Motor grade less than 3 below the neurologic level of injury
Patients with AIS grade D
- Motor grade of at least 3 below neurologic level of injury
Patients with AIS grade E
- Normal motor and sensory examinations
2. But still have abnormal reflexes or other neurologic phenomena
Grade A
- Complete
2. No motor or sensory function is preserved in the sacral segment S4-S5
Grade B
- Incomplete
- Sensory function preserved but no motor function is preserved below the neurological level and includes sacral segment S4-S5
Grade C
- Incomplete
- Motor function is preserved below the neurological level
- muscle grade less than 3
Grade D
- Incomplete
- Motor function preserved below neurological level
- At ;east half of the key muscles below neurological level have a muscle grade of 3 or more
Grade E
- Normal
2. Motor and sensory function are normal
What results show that differentiated oligodendrocytes express non permissive substrate properties?
- Importance in CNS development or regeneration
- Immature oligodendrocytes were frequently contacted by neurons and neurites
- Differentiated oligodendrocytes (O4+, A2B5-, GalC+) represented a nonpermissive substrate for neuronal adhesion and neurite growth
What was differentiated oligodendrocytes nonpermissive for?
- Cell adhesion
- Neurite growth
- Fibroblast spreading
What was nonpermissive oligodendroyctes characterised by?
- Radial, highly branched process network
2. Often contain myelin basic protein
What is Nogo expressed by?
Oligodendrocytes but not schwann cells
Associate primarily with the endoplasmic reticulum
What does a 66-residue lumenal/extracellular domain inhibit?
Axonal extension and collapses dorsal root ganglion growth cones
What is the failure of regeneration of severed axons in adult mammalian central nervous system thought to be due to?
Presence of endogenous inhibitors of axon regeneration
What is the evidence that Nogo alone is not sufficient to induce axon regeneration?
- Determine whether deletion of nogo enhances regenerative ability
- Generated two lines of mutant mice - one mice lacking Nogo-A and -B but not C and one deficient in all 3 isoforms (Nogo-A/B/C) mutant
- Although Nogo-A/B deficient myelin has reduced inhibitory activity in a neurite outgrowth assay in vitro, tracing of corticospinal tract fibres after dorsal hemisection of the spinal cord did not reveal an obvious increase in regeneration or sprouting of these fibers in either mice line
What was the Anti-Nogo study?
- Blockade of Nogo-A or its receptor(Reticulon 4 receptor or Nogo-66 receptor) with neutralizing antibodies or by peptides or fusion proteins in SCI lead to enhanced sprouting and regeneration of injured axons
Where is Nogo-66 expressed?
On the surface of oligodendrocytes and can inhibit axonal outgrowth through axonal Nogo-66 receptor
What does monoclonal antibody recognise?
- Nogo A and promote corticospinal tract regeneration and locomotor recovery
What promotes regenerative neurite growth and functional recovery?
Inthrathecal delivery of anti-Nogo-A antbodies
What did the first-in-man study assess?
The feasibility, safety, tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A antibody ATI355 following intrathecal administation in patients with acute, complete traumatic paraplegia and tetraplegia
What was the conclusion of the first-in-man study?
ATI335 was well tolerated in humans, efficacy trial using intrathecal antibody administration may be considered in acute SCI
What 3 inhibitory proteins is axon regeneration after injury to adult mammalian CNS limited by?
- Nogo A
- MAG
3, Omgp
What do the inhibitory proteins bind ti?
Nogo-66 receptor to inhibit axonal outgrowth in vitro
