Lecture 9 - Glial Biology II

Question 1

why did Geron use a hESC line (H1) to produce Oligodendrocyte Progenitor Cells [GRNOPC1] for transplantation?

Answer 1

Oligodendrocytes are lost in spinal cord injury, myelin and neuronal loss that cause paralysis in many patients with spinal cord injuries.

Question 2

geron
Investigative New Drug application (IND) 2009: preclinical rat studies

what were the results?

Answer 2

1. No teratoma formation
2. No acute/chronic systemic toxicity & absence of systemic migration of GRNOPC1 outside the nervous system.
3. Absence of allodyonia (pain induced by non-noxious stimuli)
4. Absence of allogenic Immune response to cells.
   Allogenic: “Taken from different individuals Of the same species”

Question 3

What did Geron find about onset of treatment in the clinical program?

Answer 3

Patients — subacute ‘contusion’ injuries. Treated with cells within 7-14 days of injury. > 3months of injury — scarring occurs and treatment is ineffective.

Question 4

How did it all began — science behind Clinical utility
Evidence based CASE I:
“Human Embryonic Stem Cells Differentiate into Oligodendrocytes in High Purity and Myelinate After Spinal Cord Transplantation”.

What was the objective and technical challenges?

Answer 4

Objective
Produce terminally differentiated stem cells that can myelinate axons.

Technical challenge
Directing stem cell differentiation into oligodendrocyte
Produce enough cells for transplantation.

Question 5

Evidence based CASE Il:
“Human Embryonic Stem Cell-Derived Oligodendrocyte Progen*tor Cell Transplants Remyelinate and Restore Locomotion after Spinal Cord Injury”.

What was the aim and results?

Answer 5

Aim: High-purity differentiated OPCs transplanted into spinal cord injury (SCI)
sites in rats 7d or 10 months after injury.

Locomotion is significantly improved BBB (Basso, Beattie, and Bresnahan scale - test of locomotion)

Transportation done with 10 months old injury - no improvements
Therapeutic window exceeded due to scar

Question 6

Evidence based CASE Ill:
“Oligodendrocyte Progenitor Cells Derived from Human Embryonic Stem Cells Express Neurotrophic Factors”.

What was found?

Answer 6

Some but not all neurotrophic factors are secreted by OPCs.

Trophic effects of transplanted cells may also improve function by reducing endogenous cell death and promoting axonal regeneration.

Question 7

Evidence based CASE IV:
GDNF modifies reactive astrogliosis allowing robust axonal regeneration through Schwann cell-seeded guidance channels after spinal cord injury”

What was found?

Answer 7

Glial cell line-derived neurotrophic factor (GDNF) + transplanted Schwann cells (SCs) : reversed the inhibitory properties of astrocytes at graft—host interfaces allowing robust axonal regeneration in hemisection of spinal cord.

Question 8

What are some Challenges in Cell Therapies?

Answer 8

Some issues
- Cell line may not be autologous and not all stem cells are identical.
- Immunologically different from host (use of IPSC?).
- Cell Manufacturing (QC/QA in production)
- Epigenetic status/ Genetic stability.
- Tetratomas in long term if using ES.