Last lec - neuroregen Flashcards
(26 cards)
The growing problem of neurodegen. diseases
Continuing to double
* Large economic and human burden
* Enormous investment in drug > 99% fail trials
Where does neurogenesis occur in the mammalian CNS?
In neurogenic NICHES
1. Subventricular zone (SVZ) lining the lateral ventricles.
2. Subgranular zone (SGZ) in the hippocampus.
Generate INTERNEURONS
What are the two strategies for CNS repair?
- Stimulation of endogenous neurogenesis.
- Neural transplantation.
1.Stimulation of endogenous neurogenesis
If injury occurs near one of the neurogenic niches, can encourage new neurons to migrate (will still form interneuron it was going to become)
2.Neural Transplantation.
Functional replacement of neuronal circuitry.
* Cells > directly into brain
First CNS grafting attempts
Grafting adult cat cortex into adult dog cortex (1890)
* Described cellular proliferation BUT was likely just inflammation
First success with embryonic grafts
Embryonic cortical tissue transplanted via inoculation (1940)
* Tissue is young enough to survive procedure
* Into adult brain
Functional cell grafting in the adult brain
Cells in an intermediate state of differentiation.
* Immature > survive the procedure BUT
* Specified > retain phenotype
Dopamine n. replacement in rat model
Transplant fetal tissue (containing dopamine neurons) to striatum ectopically
* Creates new terminal network
How did they model dopamine depletion in rats?
Lesion midbrain with 6-OHDA
* Typically do unilateral lesion
Principles of functional replacement of dopamine circuitry:
- Requires anatomical + functional integration
- Motor recovery proportional to striatal innervation
- Only DA N. of midbrain
- A9 subtype
Subtypes of neurons in midbrain (rodentt)
- A10 (VTA)
- A9 (SN)
A10 neurons
Project to Cx. + Limbic structures
* Small, round
* Reward
* Usually spared in PD
* Express Calbindin
A9 neurons
Project mainly to Striatum
* Large, pyramidal
* Motor
* SELECTIVELY degrade in PD
* Express Girk2
Cell arrangements in tissue grafts
Form VTA and SN from single cell suspension
* Middle graft > round/small n.
* Outside > larger/angular n.
* Indicate diff. subtypes
Why use GFP instead of TH to look at graft?
GFP shows what is innervating from graft, TH WON’T differentiate this
First clinical trials for tissue grafting in PD
80s addicts presented with “PD-like” symptoms
* Due to MPTP (toxic by-product of heroin)
* First patients to undegro transplant therapy
Open-label clinical trials for grafting in PD
90s-2000s
* >300 patients
* Some with >10y symptomatic relief
Stratification of 1st double-blind trial showed that…
Patients with less severe disease showed significant improvement
What is important forr patient selection in these grafting clinical trials?
- Less disease progression
- Younger
- Must be L-Dopa responsive
- Co-pathologies > not good candidates
What are the potential benefits of clinical studies for grafting?
Single treatment for long-term reversal of motor symptoms.
* W/o complications associated with chronic L- Dopa.
What are the potential problems of clinical studies for grafting?
- Variable outcomes
- Ethical concerns
- Impossible to standardise transplants
- Inefficient method for treating many patients
Induced pluripotent stem cells (iPSCs)
Reprogramming factor genes put in somatic cell > midbrain DA progenitors
* Much more ethical + expandable
* Can be standardised
Progression of iPSC therapy/studies
- 2005-09: first steps but saw tumors
- 2010-14: refinement, express markers, in-vitro specification
- 2015-20: anat + func integration, therapeutic efficacy, no tumors
