10: neurotrophics 2

Question 1

3 types of central administration

Answer 1

intraparenchymal. intracerebroventricular. intranasal

Question 2

intraparenchymal admin?

Answer 2

direct injection/infusion/implantation of a polymer matrix preloaded with NTF or gene therapy

Question 3

intracerebroventricular admin?

Answer 3

delivers agent directly into lateral ventrical with subsequent circulation in the CSF of the ventricular system and subarachnoid spaces

Question 4

intracerebroventricular infusion of NGF into adult monkeys?

Answer 4

prevented cholinergic neuronal degeneration BUT significant toxic effects (sympathetic axons sprout and surround cerebral vasculature, weight loss)

Question 5

clinical trial with human intrathecal NGF infusion?

Answer 5

slight cognitive benefit but significant side effect (back pain, weight loss) so intracerebroventricular infusions of NGF are impractical

Question 6

NTF implants: what (2)?

Answer 6

polymeric materials impregnated with NTFs. mini pumps that deliver NTFs.

Question 7

clinical studies on NTF implants: pros? problems?

Answer 7

good toleration, safety profiles. requires catheter reposition, poor protein stability in delivery resevoir, accumulation of NTFs close to site of delivery

Question 8

vector: what?

Answer 8

DNA molecule used as a vehicle to carry foreign genetic material into another cell, where it can be replicated and expressed

Question 9

ideal vector: 4 things it should display? most commonly used vectors?

Answer 9

high compatibility with host tissue, asbence of immunologic reaction, minimal damage at injection site, controlled release of protein within CNS. viral vectors

Question 10

NTF gene therapy with viral vectors: how?

Answer 10

engineered replication deficient viruses used to supply NTFs, placed directly into region of interest. deliver DNA directly to genes that will secreted the NTF

Question 11

2 requirements for in vivo gene therapy

Answer 11

cells accessible for infusion/injection of virus. integration and expression of transgene (selectively in target cells, and at effective levels for extended time periods)

Question 12

tissue location of NTF production by viral vectors determined by (2)?

Answer 12

NTF receptor expression on diseased neurons (cell body vs. processes). tropism of viral vector

Question 13

in vivo study: AAV2-NGF gene therapy results?

Answer 13

works: safe and well tolerated, no evidence of accelerated decline, long term targeted gene mediated NGF expression + bioactivity

Question 14

ex vivo gene therapy: how

Answer 14

host cells geneteically modified in vitro, and cells expressing desired protein are harvested and but back into the host

Question 15

ex vivo gene therapy: how to modify host cells?

Answer 15

retroviral vectors to infect cells in culture dish

Question 16

advantages of ex vivo gene therapy

Answer 16

use of autologous cells from graft recipient. minimize rejection.

Question 17

2 disadvantages of ex vivo gene therapy

Answer 17

level os therapeutic protein diminishes greatly/downregulated completely over time. not suitable for long term neurodegen diseases