Lecture 36

Question 1

Mutations affect sarcolemmal proteins, which connect the cytoskeleton and..

Answer 1

basal lamina

Question 2

The absense of one protein cases

Answer 2

disassembly of dystrophin-associated comples

increased sarcolemmal fragility

incerase Ca entry, damage to fibres

Question 3

Damaged or dead fibres are repaired/replaced by ____cells, which eventually become exhausted leading to muscle getting replaced with _______and _____tissue (causes weakness)

Answer 3

Damaged or dead fibres are repaired/replaced by satellite cells, which eventually become exhausted leading to muscle getting replaced with connective and adipose tissue (causes weakness)

Question 4

Local delivery of the therapheutic agent is proof of principle but..

Answer 4

real clinical benefit can only follow systemic delivery

Question 5

what are some ways of approaching therapeutics?

Answer 5

1. Gene repair or replacement (stem cell transfer, stop codon read through, RNA splicing)
2. Upregulation of compensatory proteins (Utrophin)
3. Blocking downstream effects (block abnormal Ca influx, anti-fibrotics, incrase muscle energy/regeneration)

Question 6

What needs to happen with Myoblast transfer therapy for it to work, and where is it at the moment?

Answer 6

The myoblasts need to be able to survive, proliferate, migrate away from injection site, fuse with myofibres and express functional dystrophin

promising in animal models

never been shown to result in clinical benefit for DMD - targeted by immune system

Question 7

Several adult-dervied stem cell lines have been trialled:

what are the variable results of this?

Answer 7

incorporated into muscle but no restoration of expression of wt protein

extreme immune response

insufficient to affect strength

Question 8

Use of ________may ameliorate phenotype by restoration of smaller dystrophin molecule and partial restoration of function

Answer 8

Use of microdystrophin may ameliorate phenotype by restoration of smaller dystrophin molecule and partial restoration of function

Question 9

What are the problems with Gene replacement?

Answer 9

immune response to vector

vectors too large to cross ECM around mature myofibres

Question 10

Ataluren (PTC124) was designed to overcome…

Answer 10

nonsense (premature stop codon) mutations in DMD

Question 11

Phase 2 trials of Ataluren (PTC124) showed significant serum creatine kinase _____

Answer 11

reduction

went back up when they came off the drug

Question 12

Final anazylsis of Ataluren showed 29m difference in walking on ___ dose

Answer 12

low dose

but drug did not meet primary outcome measure of trial

Question 13

_____ ___ ______, is where Antisense oligonucleotides act as a “gene zipper”, leads to a shortened, in-frame product

Answer 13

Targeted exon skipping, is where Antisense oligonucleotides act as a “gene zipper”, leads to a shortened, in-frame product

Question 14

Exon __is an hotspot for deletions in DMD

Answer 14

51

AON therapy looking to skip over exon 51 and get a functional protein

Question 15

Most new treatment strategies in DMD are ..

Answer 15

mutation- specific

Question 16

Utrophin is an…

Answer 16

autosomal homologue of dystrophin

Expressed in place of dystrophin in foetal muscle, but confined to the neuromuscular and myotendinous junctions

Question 17

In DMD Utrophin is ______

Answer 17

upregulated in sacrolemma

Question 18

Because utrophin is expressed in foetal muscle and in adult non-muscle tissues, its over-expression in mjuscles of people with DMD is unlikely to…

Answer 18

provoke an immune response

an attractive therapeutic approach

phase 2 trial underway

Question 19

What are some ways of blocking downstream effects in DMD

Answer 19

Block abnormal CA influx - membrane sealers

anti-fibrotics

increase muscle energy - creatine

Increase muscle regeneration - MYO-029, glutamine