Duchenne Muscular Dystrophy

Question 1

What is the cause of Duchenne muscular dystrophy?

Answer 1

result of truncating mutations in the DMD gene

Question 2

What is the clinical manifestations of DMD?

Answer 2

results in a lack of expression of the dystrophin protein in muscle fibers

Question 3

Describe the therapeutic construct delivered.

Answer 3

therapeutic minidystrophin construct

Question 4

Name the vector used to deliver the construct.

Answer 4

intramuscular adeno-associated virus-mediated delivery; a gene therapy vector designed to restore muscle function

Question 5

Describe the assay used to quantify the peripheral T-cell response to the dystrophin

Answer 5

enzyme-linked immunospot assay:

interferon (IFN) gamma enzyme linked immunospot (ELISPOT) - peripheral blood mononuclear cells (PBMC) isolated on Ficoll Hypaque gradients are cultured with synthetic peptides that span the entire dystrophin protein.
Peptide mapping pools were used to further localize the immune response. Spot forming cells (SFCs) were counted. Positive exceeded 15 SFCs/10^6 PBMCs.

Question 6

List the immune cells dominating the immune response to dystrophin.

Answer 6

Tcells CD4 helper and/or CD8+ cytotoxic

Question 7

List the difference in response in patients treated with corticosteroids compared to the untreated group.

Answer 7

treatment with either prednisone or deflazacort decreases risk of anti-Dystropin T cell immunity

Question 8

What type of chromosomal link is involved with DMD?

Answer 8

x-linked

Question 9

What is the result of the absence of expression of the dystrophin protein in skeletal and cardiac muscles?

Answer 9

myofiber degeneration occurs with subsequent accelerated rounds of myofiber regeneration and degeneration leading to myofiber loss and replacement of contractile fibers with fibrosis and fat

Question 10

When do symptoms typically present in DMD?

Answer 10

3-5: gait disturbance
12: loss of ambulation
typically lead to death by end of second decade

Question 11

What are the current therapies?

Answer 11

glucocorticoid corticosteroids:

prednisone
deflazacort

Question 12

What effect might deflazacort and prednisone have in Tcell response?

Answer 12

differential effect in modulation Tcell response in boys with DMD

Question 13

What cytokines did the CD4 cells fail to produce in the DMD patients?

Answer 13

tumor necrosis factor (TNF) alpha

interleukin (IL) 2
IL17

Question 14

Why was this research conducted?

Answer 14

better define the scope of Tcell immunity in DMD patients because of its potential to interfere with therapies that increase expression of dystrophin