Therapeutic approaches to DM

Question 1

Silencing toxic CUG)n RNA in pre-clinical DM1 with ASOs

Answer 1

ASOs bind toxic RNA and selectively induce its destruction in nucleus by enzyme RNase H

Question 2

What are the two functions ASO does for DM1 patients?

Answer 2

• Inhibit protein (MBNL1) binding to the microsatellite repeats
• Induce RNase H-mediated degradation of mRNA containing the CUG
repeat expansion, thereby reducing the amount of toxic transcript

Question 3

ASOs administered to DM1 mice via subQ injections twice/wk for 4 wks shows:

Answer 3

• Northern blot analysis demonstrated ASO-mediated reduction in CUG)n RNA
• Splicing of MBNL1-dependent exons CLCN1 exon 7a & SERCA1
exon 22 normalized
• Myotonia eliminated by ASOs, indicating rescue of CLCN1 and SERCA1
functions

Question 4

12 wk progressive RT, unilateral knee extension (3 kg+ iron boot!), patients’ CTG)n = ?

Answer 4

• Training increased 1 RM, but not isokinetic strength, tendency for increase type I fiber CSA
• Similar histopathology pre– vs. post–training, thus no evidence of training-induced damage

Question 5

12 wk cycle ergometer, 65% VO2max

Answer 5

• VO2max & Workmax increased 15% & 10%,
respectively, trend for angiogenesis
observed
• No change in serum CK
• Some improvement in self-reported ADL
• Aerobic training safe & modestly
effective