BIOM30002 Lecture Notes - Lecture 18: Cd133, Nonsense Mutation, Rna Splicing
12 Jun 2018
School
Department
Course
Professor
L18 Therapeutic challenges in MDs
Summary
- newer therapies are aimed at various points in the pathophysiology of MDs
- some are mutation specific and other not
- development of new therapies is difficult, time-coursing and expensive but there are real
prospects for better treatment or cures for these conditions
Treatment approach
1. Gene repair or replacement
Cell and Stem cell transfer: myoblast transfer therapy (MTT) – fail!; stem cell
CD133+; mesangioblasts
Gene replacement: microdystrophines to restore function partially; AVV: no
longer used, too large
Nonsense mutation suppression: Ataluren/PTC124 – ignore premature stop
codon and dose-dependent (prefer low dose), fail!
Target RNA splicing: AON gene zipper, out-of-frame in-frame
Gene repair: CRISPR – like AON, permanent skip exon to restore reading
frame
2. Upregulation of compensatory proteins
Utrophin: expressed in foetal muscle,
can bind to DPAC,
compensate restore normal muscle function in mdx mice
unlikely to provoke immune response
3. Blocking downstream effects: non-mutation specific
Increase NO
Increase muscle energy: creatine
Increase muscle regeneration
Reduce oxidative stress
Block abnormal Ca influx
Reduce fibrosis
Reduce inflammation: steroids
Document Summary
(cid:374)e(cid:449)er therapies are ai(cid:373)ed at (cid:448)arious poi(cid:374)ts i(cid:374) the pathoph(cid:455)siolog(cid:455) of mds. De(cid:448)elop(cid:373)e(cid:374)t of (cid:374)e(cid:449) therapies is diffi(cid:272)ult, ti(cid:373)e-(cid:272)oursi(cid:374)g a(cid:374)d e(cid:454)pe(cid:374)si(cid:448)e (cid:271)ut there are real so(cid:373)e are (cid:373)utatio(cid:374) spe(cid:272)ifi(cid:272) a(cid:374)d other (cid:374)ot prospe(cid:272)ts for (cid:271)etter treat(cid:373)e(cid:374)t or (cid:272)ures for these (cid:272)o(cid:374)ditio(cid:374)s. Cell a(cid:374)d ste(cid:373) (cid:272)ell tra(cid:374)sfer: (cid:373)(cid:455)o(cid:271)last tra(cid:374)sfer therap(cid:455) (cid:894)mtt(cid:895) fail! Ge(cid:374)e repla(cid:272)e(cid:373)e(cid:374)t: (cid:373)i(cid:272)rod(cid:455)strophi(cid:374)es to restore fu(cid:374)(cid:272)tio(cid:374) partiall(cid:455); avv: (cid:374)o. No(cid:374)se(cid:374)se (cid:373)utatio(cid:374) suppressio(cid:374): atalure(cid:374)/ptc(cid:1005)(cid:1006)(cid:1008) ig(cid:374)ore pre(cid:373)ature stop (cid:272)odo(cid:374) a(cid:374)d dose-depe(cid:374)de(cid:374)t (cid:894)prefer lo(cid:449) dose(cid:895), fail! Target rna spli(cid:272)i(cid:374)g: aon ge(cid:374)e zipper, out-of-fra(cid:373)e i(cid:374)-fra(cid:373)e. Ge(cid:374)e repair: crispr like aon, per(cid:373)a(cid:374)e(cid:374)t skip e(cid:454)o(cid:374) to restore readi(cid:374)g fra(cid:373)e (cid:1006). Utrophi(cid:374): e(cid:454)pressed i(cid:374) foetal (cid:373)us(cid:272)le, (cid:272)a(cid:374) (cid:271)i(cid:374)d to dpac, (cid:272)o(cid:373)pe(cid:374)sate restore (cid:374)or(cid:373)al (cid:373)us(cid:272)le fu(cid:374)(cid:272)tio(cid:374) i(cid:374) (cid:373)d(cid:454) (cid:373)i(cid:272)e.
