SMALL MOLECULE DEGRADATION METHODS FOR TREATING ALS/FTD
Described are small molecule embodiments, ALS compounds, that bind with the r(G 4 C 2 ) exp RNA repeat expansion present in chromosome 9 open reading frame 72 involved in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These ALS compounds comprise a pyridocarbazole moiety having at least one substituent and an RNase-recruiting moiety linked to the pyridocarbazole moiety by a polyethylene glycol group.
1 . A method comprising contacting a hexanucleotide repeat expansion RNA r(G 4 C 2 ) exp with an ALS compound wherein the ALS compound comprises a pyridocarbazole moiety bound to an RNase moiety according to Formula I
wherein:
R is hydrogen or a C1-C3 alkyl group, preferably a methyl group, more preferably hydrogen,
Y is —COO, —CH 2 —O—, preferably —CH 2 —O—
n is an integer of 1 to 6, preferably 2-4, more preferably 2,
and a pharmaceutically acceptable salt thereof.
2 . A method according to claim 1 wherein the contacting binds and/or complexes the r(G 4 C 2 ) exp .
3 . A method according to any of claims 1-2 wherein the r(G 4 C 2 ) exp is r(G 4 C 2 ) m wherein m is at least 20.
4 . A method according to any of the preceding claims wherein r(G 4 C 2 ) m is an abnormal number of repeats with m being at least 20-1000.
5 . A method according to any of the preceding claims wherein the r(G 4 C 2 ) exp is a repeat RNA hairpin structure.
6 . A method according to any of preceding claims wherein r(G 4 C 2 ) exp is present in a cell.
7 . A method according to claim 6 wherein the cell contains chromosome 9 open reading frame 72 (C9orf72) and r(G 4 C 2 ) exp is present in the intron 1 of C9orf72.
8 . A method according to any of claims 6 and 7 wherein the cells are patient-derived cells.
9 . A method of any of claims 6-8 wherein the cells are incubated with the ALS compound of claim 1 .
10 . A method according to claim 9 wherein the cells are HEK293T cells, patient-derived lymphoblastoid cells, induced pluripotent stem cells (c9 iPSCs cells), iPSC-derived spinal neurons (c9 iPSNs).
11 . A method according to claim 10 wherein the cells are c9ALS/FTD BAC cells in a transgenic mouse model.
12 . A method according to any of the preceding claims 6-11 wherein the ALS compound decreases RAN translation of r(G 4 C 2 ) exp .
13 . A method according to claim 12 wherein the ALS compound inhibits RAN translation of r(G 4 C 2 ) exp .
14 . A method according to any of the preceding claims 6-13 wherein the ALS compound does not inhibit transcription of C9orf72.
15 . A method according to any of the preceding claims 6-14 wherein the ALS compound decreases the number of nuclear foci.
16 . A method according to any the preceding claims 6-15 wherein the ALS compound alleviates defects in nuclear trafficking.
17 . A method according to any of the preceding claims 6-16 wherein the ALS compound facilitates degradation of the repeat expansion.
18 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an ALS compound according to Formula I of claim 1 .
19 . A pharmaceutical composition according to any of claim 18 wherein the pharmaceutically acceptable carrier comprises excipients suitable for a selected route of administration of the ALS compound.
20 . A pharmaceutical composition according to any of claims 18-19 wherein the amount of ALS compound provides an effective dose of the ALS compound for treatment of a disease caused by G 4 C 2 repeat expansion, preferably ALS/FTD disease.
21 . A method for treatment of an ALS/FTD disease comprising administration to a patient having the disease, an effective amount of an ALS compound of claim 1 .
22 . A method for treatment of an ALS/FTD disease comprising administration to a patient having the disease, a pharmaceutical composition of any of claims 18-20 .
23 . A method for treatment according to any of claims 21-22 wherein the ALS/FTD disease is amyotrophic lateral sclerosis.
24 . A method according to claim 23 wherein the administration step comprises oral, intramuscular, intravenous or intrathecal administration of the ALS compound in a pharmaceutically acceptable medium.
25 . A method according to claim 24 wherein the ALS compound in a pharmaceutically acceptable medium is a pharmaceutical composition.
26 . A method according to claim 25 wherein the pharmaceutical composition comprises pharmaceutically acceptable excipients suitable for a selected route of administration and the excipients are compatible with the ALS compound.
27 . A composition comprising an ALS compound of Formula I and a pharmaceutically acceptable salt thereof:
wherein:
R is hydrogen or a C1-C3 alkyl group, preferably a methyl group, more preferably hydrogen,
Y is —COO— or —CH 2 —O—, preferably —CH 2 —O—
n is an integer of 1 to 6, preferably 2-4, more preferably 2,
and a pharmaceutically acceptable salt thereof.