Modified peptide nucleic acid compositions

Abstract

The present disclosure relates to compounds useful for the detection or modulation of target nucleic acids, including DNA and RNA. The present disclosure further relates to methods for treatment of trinucleotide repeat disorders, which can include administration of oligonucleotide analogues that can bind pathogenic nucleotide repeats in DNA or RNA.

1 - 16 . (canceled) 
     
     
         17 . A compound comprising a peptide nucleic acid sequence and a cell permeabilizing group attached to the peptide nucleic acid sequence, wherein if a radiolabeled analogue of the compound is subjected to an assay, wherein the assay comprises:
 (a) a first component, wherein the first component comprises:
 (i) administering a 5 mg/kg intravenous bolus dose of the radiolabeled analogue to a caudal vein of a monkey, wherein the monkey is a male Cynomolgus monkey; 
 (ii) euthanizing the monkey 4 hours after the administering; 
 (iii) after (ii), freezing the monkey in a mixture of hexane and solid carbon dioxide for at least two hours to provide a frozen carcass; 
 (iv) embedding the frozen carcass, left lateral side uppermost, in 2% w/v aqueous sodium carboxymethylcellulose to provide an embedded carcass; 
 (v) sectioning the embedded carcass into 40 μm sagittal whole body sections with a cryomacrotome; 
 (vi) mounting the 40 μm sagittal whole body sections on pressure sensitive tape; 
 (vii) after (vi), dehydrating the whole body sections in the cryomacrotome at about −20° C. for about 60 hours; 
 (viii) after (vii), placing the whole body sections against an image plate sensitive to carbon-14 for no longer than four days; 
 (ix) after (viii), scanning the image plate with a phosphor imager system; and 
 (x) after (ix), determining a concentration of the radiolabeled analogue in brain tissue of the whole body sections; and 
   (b) a second component, wherein the second component is analogous to the first component except that the second component uses another monkey that is euthanized 168 hours after the administering,   wherein the radiolabeled analogue comprises an N-terminus that is substituted with a  14 C-enriched glycine residue, and the radiolabeled analogue consists of a structure that differs from the compound solely in that the compound lacks the  14 C-enriched glycine residue of the radiolabeled analogue,   then in the assay, the concentration of the radiolabeled analogue in brain tissue determined in the second component is equivalent to at least about 80% of the concentration of the radiolabeled analogue in brain tissue determined in the first component.   
     
     
         18 . The compound of  claim 17 , wherein the brain tissue of the sections is cortex tissue, caudate nucleus tissue, olfactory bulb tissue, putamen tissue, or thalamus tissue. 
     
     
         19 . The compound of  claim 17 , wherein in the assay, the concentration of the radiolabeled analogue in brain tissue determined in the second component is equivalent to at least about 100% of the concentration of the radiolabeled analogue in brain tissue determined in the first component. 
     
     
         20 . The compound of  claim 19 , wherein the brain tissue of the sections is caudate nucleus tissue, olfactory bulb tissue, putamen tissue, or thalamus tissue. 
     
     
         21 . The compound of  claim 17 , wherein in the assay, the concentration of the radiolabeled analogue in brain tissue determined in the second component is equivalent to at least about 150% of the concentration of the radiolabeled analogue in brain tissue determined in the first component. 
     
     
         22 . The compound of  claim 21 , wherein the brain tissue of the sections is olfactory bulb tissue. 
     
     
         23 . The compound of  claim 17 , wherein the cell permeabilizing group is an alpha substituent of the peptide nucleic acid. 
     
     
         24 . The compound of  claim 17 , wherein the compound is a gamma peptide nucleic acid. 
     
     
         25 . The compound of  claim 24 , wherein the cell permeabilizing group is a gamma substituent of the gamma peptide nucleic acid. 
     
     
         26 . The compound of  claim 25 , wherein a plurality of gamma substituents of the gamma peptide nucleic acid are each independently guanidinoalkylene. 
     
     
         27 . The compound of  claim 25 , wherein a plurality of gamma substituents of the gamma peptide nucleic acid are each 3-guanidino-prop-1-yl. 
     
     
         28 . The compound of  claim 25 , wherein a plurality of gamma substituents of the gamma peptide nucleic acid are each 4-guanidino-but-1-yl. 
     
     
         29 . The compound of  claim 17 , wherein the peptide nucleic acid sequence is (CTG) n , wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 
     
     
         30 . The compound of  claim 17 , wherein a C-terminus of the peptide nucleic acid is bound by a peptide bond to a peptide. 
     
     
         31 . The compound of  claim 17 , wherein a C-terminus of the peptide nucleic acid is bound by a peptide bond to an amidated lysine residue. 
     
     
         32 . The compound of  claim 17 , wherein an N-terminus of the peptide nucleic acid of the compound is unsubstituted. 
     
     
         33 - 260 . (canceled)