Modulators of telomere disease

Abstract

The disclosure relates to treating and diagnosing telomere diseases, and methods of screening agents for treating and diagnosing telomere diseases.

1 . A method of treating a disorder associated with telomerase dysfunction in a subject, the method comprising:
 a) identifying the subject as having a disorder associated with telomerase dysfunction; and   b) administering to the subject an effective amount of a pharmaceutical composition comprising an agent that decreases the level or activity of PAP Associated Domain Containing 5 (PAPD5),   thereby treating the disorder associated with telomerase dysfunction in the subject.   
     
     
         2 . The method of  claim 1 , wherein the disorder associated with telomerase dysfunction is dyskeratosis congenital, aplastic anemia, pulmonary fibrosis, idiopathic pulmonary fibrosis, hematological disorder, or hepatic disease. 
     
     
         3 . The method of  claim 1 , wherein the agent increases the level or activity of telomerase RNA component (TERC). 
     
     
         4 . The method of  claim 1 , wherein the agent is a PAPD5 inhibitor. 
     
     
         5 . The method of  claim 1 , wherein the agent is an anti-PAPD5 antibody or anti-PAPD5 antibody fragment. 
     
     
         6 . The method of  claim 1 , wherein the agent is an antisense molecule or a small interfering nucleic acid which is specific for a nucleic acid encoding PAPD5. 
     
     
         7 . The method of  claim 1 , wherein the agent is a shRNA. 
     
     
         8 . The method of  claim 7 , wherein the shRNA comprise a sequence that is selected from the group of SEQ ID NOs: 79-83. 
     
     
         9 . The method of  claim 1 , wherein the agent is an aminoglycoside or a nucleoside analogue. 
     
     
         10 . The method of  claim 1 , wherein the agent is a vector comprising guide RNAs (gRNAs) that target PAPD5 for CRISPR/Cas9, wherein CRISPR/Cas9 creates null mutations in PAPD5, thereby decreasing the level of PAPD5. 
     
     
         11 . The method of  claim 10 , wherein the guide RNA has a sequence that is selected from the group of SEQ ID NO: 84, 86, and 88. 
     
     
         12 . The method of  claim 1 , wherein the agent comprises a fusion protein or a nucleic acid encoding the fusion protein, wherein the fusion protein comprises an DNA-binding domain that binds to PAPD5, and a catalytic domain, wherein the catalytic domain decreases the expression level of PAPD5. 
     
     
         13 . The method of  claim 1 , wherein the method further comprises administering to the subject an agent that increases the level or activity of Poly(A) specific ribonuclease (PARN). 
     
     
         14 - 19 . (canceled) 
     
     
         20 . A method of treating cancer in a subject, the method comprising:
 a) identifying the subject as having a cancer; and   b) administering to the subject an effective amount of a pharmaceutical composition comprising an agent that increases the level or activity of PAPD5,   thereby treating the cancer in the subject.   
     
     
         21 - 30 . (canceled) 
     
     
         31 . A method of treating a subject having a disorder associated with telomerase dysfunction, the method comprising:
 a) identifying the subject as having a mutation at PARN; and   b) administering to the subject an effective amount of a pharmaceutical composition that alters the level or activity of Telomerase RNA Component (TERC),   thereby treating the disorder associated with telomerase dysfunction in the subject.   
     
     
         32 . The method of  claim 31 , wherein the mutation is a deletion in PARN. 
     
     
         33 . The method of  claim 31 , wherein the amino acid residue at position 87 of PARN in the subject is not serine. 
     
     
         34 . The method of  claim 31 , wherein the amino acid residue at position 7 of PARN in the subject is not asparagine. 
     
     
         35 . The method of  claim 31 , wherein the pharmaceutical composition comprises an agent that increase the level of activity of PARN. 
     
     
         36 . The method of  claim 31 , wherein the pharmaceutical composition comprises
 a) clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) protein, or DNA or RNA encoding Cas9;   b) a guide RNA that target PARN locus, or a vector that encodes guide RNA;   c) a nucleic acid sequence that encodes PARN without the mutation.   
     
     
         37 - 97 . (canceled)