A small molecule mitigates hearing loss in a mouse model of Usher syndrome III.
Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1(N48K) that involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1(N48K), followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure-activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.
Otolaryngology Head and Neck Surgery, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.|Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA.|Neurosciences, Case Western Reserve University, Cleveland, Ohio, USA.
Kumar N
KN
Alagramam
Otolaryngology Head and Neck Surgery, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
Suhasini R
0000-0002-3525-3222
SR
Gopal
Otolaryngology Head and Neck Surgery, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
Ruishuang
R
Geng
Otolaryngology Head and Neck Surgery, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
Daniel H-C
DH
Chen
Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio, USA.
Ina
I
Nemet
Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio, USA.
Richard
R
Lee
Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio, USA.
Guilian
G
Tian
Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA.
Masaru
M
Miyagi
BioFocus, a Charles River company, Chesterford Research Park, Saffron Walden, UK.
Karine F
KF
Malagu
BioFocus, a Charles River company, Chesterford Research Park, Saffron Walden, UK.
Christopher J
CJ
Lock
BioFocus, a Charles River company, Chesterford Research Park, Saffron Walden, UK.
William R K
WR
Esmieu
BioFocus, a Charles River company, Chesterford Research Park, Saffron Walden, UK.
Andrew P
AP
Owens
BioFocus, a Charles River company, Chesterford Research Park, Saffron Walden, UK.
Nicola A
NA
Lindsay
Charles River Nederland BV, Leiden, the Netherlands.
Krista
K
Ouwehand
Charles River Nederland BV, Leiden, the Netherlands.
Faywell
F
Albertus
Charles River Nederland BV, Leiden, the Netherlands.
David F
DF
Fischer
BioFocus, a Charles River company, Chesterford Research Park, Saffron Walden, UK.
Roland W
RW
Bürli
BioFocus, a Charles River company, Chesterford Research Park, Saffron Walden, UK.
Angus M
AM
MacLeod
Office of Translation and Innovation, Case Western Reserve University, Cleveland, Ohio, USA.
William E
WE
Harte
Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio, USA.
Krzysztof
K
Palczewski
Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio, USA.
Yoshikazu
0000-0003-4696-4836
Y
Imanishi
D000818:Animals; D004195:Disease Models, Animal; D057166:High-Throughput Screening Assays; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D052245:Usher Syndromes / Q000188:drug therapy* / Q000235:genetics
C000617985:BF844 compound; C437067:CLRN1 protein, human; C512668:Clrn1 protein, mouse; D008565:Membrane Proteins; D011720:Pyrazoles; D011724:Pyridazines; D054852:Small Molecule Libraries