Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology.
Mutations in cartilage oligomeric matrix protein cause pseudoachondroplasia, a severe disproportionate short stature disorder. Mutant cartilage oligomeric matrix protein produces massive intracellular retention of cartilage oligomeric matrix protein, stimulating ER and oxidative stresses and inflammation, culminating in post-natal loss of growth plate chondrocytes, which compromises linear bone growth. Treatments for pseudoachondroplasia are limited because cartilage is relatively avascular and considered inaccessible. Here we report successful delivery and treatment using antisense oligonucleotide technology in our transgenic pseudoachondroplasia mouse model. We demonstrate delivery of human cartilage oligomeric matrix protein-specific antisense oligonucleotides to cartilage and reduction of cartilage oligomeric matrix protein expression, which largely alleviates pseudoachondroplasia growth plate chondrocyte pathology. One antisense oligonucleotide reduced steady-state levels of cartilage oligomeric matrix protein mRNA and dampened intracellular retention of mutant cartilage oligomeric matrix protein, leading to a reduction of inflammatory markers and cell death and partial restoration of proliferation. This novel and exciting work demonstrates that antisense-based therapy is a viable approach for treating pseudoachondroplasia and other human cartilage disorders.
Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA. Electronic address: karen.posey@uth.tmc.edu.
Karen L
KL
Posey
Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
Francoise
F
Coustry
Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
Alka C
AC
Veerisetty
Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
Mohammad
M
Hossain
Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
Danielle
D
Gattis
Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
Sheri
S
Booten
Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
Joseph L
JL
Alcorn
Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
Punit P
PP
Seth
Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
Jacqueline T
JT
Hecht
D000818:Animals; D064236:Cartilage Oligomeric Matrix Protein / Q000235:genetics* / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006132:Growth Plate / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage
D064236:Cartilage Oligomeric Matrix Protein; D016376:Oligonucleotides, Antisense
COMP; antisense oligonucleotides; cartilage; pseudoachondroplasia