Targeted delivery to cartilage is critical for in vivo efficacy of insulin-like growth factor 1 in a rat model of osteoarthritis.
OBJECTIVE
Acute articular injuries lead to an increased risk of progressive joint damage and osteoarthritis (OA), and no therapies are currently available to repair or protect the injured joint tissue. Intraarticular delivery of therapeutic proteins has been limited by their rapid clearance from the joint space and lack of retention within cartilage. The aim of this study was to test whether targeted delivery to cartilage by fusion with a heparin-binding domain would be sufficient to prolong the in vivo function of the insulin-like growth factor 1 (IGF-1).


METHODS
We produced a humanized and optimized recombinant HB-IGF-1 fusion protein. By injecting HB-IGF-1, IGF-1, or saline alone into the knee joints of adult Lewis rats, we tested whether fusion with a heparin-binding domain 1) altered the kinetics of retention in joint tissues, 2) prolonged functional stimulation as measured by radiolabel incorporation, and 3) enhanced efficacy in a rat model of surgically induced OA, using weekly injections.


RESULTS
Fusion of heparin-binding domain with IGF-1 prolonged retention in articular and meniscal cartilage from <1 day to 8 days after injection. Unmodified IGF-1 had no functional effect 2 days after injection, whereas HB-IGF-1 stimulated meniscal cartilage at least 4 days after injection. HB-IGF-1, but not IGF-1, significantly slowed cartilage damage in a rat model of OA.


CONCLUSIONS
Heparin-binding domain fusions can transform rapidly cleared proteins into potential intraarticular therapies by targeting them to cartilage.
Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts.
Francesco S
FS
Loffredo
James R
JR
Pancoast
Lei
L
Cai
Todd
T
Vannelli
Jesse Z
JZ
Dong
Richard T
RT
Lee
Parth
P
Patwari
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D006493:Heparin / Q000378:metabolism; D007270:Injections, Intra-Articular; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome
D001786:Blood Glucose; D011993:Recombinant Fusion Proteins; D007334:Insulin-Like Growth Factor I; D006493:Heparin