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Cartilage-Targeted IGF-1 Treatment to Promote Longitudinal Bone Growth
Julian C Lui1, Max Colbert1, Crystal Sao Fong Cheung1
1Section on Growth and Development, National Institute of Child Health and Development, NIH, Bethesda, MD 20892, USA.
Insights
Targeting growth plate cartilage with novel fusion proteins improved bone growth in mice, offering a promising new approach for treating childhood growth disorders and minimizing side effects.
Area of Science:
- Biotechnology
- Endocrinology
- Pediatric Endocrinology
Background:
- Recombinant human growth hormone (GH) is a standard treatment for short stature, but its efficacy is limited in severe cases like chondrodysplasias.
- GH treatment can cause off-target effects in non-GH-deficient conditions.
- Short stature stems from reduced growth plate chondrogenesis.
Purpose of the Study:
- To develop a targeted therapeutic approach for childhood growth disorders.
- To enhance treatment efficacy and minimize adverse effects by delivering molecules directly to the growth plate.
Main Methods:
- Created cartilage-binding antibody fragments (CaAb) fused with insulin-like growth factor 1 (IGF-1).
- Tested CaAb-IGF-1 fusion proteins in an organ culture system and a GH-deficient (lit) mouse model.
- Administered subcutaneous injections and assessed growth plate height and kidney cell proliferation.
Main Results:
- CaAb-IGF-1 fusion proteins demonstrated cartilage binding and IGF-1 biological activity.
- Fusion proteins stimulated bone growth in organ cultures.
- In mice, CaAb-IGF-1 increased growth plate height without increasing kidney cell proliferation, unlike IGF-1 alone.
- Alternate-day injections of fusion proteins were effective.
Conclusions:
- Targeting therapeutics to growth plate cartilage is a viable strategy for improving treatment of childhood growth disorders.
- CaAb-IGF-1 fusion proteins show potential for on-target efficacy and reduced off-target effects.
- This approach offers a promising alternative to conventional GH therapy.
Abstract:
Recombinant human growth hormone (GH) is commonly used to treat short stature in children. However, GH treatment has limited efficacy, particularly in severe, non-GH-deficient conditions such as chondrodysplasias, and potential off-target effects. Because short stature results from decreased growth plate chondrogenesis, we developed a cartilage-targeting single-chain human antibody fragment (CaAb) aiming to deliver therapeutic molecules to the growth plate, thereby increasing treatment efficacy while minimizing adverse effects on other tissues. To this end, we created fusion proteins of these CaAbs conjugated with insulin-like growth factor 1 (IGF-1), an endocrine and/or paracrine factor that positively regulates chondrogenesis. These CaAb-IGF-1 fusion proteins retained both cartilage binding and IGF-1 biological activity, and they were able to stimulate bone growth in an organ culture system. Using a GH-deficient (lit) mouse model, we found that subcutaneous injections of these CaAb-IGF-1 fusion proteins increased overall growth plate height without increasing proliferation in kidney cortical cells, suggesting on-target efficacy at the growth plate and less off-target effect on the kidney than IGF-1 alone. Alternate-day injections of these fusion proteins, unlike IGF-1 alone, were sufficient to produce a therapeutic effect. Our findings provide proof of principle that targeting therapeutics to growth plate cartilage can potentially improve treatment for childhood growth disorders.
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