Читать книгу Nutrition and Growth - Группа авторов - Страница 26

Lui JC¹, Colbert M², Cheung CSF², Ad M², Lee A², Zhu Z³, Barnes KM², Dimitrov DS³, Baron J²

¹Section on Growth and Development, National Institute of Child Health and Development, NIH, Bethesda, MD, USA; ²Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, MD, USA; ³Present address: Center for Antibody Therapeutics, University of Pittsburgh, Medical School, Pittsburgh, PA, USA

Mol Ther 2019;27:673–680

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.

Reprinted with permission from American Society of Gene & Cell Therapy.

Comments

The authors developed an elegant and unique way to specifically deliver insulin-like growth factor (IGF)-1 to the growth plate. They also showed that the IGF-1 indeed increased growth plate and did not have an effect on other tissues (kidney). It is an important study indeed. Target-specific therapy is the desire of every physician in every specialty of medicine. Currently, physicians treating children with severe short stature with either growth hormone or IGF-1 are constantly concerned with the possible offtarget short-and long-term undesired side effects. Frequently, pediatric endocrinologists treating children with GH have to consider reducing an effective dose because of too high systemic levels of IGF-1 and the concern of potential theoretical future malignancy. The described innovation of delivering the IGF-1 specifically to the growth plate where its action is needed paves the way to other targeted therapeutic options to be delivered specifically to the growth plate.

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