ESPE Yearbook of Paediatric Endocrinology

Abstract: Mol. Ther. 2019;27:673–680.

In brief: The authors developed a fusion protein containing a cartilage-targeting antibody fragment and Insulin-like growth factor 1 (Igf1) and demonstrate that it can stimulate growth plate cartilage at lower and less frequent doses than Igf1. This is a novel approach that paves the way for the development of tissue-specific targeting of Igfs and other paracrine pathways in growth plate cartilage.

Comment: The growth hormone (GH) insulin-like growth factor-1 (IGF1) axis is a major regulator of linear growth in mammals. In addition to its endocrine functions, IGF1 also acts locally in a paracrine manner to mediate the effects of GH. Currently, there are limited strategies to specifically target paracrine pathways by systemically applied treatments.

The authors developed a cartilage-targeting single-chain human antibody fragment that targets cartilaginous tissues. They then produced a fusion protein of the antibody fragment and IGF1 in order to specifically target IGF1 to the growth plate. In this proof-of–principle study in a GH-deficient mouse model, the authors show that cartilage-targeted IGF1 has more on-target and less off-target effects than regular IGF1.

Although clinical use of recombinant IGF1 treatment is limited to rare cases of severe growth hormone insensitivity, these authors succeeded to target a systemically applied therapeutic to growth plate cartilage for the very first time.

Similar to the bone anchor of asfotase alfa in the treatment of severe hypophosphatsia, the development of cartilage-targeted growth factors could finally target growth plate pathologies at a paracrine level. This novel approach could ultimately allow the development of therapeutic strategies to selectively modify growth plate regulation while avoiding off-target effects.