Efficacy of cartilage-targeted IGF-1 in a mouse model of growth hormone insensitivity
Recombinant human IGF-1 is used to treat severe primary IGF-1 deficiency, but this treatment requires twice-daily injection, often does not fully correct the growth deficit, and has important off-target effects. We therefore sought to target IGF-1 to growth plate cartilage by generating fusion prote...
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| Format: | Article |
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2024.1523931/full |
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| author | Krishma Tailor Krishma Tailor Janine van Ree Timothy Stowe Brit Ventura Connor Sisk Joanna Courtis Anna Camp Fatima Elzamzami Jan van Deursen Robert O’Brien Jeffrey Baron Julian C. Lui |
| author_facet | Krishma Tailor Krishma Tailor Janine van Ree Timothy Stowe Brit Ventura Connor Sisk Joanna Courtis Anna Camp Fatima Elzamzami Jan van Deursen Robert O’Brien Jeffrey Baron Julian C. Lui |
| author_sort | Krishma Tailor |
| collection | DOAJ |
| description | Recombinant human IGF-1 is used to treat severe primary IGF-1 deficiency, but this treatment requires twice-daily injection, often does not fully correct the growth deficit, and has important off-target effects. We therefore sought to target IGF-1 to growth plate cartilage by generating fusion proteins combining IGF-1 with single-chain human antibody fragments that target matrilin-3, a cartilage matrix protein. We previously showed that this cartilage-targeting IGF-1 fusion protein (CV1574-1) promoted growth plate function in a GH-deficient (lit) mouse model. Here, we studied CV1574-1 in a second mouse model, C57BL/6 wild-type mice treated with pegvisomant to induce GH resistance. In this model, once-daily injections of CV1574-1 for 5 days partially restored the pegvisomant-induced decrease in growth plate height without increasing kidney cell proliferation. Furthermore, we found that subcutaneous CV1574-1 showed significantly reduced hypoglycemic effect compared to injection of IGF-1 itself. Lastly, to gain mechanistic insights into the role of matrilin-3 targeting, we assessed the ability of CV1574-1 to activate AKT signaling in vitro and found that CV1574-1 caused a prolonged increase in AKT signaling compared to IGF-1 and that this effect was dependent on matrilin-3. Taken together, our findings provide further evidence that cartilage-targeted therapy could provide new pharmacological approaches for the treatment of childhood growth disorders, such as GH-insensitivity syndrome. |
| format | Article |
| id | doaj-art-3f51efaf93634be9b22d1e8ea09997b6 |
| institution | Kabale University |
| issn | 1664-2392 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj-art-3f51efaf93634be9b22d1e8ea09997b62025-01-09T16:00:46ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-01-011510.3389/fendo.2024.15239311523931Efficacy of cartilage-targeted IGF-1 in a mouse model of growth hormone insensitivityKrishma Tailor0Krishma Tailor1Janine van Ree2Timothy Stowe3Brit Ventura4Connor Sisk5Joanna Courtis6Anna Camp7Fatima Elzamzami8Jan van Deursen9Robert O’Brien10Jeffrey Baron11Julian C. Lui12Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, United StatesCavalry Biosciences, Inc., San Francisco, CA, United StatesCavalry Biosciences, Inc., San Francisco, CA, United StatesCavalry Biosciences, Inc., San Francisco, CA, United StatesCavalry Biosciences, Inc., San Francisco, CA, United StatesSection on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, United StatesSection on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, United StatesSection on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, United StatesSection on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, United StatesCavalry Biosciences, Inc., San Francisco, CA, United StatesCavalry Biosciences, Inc., San Francisco, CA, United StatesSection on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, United StatesSection on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, United StatesRecombinant human IGF-1 is used to treat severe primary IGF-1 deficiency, but this treatment requires twice-daily injection, often does not fully correct the growth deficit, and has important off-target effects. We therefore sought to target IGF-1 to growth plate cartilage by generating fusion proteins combining IGF-1 with single-chain human antibody fragments that target matrilin-3, a cartilage matrix protein. We previously showed that this cartilage-targeting IGF-1 fusion protein (CV1574-1) promoted growth plate function in a GH-deficient (lit) mouse model. Here, we studied CV1574-1 in a second mouse model, C57BL/6 wild-type mice treated with pegvisomant to induce GH resistance. In this model, once-daily injections of CV1574-1 for 5 days partially restored the pegvisomant-induced decrease in growth plate height without increasing kidney cell proliferation. Furthermore, we found that subcutaneous CV1574-1 showed significantly reduced hypoglycemic effect compared to injection of IGF-1 itself. Lastly, to gain mechanistic insights into the role of matrilin-3 targeting, we assessed the ability of CV1574-1 to activate AKT signaling in vitro and found that CV1574-1 caused a prolonged increase in AKT signaling compared to IGF-1 and that this effect was dependent on matrilin-3. Taken together, our findings provide further evidence that cartilage-targeted therapy could provide new pharmacological approaches for the treatment of childhood growth disorders, such as GH-insensitivity syndrome.https://www.frontiersin.org/articles/10.3389/fendo.2024.1523931/fullshort staturematrilin-3GH-insensitivity syndromehypoglycemiadrug targeting |
| spellingShingle | Krishma Tailor Krishma Tailor Janine van Ree Timothy Stowe Brit Ventura Connor Sisk Joanna Courtis Anna Camp Fatima Elzamzami Jan van Deursen Robert O’Brien Jeffrey Baron Julian C. Lui Efficacy of cartilage-targeted IGF-1 in a mouse model of growth hormone insensitivity Frontiers in Endocrinology short stature matrilin-3 GH-insensitivity syndrome hypoglycemia drug targeting |
| title | Efficacy of cartilage-targeted IGF-1 in a mouse model of growth hormone insensitivity |
| title_full | Efficacy of cartilage-targeted IGF-1 in a mouse model of growth hormone insensitivity |
| title_fullStr | Efficacy of cartilage-targeted IGF-1 in a mouse model of growth hormone insensitivity |
| title_full_unstemmed | Efficacy of cartilage-targeted IGF-1 in a mouse model of growth hormone insensitivity |
| title_short | Efficacy of cartilage-targeted IGF-1 in a mouse model of growth hormone insensitivity |
| title_sort | efficacy of cartilage targeted igf 1 in a mouse model of growth hormone insensitivity |
| topic | short stature matrilin-3 GH-insensitivity syndrome hypoglycemia drug targeting |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2024.1523931/full |
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