# Targeting TGFb In Osteogenesis Imperfecta

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $607,076

## Abstract

PROJECT SUMMARY
 Osteogenesis Imperfecta (OI) is a group of heterogeneous brittle bone disorders. Over 95% of patients
harbor dominantly inherited structural mutations in the type I procollagen genes (COL1A1 and COL1A2) or
recessively inherited mutations in the protein complexes important in type I collagen post-translational assembly
and hydroxylation. Currently, there are no FDA-approved treatments for OI. While off-label use of anti-resorptive
bisphosphonates has become a de facto standard of care especially in children with OI, their clinical impact on
fracture incidence, mild OI type I (> 50% of patients), and adult, severe OI with lower bone formation is unclear.
This highlights the critical need of therapeutic innovations for OI. Taking anabolic approaches, we have shown
in adult OI that teriparatide (PTH 1-34) increases lumbar spine BMD in mild OI type I, but surprisingly, had no
significant effect in severe OI, suggesting the possibility of combinatorial therapy to overcome PTH insensitivity.
We and others have shown that collagen over-modification and altered cross-linking lead to abnormal
mineralization and altered extracellular matrix (ECM)-to-cell signaling, in particular, excessive TGFβ signaling in
OI in mice (Col1a2G610C/+ and Crtap-/-). Pan-anti-TGFβ treatment rescued the skeletal phenotype in these mice.
In primary fetal rat osteoblasts, TGFβ downregulates PTH 1 receptor, which led us to hypothesize that TGFβ
signaling contributes to PTH insensitivity in moderate and severe OI (Aim 1). On the severe end of the spectrum,
others have shown that Col1a1Jrt/+ mice also have increased TGFβ; however, they did not respond to anti-TGFβ
at doses that were effective in the moderate OI models. In our phase 1 anti-TGFβ clinical trial, increase lumbar
spine BMD was observed in moderate but not severe OI participants after a single dose. Our unpublished
preliminary data also showed increase TGFβ in our mild Col1a1+/- OI mice. We therefore hypothesize a wide
dose/frequency range requirement for anti-TGFβ among different OI severities and a bone-targeted antibody
can improve efficacy and safety across all types (Aim 2). TGFβ is also critical in fracture healing. We previously
found delayed fracture healing with reduced callus size in Col1a2G610C/+ and Crtap-/- mice and anti-TGFβ further
reduced this. This observation underscores the importance for studying the effects of anti-TGFβ in the course of
fracture repair for future clinical management (Aim 3). Finally, understanding the mechanism of TGFβ excess in
OI bone could potentially lead to new therapeutic targets. One hypothesis for this is decreased interaction
between abnormal collagen and small leucine rich proteoglycans, like Decorin, which sequester mature TGFβ
(Aim 4). Our overall goal is to answer the questions and unmet needs around targeting TGFβ in OI. Aim 1. Is
PTH insensitivity in mice and patients with OI type III/IV due to excessive TGFβ? Aim 2. Develop a bone-
targeted anti-TGFβ a...

## Key facts

- **NIH application ID:** 10922813
- **Project number:** 5R01AR081904-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Yangjin Bae
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $607,076
- **Award type:** 5
- **Project period:** 2023-09-07 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922813

## Citation

> US National Institutes of Health, RePORTER application 10922813, Targeting TGFb In Osteogenesis Imperfecta (5R01AR081904-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10922813. Licensed CC0.

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