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GBT-1118 Rescued Impaired Bone Formation but Failed to Rescue Material Properties in Humanized Sickle-Cell-Disease
Kai Clarke1, Wei He1, Nikhil Menon2
1Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, UConn Health, Farmington, CT 06032, USA.
Insights
Sickle cell disease (SCD) treatment with GBT1118 improved anemia in mice but did not restore impaired bone material or mechanical properties. Further therapies are needed for bone fragility in SCD.
Area of Science:
- Hematology
- Orthopedics
- Pharmacology
Background:
- Sickle cell disease (SCD) is a common inherited blood disorder with bone loss complications similar to osteoporosis.
- GBT1118, a sickle hemoglobin polymerization inhibitor, previously improved bone formation and reduced resorption in SCD mice.
- The effects of GBT1118 on bone material and mechanical properties in SCD were previously unknown.
Purpose of the Study:
- To investigate the impact of GBT1118 on bone material and mechanical properties in a mouse model of sickle cell disease.
Main Methods:
- Control and SCD mice were administered GBT1118 or vehicle for two months.
- Hematocrit levels were measured to assess anemia.
- Raman spectroscopy and mechanical testing were used to evaluate bone material and properties.
Main Results:
- GBT1118 treatment restored hematocrit levels in SCD mice, indicating efficacy against anemia.
- Bone mineral-to-organic matrix and carbonate-to-phosphate ratios were altered in SCD mice but not by GBT1118.
- Female SCD mice showed decreased ultimate stress and Young's modulus, which GBT1118 did not rescue.
Conclusions:
- While GBT1118 effectively improved hematological parameters in SCD mice, it did not restore impaired bone material or mechanical properties.
- Additional therapeutic strategies are necessary to address bone fragility in sickle cell disease.
Abstract:
Sickle cell disease (SCD), the most common inherited blood disorder in the United States, affects approximately 100,000 individuals annually. A major complication of SCD is sickle cell bone disease, which results in substantial bone loss comparable to osteoporosis. Previous work showed that treatment with GBT1118, a sickle hemoglobin polymerization inhibitor, improved bone formation and reduced bone resorption in humanized SCD mice. However, its effects on bone material and mechanical properties were unknown. To address this, four-month-old control and SCD mice were fed vehicle or GBT1118 chow for two months. Hematocrit levels, significantly reduced in SCD mice of both sexes, were restored by GBT1118 treatment, confirming its efficacy in improving anemia. Raman spectroscopy revealed increased mineral-to-organic matrix ratios in SCD femurs of both sexes and elevated carbonate-to-phosphate ratios in males, none of which were altered by GBT1118. Mechanical testing showed decreases in ultimate stress and Young's modulus in female SCD femurs, with no significant differences in males nor rescue by GBT1118. Thus, while GBT1118 improved hematological parameters, it failed to restore the impaired bone material properties observed in SCD mice, highlighting the need for additional therapeutic strategies to address bone fragility in sickle cell disease.
