Method for treating spinal cord injury using HMGB1 fragment
Inventors
Tamai, Katsuto • Yamazaki, Takehiko • Cui, Wenhao
Assignees
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Publication Number
US-9688733-B2
Publication Date
2017-06-27
Expiration Date
Abstract
Fragment peptides having a proper length, which consists of a portion of the HMGB1 protein were synthesized, and the peptides were confirmed to show therapeutic effects on injury of the spinal cord.
Core Innovation
The disclosed subject matter relates to HMGB1 fragment peptide therapeutics for treating injury or the spinal cord. The approach uses a peptide that has an activity of stimulating the migration of mesenchymal stem cells, and the peptide comprises an amino acid sequence selected from SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5.
The invention addresses a problem in which full-length HMGB1/cell therapies are limited by practical and safety-related concerns, including endotoxin (LPS) contamination, and by issues affecting purity, stability, and cost. The described strategy replaces the need for full-length HMGB1/cell approaches by using HMGB1 fragment peptides with mesenchymal stem cell migration-related activity.
The described rationale is that HMGB1 stimulates migration and mobilization and recruits PDGFRα-positive cells. In vitro chemotaxis experiments show that multiple HMGB1 fragments promote migration, and HMGB1 (17–25) is identified as the smallest active fragment. In vivo mouse traumatic spinal cord injury models show improved neurologic function and reduced histological damage after administering HMGB1 fragment peptides versus PBS, with fragment peptides outperforming full-length at later timepoints.
Claims Coverage
The independent claims cover methods for treating injury of the spinal cord or injury/spinal cord by administering HMGB1 fragment peptides, with inventive features focused on mesenchymal stem cell migration-stimulating activity and peptide sequence selection using SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5.
Mesenchymal stem cell migration-stimulating HMGB1 fragment peptide for treating injury or the spinal cord
A method for treating injury or the spinal cord by administering a peptide that has an activity of stimulating the migration of mesenchymal stem cells, wherein the amino acid sequence is selected from SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5.
Spinal cord injury treatment using a defined HMGB1 fragment peptide sequence
A method for treating injury of the spinal cord by administering a peptide consisting of an amino acid sequence selected from SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5.
Across the independent claims, the inventive core is administering HMGB1 fragment peptides defined by SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, with the first claim additionally requiring stimulation of mesenchymal stem cell migration activity and both claims targeting treatment of spinal cord injury or injury/spinal cord.
Stated Advantages
Improved neurologic function in traumatic spinal cord injury models as measured by BMS score after administering HMGB1 fragment peptides versus PBS.
Reduced histological damage in traumatic spinal cord injury models after administering HMGB1 fragment peptides versus PBS.
Fragment peptides outperform full-length at later timepoints in the described in vivo traumatic spinal cord injury comparison.
Smaller peptide reduces LPS/endotoxin affinity.
Improved purity/stability compared with full-length HMGB1/cell therapy.
Reduced cost compared with full-length HMGB1/cell therapy.
Documented Applications
Treating traumatic spinal cord injury in a mouse model using HMGB1 fragment peptide administration, evaluated by neurologic function and histological damage.
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