Methods and compositions for regenerating tissues
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Publication Number
US-11667684-B2
Publication Date
2023-06-06
Expiration Date
Abstract
Provided are methods for promoting the healing of injuries to tendons and ligaments by administering a NELL1 protein or a nucleic acid encoding a NELL1 protein to a subject in need thereof. Also provided are NELL1 compositions and methods for promoting tissue regeneration, promoting the healing of wounds, and enhancing fibroblast migration, proliferation, or both migration and proliferation.
Core Innovation
The disclosed invention relates to NELL1 peptide fragments or variants having at least 99% sequence identity to SEQ ID NO: 17 and lacking one or more carboxy-terminal von Willebrand factor type C (VWC) domains of the fragment's respective full-length NELL1 protein. The fragment or variant exhibits enhanced promotion of wound healing when compared to the fragment's respective full-length NELL1 protein.
The document describes methods and compositions for tendon/ligament and other tissue regeneration using NELL1 protein or a nucleic acid encoding NELL1. It addresses wound healing in injured tendons and ligaments and characterizes NELL1 domain architecture, including a TSPN/LamG region, multiple VWC domains, and EGF-like domains.
The core discovery is that truncating or removing the carboxy-terminal VWC domains of NELL1 produces a NELL1 variant with unexpected manufacturing advantages and improved biological efficacy. The text highlights removal of the carboxy-terminal 179 amino acid residues and reports enhanced promotion of wound healing for the truncated fragment compared to the respective full-length NELL1 protein.
Biological activity is associated with enhanced fibroblast migration and fibroblast proliferation, including dermal fibroblasts and ligament fibroblasts. The document also describes defined peptide fragments and variants with sequence identity relationships to SEQ ID NO: 17 and SEQ ID NO: 18, and administration as local delivery to wounds and injured tendons or ligaments in formats such as injection, matrices, wound dressings, and other pharmaceutical formats.
Claims Coverage
The claim set includes independent claims centered on NELL1 peptide fragments or variants defined by sequence identity relative to SEQ ID NO: 17 and by structural deletion of carboxy-terminal VWC content, while exhibiting enhanced promotion of wound healing versus full-length NELL1. Across the independent claims, the inventive features are sequence-identity containment and lack of carboxy-terminal VWC domains, including the carboxy-terminal 179 amino acid residues.
Sequence identity to SEQ ID NO: 17 with enhanced wound healing
A NELL1 peptide fragment or variant having at least 99% sequence identity to SEQ ID NO: 17, wherein the fragment or variant exhibits enhanced promotion of wound healing when compared to the fragment's respective full-length NELL1 protein.
Carboxy-terminal VWC domain deletion with enhanced wound healing
A NELL1 peptide fragment or variant having at least 99% sequence identity to SEQ ID NO: 17, wherein the fragment or variant exhibits enhanced promotion of wound healing when compared to the fragment's respective full-length NELL1 protein, and lacks one or more carboxy-terminal von Willebrand factor type C (VWC) domains of the fragment's respective full-length NELL1 protein.
Sequence identity to SEQ ID NO: 17 with enhanced wound healing and loss of 179 carboxy-terminal residues
A NELL1 peptide fragment or variant having at least 95% sequence identity to SEQ ID NO: 17, wherein the fragment or variant exhibits enhanced promotion of wound healing when compared to the fragment's respective full-length NELL1 protein, and lacks the carboxy-terminal 179 amino acid residues of the fragment's respective full-length NELL1 protein.
The inventive concept is centered on NELL1 peptide fragments or variants defined by sequence identity to SEQ ID NO: 17 and enhanced wound-healing promotion compared with full-length NELL1, with structural narrowing to deletion of carboxy-terminal VWC domains or the carboxy-terminal 179 amino acid residues.
Stated Advantages
Enhanced promotion of wound healing compared to the fragment's respective full-length NELL1 protein.
Unexpected manufacturing advantages for the truncated or removed carboxy-terminal VWC domain variant, including higher yield, easier purification, and reduced aggregation.
Enhanced fibroblast migration and fibroblast proliferation associated with the NELL1 truncation approach.
Documented Applications
Improved horse body wound healing associated with a horse NELL1 variant lacking C-terminal von Willebrand factor type C domains, evaluated with unhealed inner area, epithelialization, and contraction.
Wound-healing-related evaluation using scratch assays and TOMI 3D/Eykona wound imaging.
Wound-healing-related delivery evaluation using calcium alginate dressing delivery and calcium alginate elution/release.
Local administration to wounds and injured tendons or ligaments using NELL1 protein or a nucleic acid encoding it, including delivery by injection and delivery in matrices or wound dressings.
Use of pharmaceutical composition formats for wound treatment, including incorporation into hydrogels and calcium alginate wound dressing or matrix formats and use of microencapsulation with biodegradable polymers.
In vitro wound scratch assay contexts evaluating fibroblast migration and fibroblast proliferation related to NELL1 fragments or variants.
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