Methods and compositions for regenerating tissues
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Publication Number
US-11891424-B2
Publication Date
2024-02-06
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 patent describes NELL1 peptide fragments or variants for tissue regeneration and wound healing. The fragments or variants have at least 95% or at least 99% sequence identity to SEQ ID NO: 17 or 18 and lack carboxy-terminal sequences corresponding to the carboxy-terminal 179 amino acid residues of a full-length NELL1 protein. The approach links functional performance of the truncated NELL1 forms to the absence of carboxy-terminal von Willebrand factor type C (VWC) domains.
The patent further states that these NELL1 variants or fragments exhibit enhanced efficacy in tissue regeneration and enhanced promotion of wound healing compared to the respective full-length NELL1 protein. The document also identifies easier purification, higher yield, and less aggregate formation as advantages associated with the selected truncation framework. The sequences are identified as SEQ ID NO: 17 or 18.
The document describes delivery and expression contexts for the NELL1 fragments or variants. These contexts include administration of a nucleic acid sequence encoding NELL1 or a protein, with local delivery to wounds and tendon/ligament injuries. It further describes delivery via matrices, wound dressings, scaffolds, implants, and cell-based gene therapy.
Claims Coverage
The independent claims cover nucleic acid-encoded NELL1 peptide fragments or variants in vectors, recombinant expression cassettes, and host cells. Across the independent claims, the inventive features are sequence identity to SEQ ID NO: 17 or 18, truncation defined by loss of the carboxy-terminal 179 amino acid residues or absence of carboxy-terminal VWC domains, and functional selection for enhanced tissue regeneration efficacy and/or enhanced promotion of wound healing compared to full-length NELL1 protein.
NELL1 peptide fragment or variant with sequence identity to SEQ ID NO: 17 or 18
A vector, recombinant expression cassette, or host cell comprising a nucleic acid sequence encoding a NELL1 peptide fragment or variant thereof having at least 95% or at least 99% sequence identity to SEQ ID NO: 17 or 18.
Enhanced properties versus full-length NELL1
The NELL1 peptide fragment or variant thereof has enhanced efficacy in tissue regeneration, enhanced promotion of wound healing, easier purification, higher yield, or less aggregate formation when compared to the respective full-length NELL1 protein.
Carboxy-terminal 179 amino acid truncation
The NELL1 peptide fragment or variant thereof lacks the carboxy-terminal 179 amino acid residues of the respective full-length NELL1 protein.
Absence of carboxy-terminal VWC domains
The NELL1 peptide fragment or variant thereof lacks one or more carboxy-terminal von Willebrand factor type C (VWC) domains of the respective full-length NELL1 protein.
Operably linked promoter with truncated NELL1 encoding cassette
A recombinant expression cassette comprising a nucleic acid sequence encoding a NELL1 peptide fragment or variant thereof and an operably linked promoter.
Coverage centers on vectors, recombinant expression cassettes, and host cells encoding NELL1 peptide fragments or variants that meet defined sequence identity thresholds to SEQ ID NO: 17 or 18 and contain truncations that remove carboxy-terminal 179 amino acid residues or carboxy-terminal VWC domains. The fragments or variants are functionally selected for enhanced tissue regeneration efficacy and/or enhanced promotion of wound healing compared to the corresponding full-length NELL1 protein.
Stated Advantages
Enhanced efficacy in tissue regeneration
Enhanced promotion of wound healing
Easier purification
Higher yield
Less aggregate formation
Documented Applications
Local administration to wounds and tendon/ligament injuries for tissue regeneration and wound healing.
Delivery in cell-based gene therapy contexts to promote fibroblast-driven wound closure and tissue regeneration.
Use of matrices, wound dressings, scaffolds, and implants as delivery formats for the NELL1 fragments or variants or encoding nucleic acids.
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