Therapeutic agent for spinal cord injuries
Inventors
Okano, Hideyuki • Toyama, Yoshiaki • Nakamura, Masaya • IWANAMI, Akio • Kitamura, Kazuya • Nakamura, Toshikazu • Funakoshi, Hiroshi • Hanada, Keigo
Assignees
Keio University • Kringle Pharma Inc • University of Osaka NUC
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Publication Number
US-8518880-B2
Publication Date
2013-08-27
Expiration Date
Abstract
Disclosed is a therapeutic agent effective for the fundamental treatment of a spinal cord injury and a demyelinating disease. Specifically disclosed are a therapeutic agent for a spinal cord injury and a therapeutic agent for a demyelinating disease, each of which comprises an HGF protein as an active ingredient.
Core Innovation
The invention relates to improving motor function in a human or an animal having a spinal cord injury by providing a hepatocyte growth factor (HGF) preparation whose active ingredient is an HGF protein. The HGF protein is selected from defined amino acid sequence embodiments including SEQ ID NO:1 and SEQ ID NO:2, and includes HGF amino acid sequences having at least 95% identity with SEQ ID NO:1 or SEQ ID NO:2 while possessing HGF activity.
The invention encompasses HGF preparations in which the HGF is produced by recombinant methods involving integrating a gene encoding SEQ ID NO:1 or SEQ ID NO:2 into a vector, transforming a host cell with the vector, expressing recombinant HGF from the vector, and obtaining the recombinant HGF from a culture supernatant of the transformant. The document describes treatment delivered by intrathecal administration and implantation at a site near the tissue affected by the spinal cord injury to improve motor function.
The preparation further comprises an HGF protein and a biopolymer for localized delivery, including a lactic acid-glycolic acid copolymer with a specified weight average molecular weight range and a specified proportion of HGF to the biopolymer in w/w %, and alternatively a biodegradable polymer selected from lactic acid polymer, lactic acid-glycolic acid copolymer, atelocollagen, collagen, and hyaluronan. The document characterizes performance of the HGF protein-based preparation using rat models for spinal cord injury and reports effects including reduced cavity formation, suppressed demyelination, increased 5HT and GAP43-positive regenerated fibers, and improved BBB motor scores depending on dosing amount and start time.
Claims Coverage
The independent claims cover methods of improving motor function in humans or animals with spinal cord injury using an HGF protein-based preparation delivered either intrathecally or by implantation near affected tissue. Across the independent claims, the inventive features are characterized by defined HGF protein sequence, identity, and activity constraints and, for implantation formats, defined biopolymer formulation constraints.
Intrathecal HGF protein preparation with defined sequence variants
Improving motor function in a human or an animal having a spinal cord injury by selecting a subject and providing the subject with a hepatocyte growth factor (HGF) preparation whose active ingredient is an HGF protein by intrathecal administration, where the HGF is selected from SEQ ID NO:1, SEQ ID NO:2, variants with at least 95% identity to SEQ ID NO:1 or SEQ ID NO:2 possessing HGF activity, and recombinant forms produced by integrating a gene encoding SEQ ID NO:1 or SEQ ID NO:2 into a vector, transforming a host cell, expressing recombinant HGF, and obtaining recombinant HGF from a culture supernatant.
Implantation near injury using HGF protein in lactic acid-glycolic acid copolymer
Improving motor function in a human or an animal having a spinal cord injury by selecting a subject and providing the subject with an HGF preparation whose active ingredient is an HGF protein by implantation at a site near the tissue affected by the spinal cord injury, where the HGF is selected from SEQ ID NO:1, SEQ ID NO:2, variants with at least 95% identity to SEQ ID NO:1 or SEQ ID NO:2 possessing HGF activity, and recombinant forms produced by integrating a gene encoding SEQ ID NO:1 or SEQ ID NO:2 into a vector, transforming a host cell, expressing recombinant HGF, and obtaining recombinant HGF from a culture supernatant; and where the HGF preparation comprises the HGF protein and a lactic acid-glycolic acid copolymer with a specified weight average molecular weight range and a specified HGF-to-biopolymer proportion in w/w %.
Implantation near injury using HGF protein in biodegradable polymers
Improving motor function in a human or an animal having a spinal cord injury by selecting a subject and providing the subject with an HGF preparation whose active ingredient is an HGF protein by implantation at a site near the tissue affected by the spinal cord injury, where the HGF is selected from SEQ ID NO:1, SEQ ID NO:2, variants with at least 95% identity to SEQ ID NO:1 or SEQ ID NO:2 possessing HGF activity, and recombinant forms produced by integrating a gene encoding SEQ ID NO:1 or SEQ ID NO:2 into a vector, transforming a host cell, expressing recombinant HGF, and obtaining recombinant HGF from a culture supernatant; and where the HGF preparation comprises the HGF protein and a biodegradable polymer selected from lactic acid polymer, lactic acid-glycolic acid copolymer, atelocollagen, collagen, and hyaluronan.
Collectively, the independent claims require selecting a human or animal with spinal cord injury and administering an HGF protein-based preparation with defined sequence and identity/activity constraints, including recombinant production options, with delivery performed either intrathecally or via implantation near injured tissue. For implantation formats, the claims additionally constrain the formulation biopolymer, including specific lactic acid-glycolic acid copolymer properties or selection among several biodegradable polymers.
Stated Advantages
Improves motor function in a human or an animal having a spinal cord injury.
Suppresses demyelination.
Reduces cavity formation.
Increases 5HT and GAP43-positive regenerated fibers.
Improves BBB motor scores.
Documented Applications
Treatment of a spinal cord injury to improve motor function in a human or an animal, using an HGF protein preparation delivered intrathecally or implanted near injured tissue.
Documented preclinical application in rat models of spinal cord injury, with reported outcomes including reduced cavity formation, suppressed demyelination, increased 5HT and GAP43-positive regenerated fibers, and improved BBB motor scores.
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