Chondroitin sulphate proteoglycans (CSPGs) are inhibitors to axon regeneration and plasticity. Bacterial chondroitinase ABC degrades CSPGs and has been extensively reported to be therapeutic after SCI but there remain concerns for its clinical translation. A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS4) is a human enzyme that catalyses the proteolysis of CSPG protein cores. Infusion of ADAMTS4 into the damaged spinal cord was previously shown to improve functional recovery after SCI, however, this therapy is limited in its enzyme form. Adeno-associated viral (AAV) vector gene therapy has emerged as the vector of choice for safe, robust and long-term transgene expression in the central nervous system. Here, an AAV expression cassette containing ADAMTS4 under the control of the astrocytic GfaABC 1 D promoter was packaged into an AAV5 vector. Sustained expression of ADAMTS4 was achieved in vitro and in vivo, leading to widespread degradation of CSPGs. AAV-ADAMTS4 resulted in significantly decreased lesion size, increased sprouting of hindlimb corticospinal tract axons, increased serotonergic fiber density caudal to the injury, and improved functional recovery after moderate contusive SCI.Hindlimb-specific exercise rehabilitation was used to drive neuroplasticity towards improving functional connections. The combination of hindlimb rehabilitation with AAV-ADAMTS4 led to enhanced functional recovery after SCI. Thus, widespread and long-term degradation of CSPGs through AAV-ADAMTS4 gene therapy in a combinational approach with rehabilitation represents a promising candidate for further preclinical development. AbbreviationsAAV Adeno-associated virus ADAMTS A disintegrin and metalloproteinase with thrombospondin motifs ChABC Chondroitinase ABC CS-GAG Chondroitin sulphate glycosaminoglycan CSPG Chondroitin sulphate proteoglycan ECM Extracellular matrix GAG Glycosaminoglycan LV Lentiviral vector

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Lipidated Peptide5 analogues are able to mediate hemichannel openings leading to inhibition of chemical messengers to the extracellular matrix.

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Peptide5 is a 12–amino acid mimetic peptide that corresponds to a region of the extracellular loop 2 (EL2) of connexin43. Peptide5 regulates both cellular communication with the cytoplasm (hemichannels) and cell-to-cell communication (gap junctions), and both processes are implicated in neurological pathologies. To address the poor in vivo stability of native peptide5 and to improve its activity, twenty-five novel peptide5 mimetics were designed and synthesized. All the analogues underwent biological evaluation as a hemichannel blocker and as a gap junction disruptor, and several were assessed for stability in human serum. From this study, it was established that several acylations on the N-terminus were tolerated in the hemichannel assay. However, the replacement of the L-Lys with an N-methylated L-Lys to give H-VDCFLSRPTE-N-MeKT-OH showed good hemichannel and gap junction activity and was more stable in human serum. The cyclic peptide variants generally were not tolerated in either the hemichannel and gap junction assay although several possessed outstanding stability in human serum.