Proteinaceous molecules and uses therefor

Abstract

Disclosed are proteinaceous molecules that are useful for reducing axonal degeneration (e.g., SARM1-mediated axonal degeneration), inducing synapse formation, inhibiting or minimising neuronal injury and treating, or reducing the severity of, neurodegenerative diseases in subjects.

Description

TITLE OF THE INVENTION" PROTEINACEOUS MOLECULES AND USES THEREFOR"

[0001] This application claims priority to Australian Provisional Patent Application No. 2024904221 entitled " Proteinaceous molecules and uses therefor" filed 19 December 2024, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] This invention relates generally to proteinaceous molecules that are useful for reducing axonal degeneration (e.g., SARMl-mediated axonal degeneration), stimulating synapse formation and treating, or reducing the severity of, neurodegenerative diseases in subjects.BACKGROUND OF THE INVENTION

[0003] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0004] Dementia is a term for several diseases (e.g., neurodegenerative diseases (e.g., Alzheimer's disease)) that affect memory, thinking, and a subject's ability to perform daily activities. According to the World Health Organization, more than 55 million people have dementia worldwide, and more than 10 million new cases are diagnosed every year. In 2019, dementia cost global economies an estimated $1.3 trillion U. S. dollars. Dementia is also the seventh leading cause of death throughout the world (World Health Organization, 2023; https: / / www.who.int / news-room / fact-sheets / detail / dementia).

[0005] Axons are disproportionately large structures, accounting for 99.9% of neuronal cell volume. Neurons have an evolutionarily conserved axonal self-destruction mechanism, independent of apoptosis, to promptly remove these large structures when they are injured, damaged or unhealthy (Figley, M. D. and DiAntonio, A., Curr. Opin. Neurobiol. 2020, 63:59-66). SARM1 plays a crucial role in execution of such axonal selfdestruction. SARM1 acts as a hydrolase digesting nicotinamide adenine dinucleotide (NAD+), an essential molecule required for adenosine triphosphate (ATP) synthesis and energy homeostasis. Upon injury or blockage of axonal transport, the generation of NAD+ in the axons is impaired. The fall in NAD+ levels unhealthy axons activating SARM1 (Figley, M. D. et al., Neuron. 2021, 109(7)). Hence, SARM1 is a sensor formetabolic changes in axons that, once activated, drives catastrophic depletion of NAD+, causing rapid axon degeneration.

[0006] Axonal degeneration occurs in various forms of dementia and is linked with the accumulation of toxic misfolded proteins, such as amyloid beta, tau, and TAR DNA binding protein 43 (TDP-43) (Salvadores, N. et al., Front. Aging Neurosci. 2020, 12:581767; Figley, M. D. et al., Neuron. 2021, 109(7); and Altman, T. et al., Nat.Common. 2021, 12(1)). Pathological forms of these proteins induce chronic axonal stress by various mechanisms, including defective axonal transport or inhibition of local axonal protein synthesis. Together, toxic forms of TDP-43 and tau account for 90% of frontotemporal dementia (FTD) cases (Rademakers, R. et al., Nat. Rev. Neurol. 2013, 9(5):240). TDP-43 is a mRNA binding protein which delivers mRNA to distal axon sites and mediates local synthesis of essential axonal and synaptic proteins (Melamed, Z. et al., Nat. Neurosci. 2019, 22(2): 180). Similarly, tau is an essential microtubule stabilising protein which maintains axonal transport (Kneynsberg, A. et al., Fronti Neurosci-Switz.2017, 11). Aberrant forms of tau and TDP-43 do not function normally leading to unhealthy axons and their degeneration (Melamed, Z. et al., Nat. Neurosci. 2019, 22(2): 180; and Kneynsberg, A. et al., Fronti Neurosci-Switz. 2017, 11). Gain of toxic function by pathological forms of tau and TDP-43 has also been shown to cause axon loss (Salvadores, N. et al., Front. Aging Neurosci. 2020, 12:581767; Altman, T. et al., Nat. Common. 2021, 12(1); Walker, A. K. et al., Acta. Neuropathol. 2015, 130(5):643-60). Early activation of axonal degeneration is also observed in other forms of dementia associated with p-amyloid plaques (Yuan, P. et al., Nature 2022, 612(7939):328-37) and chronic traumatic encephalopathy (CTE) dementia (Stein, T. D. et al., Alzheimers Res. Ther. 2014, 6(1):4). Hence, blocking axonal degeneration is a promising strategy to slow cognitive decline in various forms of dementia.

[0007] Despite significant interest in developing anti-SARMl therapeutics, it remains unclear whether blocking SARM1 activity can be effective in all conditions (Collins, J. M. et al., Neurobiol. Dis. 2022, 172:105821; and White, M. A. et al., Acta Neuropathol. Common. 2019, 7(1):1669). Current evidence suggests that SARM1 executes rapid axon degeneration (Figley, M. D. et al., Neuron. 2021, 109(7)). However, in chronic conditions like dementia, rapid axon degeneration does not occur. Rather, a slow degeneration occurs over several years, and a sudden drop in NAD+ is not expected to occur.

[0008] Accordingly, there exists a need for new therapeutic agents that modulate SARM1 activity via alternative pathways and which may be useful in conditions associated with axonal degeneration, such as neurodegenerative diseases.SUMMARY OF THE INVENTION

[0009] Provided herein are proteinaceous molecules that are useful for reducing axonal degeneration (e.g., SARMl-mediated axonal degeneration) and stimulating synapse formation.

[0010] In one aspect, the present invention provides a proteinaceous molecule comprising, consisting, or consisting essentially of an amino acid sequence represented by Formula (I):Z1X1X2X3X4MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2(I)wherein:X1is absent or is any amino acid residue, preferably an aromatic amino acid residue such as Y;X2 is absent or is any amino acid residue, preferably a small amino acid residue such as T; X3 is absent or is any amino acid residue, preferably a hydrophobic amino acid residue such as I;X4 is absent or is any amino acid residue, preferably an aromatic amino acid residue such as W;X5 is any amino acid residue, preferably a small amino acid residue such as P, or a hydrophobic amino acid residue, preferably an aliphatic amino acid residue such as V; X6is any amino acid residue, preferably a basic amino acid residue such as R, or a small amino acid residue such as G;X7 is any amino acid residue, preferably a hydrophobic amino acid residue, more preferably an aliphatic amino acid residue such as L, or a small amino acid residue such as P;X8is any amino acid residue, preferably a small amino acid residue such as G, or a basic amino acid residue such as R;X9 is any amino acid residue, preferably a small amino acid residue such as T, or a hydrophobic amino acid residue, preferably an aliphatic amino acid residue such as M; X10 is absent or is any amino acid residue, such as C;X11is absent or is any amino acid residue, preferably an acidic amino acid residue such as D;X12 is absent or is any amino acid residue, preferably a hydrophobic amino acid residue such as I;X13 is absent or is any amino acid residue, preferably a hydrophobic amino acid residue including an aromatic amino acid residue such as F, or an aliphatic amino acid residue such as L;X14 is absent or is any amino acid residue, preferably a small amino acid residue such as T, or a hydrophobic amino acid residue, preferably an aliphatic amino acid residue such as V;X15 is absent or is any amino acid residue, preferably a neutral / polar amino acid residue such as N;X16is absent or is any amino acid residue, preferably a small amino acid residue such as S;X17 is absent or is any amino acid residue, preferably a basic amino acid residue such as R;X18is absent or is any amino acid residue, preferably a small amino acid residue such as G;X19 is absent or is any amino acid residue, preferably a basic amino acid residue such as K;X20 is absent or is any amino acid residue, preferably a basic amino acid residue such as R;X21 is absent or is any amino acid residue, preferably a small amino acid residue such as A, or an acidic amino acid residue such as E;X22 is absent or is any amino acid residue, preferably a small amino acid residue such as S or P;X23 is absent or is any amino acid residue, preferably a basic amino acid residue such as K, or a neutral / polar amino acid residue such as N;X24 is absent or is any amino acid residue, preferably a small amino acid residue such as G, or a basic amino acid residue such as R;X25 is absent or is any amino acid residue, preferably a small amino acid residue such as S, G or T, or a neutral / polar amino acid residue such as N;X26 is absent or is any amino acid residue, preferably a basic amino acid residue such as K;X27 is absent or is any amino acid residue, preferably a small amino acid residue such as T or A;X28 is absent or is any amino acid residue, preferably C;Zi and Z2 are independently absent or independently selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.

[0011] In some embodiments, at least one of:Xi is Y; X2is T; X3is I; and X4is W.

[0012] In some embodiments, at least one of:Xi is absent; X2 is absent; X3 is absent; and X4 is absent.

[0013] In some embodiments, X5 is a small amino acid residue. In particular embodiments, X5 is P.

[0014] In some embodiments, X6is a basic amino acid residue. In particular embodiments, X6is R.

[0015] In some embodiments, X7 is a small amino acid residue. In particular embodiments, X7 is P.

[0016] In some embodiments, X6is a basic amino acid residue. In particular embodiments, X6is R.

[0017] In some embodiments, X9 is a small amino acid residue. In particular embodiments, X9 is T.

[0018] In some embodiments, at least one of:X10is C; X11is D; and X12is I.

[0019] In alternative embodiments, at least one of:X10 is absent; X11is absent; and X12is absent.

[0020] In some embodiments, X13 is an aromatic amino acid residue. In some embodiments, X13 is F.

[0021] In some embodiments, X14 is a small amino acid residue. In particular embodiments, X14 is T.

[0022] In some embodiments, X15 is N.

[0023] In some embodiments, at least one of:X16is S; X17is R; X18is G; and X19is K.

[0024] In alternative embodiments, at least one of:X16is absent; X17is absent; X18is absent; and X19is absent.

[0025] In some embodiments, X20 is a basic amino acid residue. In some embodiments, X20 is R.

[0026] In some embodiments, X21 is a small amino acid residue. In particular embodiments, X21 is A.

[0027] In some embodiments, X22 is a small amino acid residue. In particular embodiments, X22 is S.

[0028] In some embodiments, X23 is a neutral / polar amino acid residue. In particular embodiments, X23 is N.

[0029] In some embodiments, X24 is a small amino acid residue. In particular embodiments, X24 is G.

[0030] In some embodiments, X25 is a neutral / polar amino acid residue. In particular embodiments, X25 is N.

[0031] In some embodiments, X26 is a basic amino acid residue. In particular embodiments, X26 is K.

[0032] In some embodiments, X27 is a small amino acid residue. In particular embodiments, X27 is T.

[0033] In some embodiments, X28 is C.

[0034] In particular embodiments, at least one of X1, X2, X3, X4, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28is absent.

[0035] In some embodiments, X1, X2, X3, X4, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28are absent.

[0036] In some embodiments, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28are absent.

[0037] In some embodiments, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28are absent.

[0038] In some embodiments, X20, X21, X22, X23, X24, X25, X26, X27, and X28are absent.

[0039] In particular embodiments, X5is P, X6is R, X7is P, X8is R, and X9is T.

[0040] In some embodiments, each of Zi and Z2 are absent. Alternatively, in some embodiments, one of Zi and Z2 is absent and the other of Zi and Z2 is selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.

[0041] In some embodiments, each of Zi and Z2 are independently selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.

[0042] In particular embodiments, the proteinaceous molecule is between 10 amino acid residues and 100 amino acid residues in length, or comprises between 10 amino acid residues and 100 amino acid residues.

[0043] In particular embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula (I-P):Z1X1X2X3X4MPENPRPRTPX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2(I-P),wherein each of Zi, Xi, X2, X3, X4, X10, Xu, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, and Z2are as defined for Formula I above.

[0044] In specific embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-16:YTIWMPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 1];MPENPRPRTP [SEQ ID NO: 2];WMPENPRPRTP [SEQ ID NO: 3];IWMPENPRPRTP [SEQ ID NO: 4];TIWMPENPRPRTP [SEQ ID NO: 5];YTIWMPENPRPRTP [SEQ ID NO: 6];YTIWMPENPRPRTPCDIFTNSRGK [SEQ ID NO: 7];YTIWMPENPRPRTPCDIFTN [SEQ ID NO: 8];MPENPRPRTPCDIFTNSRGK [SEQ ID NO: 9];MPENPRPRTPCDIFTN [SEQ ID NO: 10];MPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 11];MPENPRPRTPCDIFTNSRGKRASNG [SEQ ID NO: 12];WMPENPRPRTPCDIFTNSRGKRASNGN [SEQ ID NO: 13];IWMPENPRPRTPCDIFTNSRGKRASNGNK [SEQ ID NO: 14];TIWMPENPRPRTPCDIFTNSRGKRASNGNKT [SEQ ID NO: 15]; and NHDYTIWMPENPRPRTPCDIFTNSRGKRASN [SEQ ID NO: 16].

[0045] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1, 2, 7 and 8.

[0046] In another aspect, the present invention provides an isolated or recombinant proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence selected from:a) the amino acid sequence:FGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGYISAIKVNGF TCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYPD YHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIW MPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMD GTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVKKREECLDTLESIMTTKSV SFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHV NGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHPLADPSTVFKEGDEAEDF VEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSLMTWCRRANRPESKQRS FGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 31];b) the amino acid sequence:MVPQVLLFVLLLGFSLCFGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFS YMELKVGYISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWK MAGDPRYEESLHNPYPDYHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSG ITVSSTYCSTNHDYTIWMPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLK GACRLKLCGVLGLRLMDGTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVK KREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEI IPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHP LADPSTVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSL MTWCRRANRPESKQRSFGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 32];c) the amino acid sequence:FGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGYISAIKVNGF TCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYPD YHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIW MPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMD GTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVKKREECLDTLESIMTTKSV SFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHV NGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHPLADPSTVFKEGDEAEDF VEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSLMTWC [SEQ ID NO: 33]; andd) the amino acid sequence:MVPQVLLFVLLLGFSLCFGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFS YMELKVGYISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWK MAGDPRYEESLHNPYPDYHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSG ITVSSTYCSTNHDYTIWMPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLK GACRLKLCGVLGLRLMDGTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVK KREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEI IPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHP LADPSTVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSL MTWC [SEQ ID NO: 34],

[0047] In another aspect, the present invention provides a chimeric molecule comprising a proteinaceous molecule as described herein and at least one ancillary moiety.

[0048] In some embodiments, the at least one ancillary moiety comprises a polypeptide transport moiety that facilitates transport of the proteinaceous molecule across a biological membrane. In other embodiments, the polypeptide transport moiety comprises a cell-penetrating moiety that facilitates entry of the proteinaceous molecule into a cell. For example, the cell-penetrating moiety may comprise polyarginine.

[0049] In other embodiments, the cell-penetrating moiety comprises a cellpenetrating peptide. For example, the cell-penetrating peptide may be derived from the transactivator of transcription (TAT) of human immunodeficiency virus. In some embodiments, the cell-penetrating peptide comprises, consists, or consists essentially of the amino acid sequence YGRKKRRQRRR [SEQ ID NO: 35] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 35.

[0050] In some embodiments, the polypeptide transport moiety comprises a signal peptide moiety that directs secretion of the proteinaceous molecule outside of a cell. For example, the signal peptide moiety may comprise, consist, or consist essentially of the amino acid sequence MVPQVLLFVLLLGFSLC [SEQ ID NO: 24] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 24.

[0051] In some embodiments, the polypeptide transport moiety comprises a transmembrane peptide moiety that localises the proteinaceous molecule to a synaptic membrane. For example, the transmembrane peptide moiety may comprise, consist, or consist essentially of the amino acid sequence KYVLMTAGAMIGLVLIFSLMTWC [SEQ ID NO: 25] or an amino acid sequence having at least 85% (such as from 85% to 99% andall integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 25.

[0052] In some embodiments, the polypeptide transport moiety comprises a receptor binding moiety that binds to a receptor that aids cellular uptake of the proteinaceous molecule. In other embodiments, the receptor binding moiety binds to p75 neurotrophin receptor (p75NTR). For example, the receptor binding moiety may comprise, consist, or consist essentially of the amino acid sequence MTTKSVSFRRL [SEQ ID NO: 26], SHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPS [SEQ ID NO: 27], KGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLL [SEQ ID NO: 28], or MTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHVNG VFFNGIILGPDDHVLIPEMQSSLL [SEQ ID NO: 29], or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by any one of SEQ ID NOs: 26-29.

[0053] In some embodiments, the polypeptide transport moiety comprises a PDZ domain. In other embodiments, the PDZ domain binds to MAST2. For example, the PDZ domain may comprise, consist, or consist essentially of the amino acid sequence RRANRPESKQRSFGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 30] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 30.

[0054] In some embodiments, the at least one ancillary moiety comprises a targeting ligand.

[0055] In some embodiments, the at least one ancillary moiety is directly linked to the proteinaceous molecule. In other embodiments, the at least one ancillary moiety is linked to the proteinaceous molecule via a covalent linker. In some embodiments, the at least one ancillary moiety is a plurality of ancillary moieties, wherein at least one of the ancillary moieties is directly linked to the proteinaceous molecule, and wherein at least one of the ancillary moieties is linked to the proteinaceous molecule via a covalent linker. In some embodiments, the at least one ancillary moiety is linked to the N-terminus of the proteinaceous molecule. In other embodiments, the at least one ancillary moiety is linked to the C-terminus of the proteinaceous molecule. In some embodiments, the at least one ancillary moiety is a plurality of ancillary moieties, wherein at least one of the ancillary moieties is linked to the N-terminus of the proteinaceous molecule, and wherein at least one of the ancillary moieties is linked to the C-terminus of the proteinaceous molecule.

[0056] In a further aspect, the present invention provides an expression vector comprising a nucleic acid sequence that encodes a proteinaceous molecule as described herein or a chimeric molecule as described herein. In some embodiments, the expression vector is other than a rabies virus or virion. In some embodiments, the nucleic acid sequence is operably connected to a heterologous promoter.

[0057] In one aspect, the present invention provides a construct comprising a nucleic acid sequence that encodes a proteinaceous molecule as described herein or a chimeric molecule as described herein, operably connected to a heterologous promoter.

[0058] In another aspect, the present invention provides a host cell comprising an expression vector as described herein or a construct as described herein.

[0059] In yet a further aspect, the present invention provides a composition comprising, consisting, or consisting essentially of a proteinaceous molecule as described herein or a chimeric molecule as described herein, and a pharmaceutically acceptable carrier or diluent. In some embodiments, the composition further comprises at least one of a nanoparticle and a liposome.

[0060] Also provided herein is a use of a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein, for treating or inhibiting axonal degeneration in a subject. In one aspect, the present invention provides a method of treating or inhibiting axonal degeneration in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein. In some embodiments, the axonal degeneration is SARMl-mediated axonal degeneration.

[0061] Further provided herein is a use of a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein, for treating a neurodegenerative disease in a subject. In another aspect, the present invention provides a method of treating a neurodegenerative disease in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein. In some embodiments, the neurodegenerative disease is motor neuron disease, dementia (e.g., Alzheimer's disease), Parkinson's disease, multiple sclerosis, traumatic brain injury, traumatic spinal cord injury, glaucoma, peripheral neuropathy, Guillain-Barre syndrome, chemotherapy-induced or diabetes-induced neuropathy, or chronic traumatic encephalopathy.

[0062] In a further aspect, the present invention provides a use of a proteinaceous molecule as described herein, a chimeric molecule as described herein, ora composition as described herein, for modulating CaMKII in a subject. In another aspect, the present invention provides a method of modulating CaMKII in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein.

[0063] In yet another aspect, the present invention provides a use of a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein, for decreasing a rate of brain ageing in a subject. Also provided herein is a method of decreasing a rate of brain ageing in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein.

[0064] Further provided herein is a use of a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein, for inhibiting or minimising neuronal injury in a subject. In one aspect, the present invention provides a method of inhibiting or minimising neuronal injury in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein.

[0065] In another aspect, there is provided a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein, for use in treating or inhibiting axonal degeneration in a subject.

[0066] In some embodiments, the axonal degeneration is SARMl-mediated axonal degeneration.

[0067] Also provided, in a further aspect, is a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein, for use in treating a neurodegenerative disease in a subject.

[0068] In some embodiments, the neurodegenerative disease is motor neuron disease, dementia (e.g., Alzheimer's disease), Parkinson's disease, multiple sclerosis, traumatic brain injury, traumatic spinal cord injury, glaucoma, peripheral neuropathy, Guillain-Barre syndrome, chemotherapy-induced or diabetes-induced neuropathy, or chronic traumatic encephalopathy.

[0069] In a further aspect, there is provided a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein, for use in modulating CaMKII in a subject.

[0070] In yet another aspect, there is provided a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein, for use in decreasing a rate of brain ageing in a subject.

[0071] In a further aspect, there is provided a proteinaceous molecule as described herein, a chimeric molecule as described herein, or a composition as described herein, for use in inhibiting or minimising neuronal injury in a subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1A provides images of mouse primary cortical neurons that were either mock infected or infected with a parental stock of a rabies strain (rabies isolated from an infected dog in Zimbabwe (Z. DOG)). The image of the mock infected neurons show co-staining of shorter dendrites with MAP2 antibody (green) and longer axons with neurofilament antibody (red) in the same neurons. Infection with Z. DOG strain for 24 hours resulted in significant loss of filamentous dendritic and axonal staining in neurons. Rabies infection is identified by staining with anti-rabies nucleoprotein antibody (magenta) and nuclei are stained in blue.

[0073] Figure IB is an image of neurons cultured in a microfluidic chamber for axonal infection studies with rabies (Tubulin-red).

[0074] Figure 1C provides images of dorsal root ganglion (DRG) mouse neurons that are either mock infected or infected with a rabies strain (rabies isolated from an infected dog in Thailand (T. DOG)). The T. DOG infected DRG neuronal axons separated in the microfluidic device, indicating axonal self-destruction.

[0075] Figure ID is a graphical representation of MAP2-positive neurites relative to cell nuclei in WT, SARM1- / -cortical neurons infected with different strains of rabies virus from 24 hours up to 7 days. At least 500 neurons were quantified per sample. ****p < 0.0001, ***p < 0.001 versus mock infection, N = 3, data presented as mean ± standard error of the mean (SEM).

[0076] Figure 2A provides images of cortical neurons stained with MAP2 antibody to indicate axons and 4',6-diamidino-2-phenylindole (DAPI) to indicate nuclei. Neurons infected with a highly neuroinvasive strain of rabies virus (CVS-11; also referred to herein as "rabies X") showed an increase in MAP2-positive axons when treated with 20 nM vincristine (VNC) as compared to uninfected neurons treated with VNC.

[0077] Figure 2B is a graphical representation of MAP2-positive neurites relative to cell nuclei for the cortical neurons of Figure 2A. ***p < 0.001, N = 3, data presented as mean ± SEM.

[0078] Figure 2C provides images of axons of DRG neurons that were either uninfected or infected with CVS-11 over 24 hours. Axons of uninfected DRG neuronsrapidly disintegrated into granular debris within about 8 hours, whereas axons of CVS-11 infected DRG neurons showed gradual axonal degeneration.

[0079] Figure 2D is a graphical representation of axonal degeneration for the DRG neurons of Figure 2C. N = 3, data presented as mean ± SEM.

[0080] Figure 3A provides images of cortical neurons stained with MAP2 antibody to indicate axons (green) and DAPI to indicate nuclei (blue). A glycoprotein (gp-X) from CVS-11 was expressed in one sample of neurons (red). The neurons expressing gp-X showed intact MAP2-positive axons when treated with 100 nM VNC as compared to uninfected neurons treated with VNC.

[0081] Figure 3B is a graphical representation of axonal degeneration in wild type neurons, neurons expressing gp-X, and SARM knockout neurons, each treated with VNC or subjected to axotomy. ***P<0.0001, N = 3, at least 1,000 neurons were counted from each sample, data presented as mean ± SEM.

[0082] Figure 4A provides images of neuronal membranes expressing either gp-X or a corresponding glycoprotein from Z. DOG (gp-Y). Gp-X forms numerous protrusions (green) from a dendrite (magenta) that appear to be connecting with a neighbouring axon (red). In contrast, gp-Y does not form protrusions.

[0083] Figure 4B provides live-cell confocal images showing dynamic motility of the gp-X formed protrusions of Figure 4A. Representative images are shown at 0, 29, and 46 seconds of live imaging. Arrows point to the protrusions in live neurons.

[0084] Figure 4C provides high-resolution airyscan images showing extensive co-localisation of gp-X (green) with pre-synaptic terminals (synapsin 1 positive, red) and increased synapses (red) as compared with gp-Y.

[0085] Figure 4D is a graphical representation of the number of pre-synaptic terminals in the images of Figure 4C. Data are represented as the mean ± SEM;***P<0.001, N = 3.

[0086] Figures 5A and 5B provide representative confocal images of mouse cortical neurons expressing gp-X, gp-Y, or gp-Y mutants.

[0087] Figure 5C provides high magnification confocal images (40x) of mouse cortical neurons expressing gp-X, gp-Y, and a particular gp-Y mutant (gp-Y-S207P). Localization of gp-X and gp-Y-S207P in synapse-forming membrane protrusions are similar.

[0088] Figure 5D provides super resolution dSTORM images of mouse cortical neurons expressing gp-X, gp-Y, and a particular gp-Y mutant (gp-Y-S207P). Localizationof gp-X protein observed with presynaptic marker (Bassoon) and postsynaptic marker (HOMER1).

[0089] Figure 5E is a graphical representation of the quantification of colocalisation of glycoproteins with both Bassoon and HOMER1 from the images in Figure 5D, showing a significantly high number of synapses in neurons expressing gp-X and gp-Y-S207P mutant proteins but not gp-Y protein.

[0090] Figure 6A is a representation of neuronal synaptic proteins identified as interacting with gp-X and gp-Y glycoproteins according to green fluorescent protein (GFP) tag and TurboID tag pull down approaches, and mass spectrometry. Analysis shows a significantly high interaction of synaptic proteins with gp-X compared to gp-Y protein. Specifically, a higher interaction of CaMKII was observed with gp-X compared to gp-Y.

[0091] Figure 6B is a western blot showing an interaction between gp-X and calcium / calmodulin-dependent protein kinase II (CaMKII).

[0092] Figure 7 is a heatmap of kinase activity score based on the phosphoproteome of neuronal lysates expressing gp-X, gp-Y, and gp-Y mutant (gp-Y-S207P). In this analysis, kinase activity CaMKIIa was found be significantly upregulated in neurons expressing gp-X and gp-Y-S207P compared to control or gp-Y.

[0093] Figure 8A is a western blot wherein neuronal lysates expressing gp-X and gp-Y were untreated or treated with CaMKII inhibitor KN93. The western blot shows an increase in phosphorylated CaMKII in neurons expressing gp-X.

[0094] Figure 8B is a graphical representation of phosphorylated CaMKII in the western blot of Figure 8A.

[0095] Figure 8C is a graphical representation of axonal degeneration in neurons expressing gp-X, neurons expressing a particular gp-X mutant (gp-X-P207S), and neurons expressing gp-Y upon treatment with 100 nM of VNC. Data are represented as the mean ± SEM; ***P<0.001, N = 2.

[0096] Figures 9A and 9B depict an AlphaFold2 prediction of a gp-X / CaMKII complex.

[0097] Figure 10 provides representative confocal images of mouse cortical neuronal axons treated with gp-X-33 (FITC, green) with [gp-X-33-9R-FITC (right)] and without the cell penetration tag [gp-X-33-FITC (left)] showing its level of uptake.

[0098] Figure 11A provides an outline of the high-throughput axonal degeneration assay of Example 11.

[0099] Figure 11B provides representative confocal images of mouse primary cortical neurons that were incubated with vincristine or vincristine and 100 nM gp-X-24.

[0100] Figure 11C is a graphical representation of axonal degeneration (%) induced by vincristine and its inhibition by 5 nM, 50 nM, 500nM or 2.5 pM gp-X-20, gp-X-24, gp-X-33 or gp-X-33-9R in mouse neurons. 10 images from 10 technical repeats were quantified for each biological repeat (N = 3). ****p < 0.0001, ***p < 0.001, **p < 0.01 versus VNC treated, N = 3, data presented as mean ± standard error of the mean (SEM).

[0101] Figure 12A provides high-resolution confocal image of gp-X peptide (green) membrane distribution in mouse cortical neuronal axon (TUJ1) and the membrane colocalisation of gp-X-20 (green) with CaMKII (red).

[0102] Figure 12B provides an outline of the gp-X peptide interaction analysis using the biotin tag with streptavidin magnetic beads of Example 12.

[0103] Figure 12C is a western blot of mouse neuronal lysates showing the interaction of CaMKII with gp-X-10 and gp-X-20.

[0104] Figure 13A provides an outline of the drop culture and axonal degeneration assay of Example 13.

[0105] Figures 13B and 13C provide representative confocal images (Figure 13B) and quantification (Figure 13C) of axonal degeneration induced by vincristine (VNC) and its inhibition by gp-X-10 in mouse cortical neurons. 10 images from 10 technical repeats were quantified for each biological repeat (N = 2). ****p < 0.0001, *p < 0.05 versus VNC treated, N = 3, data presented as mean ± standard error of the mean (SEM).

[0106] Figure 14A provides an outline of the drop culture and axonal degeneration assay of Example 14.

[0107] Figures 14B and 14C provide representative confocal images (Figure 14B) and quantification (Figure 14C) of axonal degeneration induced by rotenone and its inhibition by gp-X-10 in mouse cortical neurons. 10 images from 10 technical repeats were quantified for each biological repeat (N = 2). ****p < 0.0001, **p < 0.01 versus rotenone treated, data presented as mean ± standard error of the mean (SEM). is a

[0108] Figure 15A provides an outline of the drop culture and axonal degeneration assay of Example 15.

[0109] Figures 15B and 15C provide representative confocal images (Figure 15B) and quantification (Figure 15C) of axonal degeneration induced by vincristine (VNC, 40 nM) and its inhibition by gp-X-10 in IPSC-derived human motor neurons. 10 images from 10 technical repeats were quantified for each biological repeat (N = 3). ****p < 0.0001, versus VNC treated, N = 3, data presented as mean ± standard error of the mean (SEM).

[0110] Figure 16A provides an outline of the drop culture and axonal degeneration assay of Example 16.

[0111] Figures 16B and 16C provide representative confocal images (Figure 16B) and quantification (Figure 16C) of axonal degeneration induced by rotenone and its inhibition by gp-X-10 in IPSC-derived human motor neurons. 10 images from 10 technical repeats were quantified for each biological repeat (N = 3). ****p < 0.0001, versus rotenone treated, N = 3, data presented as mean ± standard error of the mean (SEM).

[0112] Figures 17A, 17B and 17C are graphical representations of the clinical signs of motor neurone syndrome (MND) and frontotemporal dementia (FTD) including tremor (Figure 17A), hindlimb clasping (Figure 17B) and grill agility (Figure 17C) in a mouse model of MND and FTD following administration of low (1 pg / day) and high (10 pg / day) doses of gp-X-10 by intracerebroventricular infusion for 26 days.

[0113] Figures 18A and 18B are graphical representations of the neurofilament light chain (NfL) concentration in the cerebrospinal fluid (CSF) (Figure 18A) and plasma (Figure 18B) in a mouse model of MND and FTD following administration of low (1 pg / day) and high (10 pg / day) doses of gp-X-10 by intracerebroventricular infusion for 26 days.

[0114] Figure 19A is a Western blot showing the levels of synapsin, neurofilament (NF), phosphorylated glycogen synthase kinase-3 beta (pGSK3b) and glyceraldehyde 3-phosphate dehydrogenase (GADPH) in brain lysates from a mouse model of MND and FTD following administration of low (1 pg / day) and high (10 pg / day) doses of gp-X-10 by intracerebroventricular infusion for 26 days.

[0115] Figure 19B is a graphical representation of synapsin, NF and pGSK3b in the western blot of Figure 19A.DETAILED DESCRIPTION OF THE INVENTION

[0116] As used herein, the following definitions shall apply unless otherwise indicated.1. Definitions

[0117] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0118] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0119] Amino acid residues are defined herein on the basis of the side chain classification in some instances. Families of amino acid residues having similar side chains have been defined in the art, which can be generally sub-classified as follows:TABLE 1AMINO ACID SUB-CLASSIFICATIONSub-Classes Amino acidsAcidic Aspartic acid (Asp; D) and Glutamic acid (Glu; E)Basic Noncyclic: Arginine (Arg; R) and Lysine (Lys; K)Cyclic: Histidine (His; H)Charged Aspartic acid, Glutamic acid, Arginine, Lysine, and Histidine Small Glycine (Gly; G), Serine (Ser; S), Alanine (Ala; A), Threonine (Thr,T), and Proline (Pro; P)Neutral / Polar Asparagine (Asn, N), Histidine, Glutamine (Gin; Q), Cysteine (Cys;C), Serine, and ThreoninePolar / large Asparagine and GlutamineHydrophobic Tyrosine (Tyr; Y), Valine (Vai; V), Isoleucine (He; I), Proline,Alanine, Leucine (Leu; L), Methionine (Met; M), Phenylalanine (Phe; F), and Tryptophan (Trp; W)Aliphatic Valine, Isoleucine, Leucine, Proline, Methionine, and Alanine Aromatic Tryptophan, Tyrosine, and PhenylalanineResidues that Glycine and Prolineinfluence chainorientationAmide containing Asparagine and Glutamineamino acid residues

[0120] As used herein, the term "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (or).

[0121] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step orgroup of integers or steps but not the exclusion of any other integer or step or group of integers or steps. Thus, the use of the term "comprising" and the like indicates that the listed integers are required or mandatory, but that other integers are optional and may or may not be present. By "consisting of" is meant including, and limited to, whatever follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of" is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements. In specific embodiments, the term "consisting essentially of", in the context of a specific amino acid sequence disclosed herein, includes within its scope about 1 to about 40 optional amino acids (and all integer optional amino acids in between) upstream of the specific amino acid sequence and / or about 1 to about 40 optional amino acids (and all integer optional amino acids in between) downstream of the specific amino acid sequence, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 optional amino acids upstream and / or downstream of the specific amino acid sequence.

[0122] The term "expression" refers to the biosynthesis of a gene product. For example, in the case of a coding sequence, expression involves transcription of the coding sequence into mRNA and translation of mRNA into one or more polypeptides. Conversely, expression of a non-coding sequence involves transcription of the non-coding sequence into a transcript only. The term "expression" is also used herein to refer to the presence of a protein or molecule in a particular location and, thus, may be used interchangeably with "localization".

[0123] By "expression vector" is meant any genetic element capable of directing the transcription of a polynucleotide contained within the vector and suitably the synthesis of a peptide or polypeptide encoded by the polynucleotide. Such expression vectors are known to practitioners in the art.

[0124] The term "host cell" includes an individual cell or cell culture which can be or has been a recipient of any recombinant vector(s) or isolated polynucleotide of the invention. Host cells include progeny of a single host cell and the progeny may not necessarily be completely identical (in morphology or in total DNA complement) to the original parent cell due to natural, accidental or deliberate mutation and / or change. A host cell includes cells transfected or infected in vivo or in vitro with a recombinantvector or a polynucleotide of the invention. A host cell which comprises a recombinant vector of the invention is a recombinant host cell.

[0125] As used herein, the term "isolated" refers to material that is substantially or essentially free from components that normally accompany it in its native state. For example, an "isolated proteinaceous molecule" refers to in vitro isolation and / or purification of a proteinaceous molecule from its natural cellular environment and from association with other components of the cell. " Substantially free" means that a preparation of proteinaceous molecule is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% pure. In a preferred embodiment, the preparation of proteinaceous molecule has less than about 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% (by dry weight), of molecules that are not the subject of this invention (also referred to herein as "contaminating molecules"). When the proteinaceous molecule is recombinantly produced, it is also desirably substantially free of culture medium, i.e., culture medium represents less than about 20, 15, 10, 5, 4, 3, 2 or 1% of the volume of the preparation. The invention includes isolated or purified preparations of at least 0.01, 0.1, 1.0, and 10 milligrams in dry weight.

[0126] By "modulating" is meant increasing or decreasing, either directly or indirectly, the level or functional activity of a target molecule (e.g., calcium / calmodulin-dependent protein kinase II (CaMKII)). For example, an agent may directly or indirectly (e.g., by interacting with a molecule other than the target molecule) modulate the level or functional activity of the molecule. As used herein, "modulating CaMKII" may refer to activation of CaMKII to thereby inhibit SARMl-mediated axonal degeneration and / or induce synapse formation.

[0127] By "pharmaceutically acceptable carrier" is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction. Carriers may include excipients and other additives such as diluents, detergents, coloring agents, wetting or emulsifying agents, pH buffering agents, preservatives, transfection agents and the like.

[0128] Similarly, a "pharmaceutically acceptable" salt, ester, amide, prodrug or derivative of a compound as provided herein is a salt, ester, amide, prodrug or derivative that this not biologically or otherwise undesirable.

[0129] As used herein, the terms "polypeptide", "proteinaceous molecule", "peptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues and to variants and synthetic analogues of the same. Thus, these terms apply to amino acid polymers in which one or more amino acid residues is a synthetic non-naturally-occurring amino acid, such as a chemical analogue of a correspondingnaturally-occurring amino acid, as well as to naturally-occurring amino acid polymers. These terms do not exclude modifications, for example, glycosylations, acetylations, phosphorylations and the like. Soluble forms of the subject proteinaceous molecules are particularly useful. Included within the definition are, for example, polypeptides containing one or more analogues of an amino acid including, for example, unnatural amino acids or polypeptides with substituted linkages. Unless otherwise specified (such as when the proteinaceous molecule is isolated or purified), the term "proteinaceous molecule" may include any agent that produces or is capable of producing the proteinaceous molecule of the invention, illustrative examples of which include a nucleic acid molecule from which the proteinaceous molecule is expressible or a cell containing such a nucleic acid molecule.

[0130] As used herein, a "chimeric molecule" refers to an engineered construct comprising a proteinaceous molecule and an ancillary moiety. The proteinaceous molecule is linked to the ancillary moiety. For example, the proteinaceous molecule may be directly linked (e.g., covalently linked) to the ancillary moiety. In other embodiments, the proteinaceous molecule may be indirectly linked (e.g., via a linker) to the ancillary moiety.

[0131] As used herein, an "ancillary moiety" refers to a moiety that contributes to therapeutic efficacy of the chimeric molecule. The manner in which the ancillary moiety contributes to therapeutic efficacy is not particularly limited. For example, the ancillary moiety may aid the ability of the chimeric molecule to cross the blood-brain barrier, and / or the ancillary moiety may localize the chimeric molecule at a particular site within a subject.

[0132] As used herein, the terms "prevent", "prevented" or "preventing", refer to a prophylactic treatment which increases the resistance of a subject to developing the disease or condition or, in other words, decreases the likelihood that the subject will develop the disease or condition as well as a treatment after the disease or condition has begun in order to reduce or eliminate it altogether or prevent it from becoming worse. These terms also include within their scope preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it.

[0133] The terms "reduce", "inhibit", "suppress", "decrease", and grammatical equivalents when used in reference to the level of a substance and / or phenomenon in a first sample relative to a second sample, mean that the quantity of substance and / or phenomenon in the first sample is lower than in the second sample by any amount that is statistically significant using any art-accepted statistical method of analysis. In one embodiment, the reduction may be determined subjectively, for example when a patientrefers to their subjective perception of disease symptoms, such as pain, fatigue, etc. In another embodiment, the reduction may be determined objectively, for example when the axonal degeneration in a sample is lower than another, untreated sample. In another embodiment, the quantity of substance and / or phenomenon in the first sample is at least 10% lower than the quantity of the same substance and / or phenomenon in a second sample. In another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 25% lower than the quantity of the same substance and / or phenomenon in a second sample. In yet another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 50% lower than the quantity of the same substance and / or phenomenon in a second sample. In a further embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 75% lower than the quantity of the same substance and / or phenomenon in a second sample. In yet another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 90% lower than the quantity of the same substance and / or phenomenon in a second sample. Alternatively, a difference may be expressed as an "n-fold" difference.

[0134] As used herein, an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat neurodegenerative disease, modulate CaMKII, decrease a rate of brain ageing, minimise neuronal injury, stimulate synapse formation and / or treat or inhibit axonal degeneration in a subject. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound (e.g., a proteinaceous molecule, a chimeric molecule, etc.) of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0135] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound (e.g., a proteinaceous molecule, a chimeric molecule, etc.) or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound (e.g., a proteinaceous molecule, a chimeric molecule, etc.) or composition means an amount of compound, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids a symptom or cause of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0136] The present invention also contemplates administration of the compounds (e.g., a proteinaceous molecule, a chimeric molecule, etc.) or compositions of the present invention, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition. As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound (e.g., a proteinaceous molecule, a chimeric molecule, etc.) or composition is an amount, alone or in combination with other therapeutic agents, sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0137] As used herein, the terms "salts" and "prodrugs" include any pharmaceutically acceptable salt, ester, hydrate or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a proteinaceous molecule of the invention, or an active metabolite or residue thereof. Suitable pharmaceutically acceptable salts include salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, sulfanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium. Also, basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl and diethyl sulfate; and others. However, it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts and prodrugs can be carried out by methods known in the art. For example, metal salts can be prepared by reaction of a compound of the invention with a metal hydroxide. An acid salt can be prepared by reacting an appropriate acid with a proteinaceous molecule of the invention.

[0138] The term "subject" as used herein refers to a vertebrate subject, particularly a mammalian or avian subject, for whom therapy or prophylaxis is desired. Suitable subjects include, but are not limited to, primates; avians (birds); livestock animals such as sheep, cows, horses, deer, donkeys and pigs; laboratory test animals such as rabbits, mice, rats, guinea pigs and hamsters; companion animals such as cats and dogs; and captive wild animals such as foxes, deer and dingoes. In particular, thesubject is a human. However, it will be understood that the aforementioned terms do not imply that symptoms are present.

[0139] As used herein "a neurodegenerative disease" refers to a disease that is characterised, at least in part, by neuron loss. In some embodiments, the neurodegenerative disease is motor neuron disease, dementia (e.g., Alzheimer's disease), Parkinson's disease, multiple sclerosis, traumatic brain injury, traumatic spinal cord injury, glaucoma, peripheral neuropathy, Guillain-Barre syndrome, chemotherapy-induced or diabetes-induced neuropathy, or chronic traumatic encephalopathy.

[0140] As used herein, " SARM1 mediated axonal degeneration" refers to Sterile alpha and TIR motif containing 1 (SARM1) triggered axon degeneration.

[0141] As used herein, the term "vector" refers to a polynucleotide molecule, suitably a DNA molecule derived, for example, from a plasmid, bacteriophage, yeast or virus, into which a polynucleotide can be inserted or cloned. A vector may contain one or more unique restriction sites and can be capable of autonomous replication in a defined host cell including a target cell or tissue or a progenitor cell or tissue thereof, or be integrable with the genome of the defined host such that the cloned sequence is reproducible. Accordingly, the vector can be an autonomously replicating vector, i.e. a vector that exists as an extra-chromosomal entity, the replication of which is independent of chromosomal replication, e.g., a linear or closed circular plasmid, an extra-chromosomal element, a mini-chromosome or an artificial chromosome. The vector can contain any means for assuring self-replication. Alternatively, the vector can be one which, when introduced into the host cell, is integrated into the genome and replicated together with the chromosome(s) into which it has been integrated. A vector system can comprise a single vector or plasmid, two or more vectors or plasmids, which together contain the total DNA to be introduced into the genome of the host cell, or a transposon. The choice of the vector will typically depend on the compatibility of the vector with the host cell into which the vector is to be introduced. In the present case, the vector is preferably a viral or viral-derived vector, which is operably functional in fungi, bacterial or animal cells, preferably mammalian cells. Such vector may be derived from a poxvirus, an adenovirus or yeast, or may be a modified rabies virus vector. The vector can also include a selection marker such as an antibiotic resistance gene that can be used for selection of suitable transformants. Examples of such resistance genes are known to those of skill in the art and include the nptll gene that confers resistance to the antibiotics kanamycin and G418 (Geneticin®) and the hph gene which confers resistance to the antibiotic hygromycin B.

[0142] Each embodiment described herein is to be applied mutatis mutandis to each and every embodiment unless specifically stated otherwise.2. Abbreviations

[0143] The following abbreviations are used throughout the application:SARM1 = Sterile alpha and TIR motif containing 1CaMKII =Calcium / calmodulin-dependent protein kinase II 3. Proteinaceous Molecules

[0144] The present invention is based, in part, on the discovery that particular proteinaceous molecules based on and / or derived from a portion of a protein of a highly neuroinvasive strain of rabies virus (CVS-11; also referred to herein as "rabies X") inhibit SARMl-mediated axonal degeneration. Without wishing to be bound by theory, it is believed that the proteinaceous molecules bind CaMKII, an upstream regulator of SARMl-mediated axonal degeneration. Further, and also without wishing to be bound by theory, it is believed that the proteinaceous molecules cause atypical activation of CaMKII, thereby controlling SARMl-mediated axonal degeneration and inducing synapse formation.

[0145] Accordingly, in one aspect, there is provided a proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula (I):Z1X1X2X3X4MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2(I)wherein:X1is absent or is any amino acid residue, preferably an aromatic amino acid residue such as Y;X2 is absent or is any amino acid residue, preferably a small amino acid residue such as T; X3 is absent or is any amino acid residue, preferably a hydrophobic amino acid residue such as I;X4 is absent or is any amino acid residue, preferably an aromatic amino acid residue such as W;X5 is any amino acid residue, preferably a small amino acid residue such as P, or a hydrophobic amino acid residue, preferably an aliphatic amino acid residue such as V; X6is any amino acid residue, preferably a basic amino acid residue such as R, or a small amino acid residue such as G;X7 is any amino acid residue, preferably a hydrophobic amino acid residue, more preferably an aliphatic amino acid residue such as L, or a small amino acid residue such as P;X8is any amino acid residue, preferably a small amino acid residue such as G, or a basic amino acid residue such as R;X9 is any amino acid residue, preferably a small amino acid residue such as T, or a hydrophobic amino acid residue, preferably an aliphatic amino acid residue such as M; X10 is absent or is any amino acid residue, such as C;X11is absent or is any amino acid residue, preferably an acidic amino acid residue such as D;X12 is absent or is any amino acid residue, preferably a hydrophobic amino acid residue such as I;X13 is absent or is any amino acid residue, preferably a hydrophobic amino acid residue including an aromatic amino acid residue such as F, or an aliphatic amino acid residue such as L;X14 is absent or is any amino acid residue, preferably a small amino acid residue such as T, or a hydrophobic amino acid residue, preferably an aliphatic amino acid residue such as V;X15 is absent or is any amino acid residue, preferably a neutral / polar amino acid residue such as N;X16is absent or is any amino acid residue, preferably a small amino acid residue such as S;X17 is absent or is any amino acid residue, preferably a basic amino acid residue such as R;X18is absent or is any amino acid residue, preferably a small amino acid residue such as G;X19 is absent or is any amino acid residue, preferably a basic amino acid residue such as K;X20 is absent or is any amino acid residue, preferably a basic amino acid residue such as R;X21 is absent or is any amino acid residue, preferably a small amino acid residue such as A, or an acidic amino acid residue such as E;X22 is absent or is any amino acid residue, preferably a small amino acid residue such as S or P;X23 is absent or is any amino acid residue, preferably a basic amino acid residue such as K, or a neutral / polar amino acid residue such as N;X24 is absent or is any amino acid residue, preferably a small amino acid residue such as G, or a basic amino acid residue such as R;X25 is absent or is any amino acid residue, preferably a small amino acid residue such as S, G or T, or a neutral / polar amino acid residue such as N;X26 is absent or is any amino acid residue, preferably a basic amino acid residue such as K;X27 is absent or is any amino acid residue, preferably a small amino acid residue such as T or A;X28 is absent or is any amino acid residue, preferably C; andZi and Z2 are independently absent or independently selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.

[0146] In some embodiments, Xi is absent. In other embodiments, Xi is an aromatic amino acid residue, such as Y, W or F. In some embodiments, Xi is Y.

[0147] In some embodiments, X2 is absent. In other embodiments, X2 is a small amino acid residue, such as A, S, G, T or P. In some embodiments, X2 is T.

[0148] In some embodiments, X3 is absent. In other embodiments, X3 is a hydrophobic amino acid residue, such as Y, V, I, P, A, L, M, F or W, such as V, I or L. In some embodiments, X3 is I.

[0149] In some embodiments, X4 is absent. In other embodiments, X4 is an aromatic amino acid residue, such as Y, W or F. In some embodiments, X4 is W.

[0150] In some embodiments, at least one of Xi is Y; X2 is T; X3 is I; and X4 is W. For example, in some embodiments, Xi is Y; X2 is T; X3 is I; and X4 is W.

[0151] In some embodiments, at least one of Xi is absent; X2 is absent; X3 is absent; and X4 is absent. In other embodiments, at least two of Xi is absent; X2 is absent; X3 is absent; and X4 is absent. In some embodiments, at least three of Xi is absent; X2 is absent; X3 is absent; and X4 is absent. In some embodiments, each of Xi, X2, X3, and X4 are absent.

[0152] In some embodiments, when X4 is absent, X1-X3 are also absent. In other embodiments, when X3 is absent, Xi and X2 are also absent. In some embodiments, when X2 is absent, Xi is also absent.

[0153] X5 may be any amino acid residue. In some embodiments, Xs is a small amino acid residue or an aliphatic amino acid residue. In some embodiments, Xs is a small amino acid residue. In other embodiments, Xs is an aliphatic amino acid residue.For example, X5 may be G, S, A, T, P, V, I, L, or M. In some embodiments, X5 is G, S, A, T, or P. In other embodiments, X5 is V, I, L, P, M, or A. In some embodiments, X5 is P or V. In some embodiments, X5 is P. In other embodiments, X5 is V.

[0154] Xs may be any amino acid residue. In some embodiments, Xs is a basic amino acid residue or a small amino acid residue. In other embodiments, Xs is a basic amino acid residue. In some embodiments, Xs is a small amino acid residue. For example, Xs may be R, K, H, G, S, A, T, or P. In some embodiments, Xs is R, K, G, S, A, or T. In some embodiments, Xs is R, K, or H. In some embodiments, Xs is R or K. In other embodiments, Xs is G, S, A, T, or P. For example, Xs may be G, S, A, or T. In some embodiments, Xs is R or G. In some embodiments, Xs is R. In other embodiments, Xs is G.

[0155] X7 may be any amino acid residue. In some embodiments, X7 is a hydrophobic amino acid residue or a small amino acid residue. In other embodiments, X7 is a hydrophobic amino acid residue. In some embodiments, X7 is a small amino acid residue. For example, X7 may be G, S, T, Y, V, I, P, A, L, M, F, or W. In some embodiments, X7 is G, S, A, T, or P. In some embodiments, X7 is Y, V, I, P, A, L, M, F, or W. In other embodiments, X7 is L or P. In some embodiments, X7 is L. In some embodiments, X7 is P.

[0156] Xs may be any amino acid residue. In some embodiments, Xs is a small amino acid residue or a basic amino acid residue. In other embodiments, Xs is a small amino acid residue. In some embodiments, Xs is a basic amino acid residue. For example, Xs may be G, S, A, T, P, R, K, or H. In some embodiments, Xs is G, S, A, T, R, or K. In some embodiments, Xs is G, S, A, T, or P. In some embodiments, Xs is G, S, A, or T. In other embodiments, Xs is R, K, or H. In some embodiments, Xs is R or K. In some embodiments, Xs is G or R. For example, Xs may be G. In other embodiments, Xs is R.

[0157] X9 may be any amino acid residue. In some embodiments, X9 is a small amino acid residue or a hydrophobic amino acid residue. In other embodiments, X9 is a small amino acid residue. In some embodiments, X9 is a hydrophobic amino acid residue. For example, X9 may be G, S, A, T, P, Y, V, I, L, M, F, or W. In some embodiments, X9 is G, S, A, T, Y, V, I, L, M, F, or W. In some embodiments, X9 is G, S, A, T, or P. For example, X9 may be G, S, A, or T. In other embodiments, X9 is Y, V, I, P, A, L, M, F, or W. In some embodiments, X9 is Y, V, I, A, L, M, F, or W. In some embodiments, X9 is T or M. For example, X9 may be T. In other embodiments, X9 is M.

[0158] In some embodiments, X5 is P, Xs is R, X7 is P, Xs is R, and X9 is T. In some embodiments, Xi, X2, X3, and X4 are absent, X5 is P, Xs is R, X7 is P, Xs is R, and X9is T. In other embodiments, Xi is Y, X2 is T, X3 is I, X4 is W, X5 is P, Xs is R, X7 is P, Xs is R, and X9 is T.

[0159] In some embodiments, X10 is absent. In other embodiments, X10 is any amino acid residue, such as C.

[0160] In some embodiments, Xu is absent. In other embodiments, Xu is an acidic amino acid residue, such as D or E. In some embodiments, Xu is D.

[0161] In some embodiments, X12 is absent. In other embodiments, X12 is a hydrophobic amino acid residue, such as Y, V, I, P, A, L, M, F or W, such as V, I or L. In some embodiments, X12 is I.

[0162] In some embodiments, at least one of X10is C; X11is D; and X12is I. For example, in some embodiments, X10is C; X11is D; and X12is I.

[0163] In some embodiments, at least one of X10 is absent; X11is absent; and X12is absent. In other embodiments, at least two of Xw is absent; X11is absent; and X12is absent. In some embodiments, each of Xw, Xu, and X12 are absent.

[0164] In some embodiments, when Xw is absent, Xu and X12 are also absent. In other embodiments, when Xu is absent, X12 is also absent.

[0165] When present, X13 may be any amino acid residue. In some embodiments, X13 is a hydrophobic amino acid residue or an aromatic amino acid residue. In other embodiments, X13 is a hydrophobic amino acid residue. In some embodiments, X13 is an aromatic amino acid residue. For example, X13 may be Y, V, I, P, A, L, M, F, or W. In some embodiments, X13 is Y, V, I, A, L, M, F, or W. In some embodiments, X13 is W, Y, or F. In other embodiments, X13 is F or L. For example, X13 may be F. In other embodiments, X13 is L.

[0166] When present, X14 may be any amino acid residue. In some embodiments, X14 is a small amino acid residue or a hydrophobic amino acid residue. In other embodiments, X14 is a small amino acid residue. In some embodiments, X14 is a hydrophobic amino acid residue. For example, X14 may be G, S, A, T, P, Y, V, I, L, M, F, or W. In some embodiments, X14 is G, S, A, T, Y, V, I, L, M, F, or W. In some embodiments, X14 is G, S, A, T, or P. For example, X14 may be G, S, A, or T. In other embodiments, X14 is Y, V, I, P, A, L, M, F, or W. In some embodiments, X14 is Y, V, I, A, L, M, F, or W. In some embodiments, X14 is T or V. For example, X14 may be T. In other embodiments, X14 is V.

[0167] In some embodiments, X15 is absent. In other embodiments, X15 is a neutral / polar amino acid residue, such as N, H, Q, C, S or T. In some embodiments, X15 is N.

[0168] In some embodiments, X10-X15 are absent. In other embodiments, X10 is C; Xu is D; X12 is I; X13 is F; X14 is T; and X15 is N.

[0169] In some embodiments, Xis is absent. In other embodiments, Xis is a small amino acid residue, such as A, G, S, T or P. In some embodiments, Xis is S.

[0170] In some embodiments, X17 is absent. In other embodiments, X17 is a basic amino acid residue, such as R, K or H. In some embodiments, X17 is R.

[0171] In some embodiments, Xis is absent. In other embodiments, Xis is a small amino acid residue, such as A, G, S, T or P. In some embodiments, Xis is G.

[0172] In some embodiments, X19 is absent. In other embodiments, X19 is a basic amino acid residue, such as R, K or H. In some embodiments, X19 is K.

[0173] In some embodiments, at least one of X16is S; X17is R; X18is G; and X19is K. For example, in some embodiments, X16is S; X17is R; X18is G; and X19is K.

[0174] In some embodiments, at least one of X16is absent; X17is absent; X18is absent; and X19is absent. In other embodiments, at least two of X16is absent; X17is absent; X18is absent; and X19is absent. In some embodiments, at least three of X16is absent; X17is absent; X18is absent; and X19is absent. In some embodiments, each of Xis, X17, Xis, and X19 are absent.

[0175] In some embodiments, when Xis is absent, X17-X19 are also absent. In some embodiments, when X17 is absent, Xis and X19 are also absent. In some embodiments, when Xis is absent, X19 is also absent.

[0176] In some embodiments, X20 is absent. In other embodiments, X20 is a basic amino acid residue, such as R, K or H. In some embodiments, X20 is R.

[0177] When present, X21 may be any amino acid residue. In some embodiments, X21 is a small amino acid residue or an acidic amino acid residue. In other embodiments, X21 is a small amino acid residue. In some embodiments, X21 is an acidic amino acid residue. For example, X21 may be G, S, A, T, P, D, or E. In some embodiments, X21 is G, S, A, T, D, or E. In some embodiments, X21 is G, S, A, T, or P. For example, X21 may be G, S, A, or T. In other embodiments, X21 is D or E. In some embodiments, X21 is A or E. For example, X21 may be A. In other embodiments, X21 is E.

[0178] When present, X22 may be any amino acid residue. In some embodiments, X22 is a small amino acid residue. For example, X22 may be G, S, A, T, or P. In some embodiments, X22 is S or P. For example, X22 may be S. In other embodiments, X22 is P.

[0179] When present, X23 may be any amino acid residue. In some embodiments, X23 is a basic amino acid residue or a neutral / polar amino acid residue. Inother embodiments, X23 is a basic amino acid residue. In some embodiments, X23 is a neutral / polar amino acid residue. For example, X23 may be R, K, H, N, Q, C, S, or T. In some embodiments, X23 is R, K, N, Q, S, or T. In other embodiments, X23 is R, K, or H. For example, X23 may be R or K. In some embodiments, X23 is N, H, Q, C, S, or T. In some embodiments, X23 is N, Q, S, or T. In some embodiments, X23 is K or N. For example, X23 may be K. In other embodiments, X23 is N.

[0180] When present, X24 may be any amino acid residue. In some embodiments, X24 is a small amino acid residue or a basic amino acid residue. In other embodiments, X24 is a small amino acid residue. In some embodiments, X24 is a basic amino acid residue. For example, X24 may be G, S, A, T, P, R, K, or H. In some embodiments, X24 is G, S, A, T, R, or K. In other embodiments, X24 is G, S, A, T, or P. In some embodiments, X24 is G, S, A, or T. In some embodiments, X24 is R, K, or H. In some embodiments, X24 is R or K. In some embodiments, X24 is G or R. For example, X24 may be G. In other embodiments, X24 is R.

[0181] When present, X25 may be any amino acid residue. In some embodiments, X25 is a small amino acid residue or a neutral / polar amino acid residue. In other embodiments, X25 is a small amino acid residue. In some embodiments, X25 is a neutral / polar amino acid residue. For example, X25 may be G, S, A, T, P, N, H, Q, or C. In some embodiments, X25 is G, S, A, T, N, or Q. In other embodiments, X25 is G, S, A, T, or P. For example, X25 may be G, S, A, or T. In some embodiments, X25 is N, H, Q, C, S, or T. In other embodiments, X25 is N, Q, S, or T. In some embodiments, X25 is S, G, T, or N. For example, X25 may be S. In some embodiments, X25 is G. In some embodiments, X25 is T. In other embodiments, X25 is N.

[0182] When present, X26 may be any amino acid residue. In some embodiments, X26 is a basic amino acid residue. For example, X26 may be R, K, or H. In some embodiments, X26 is R or K. In other embodiments, X26 is K.

[0183] When present, X27 may be any amino acid residue. In some embodiments, X27 is a small amino acid residue. For example, X27 may be G, S, A, T, or P. In some embodiments, X27 is G, S, A, or T. In some embodiments, X27 is T or A. In some embodiments, X27 is T. In other embodiments, X27 is A.

[0184] In some embodiments, X28 is absent. In other embodiments, X28 is C.

[0185] In some embodiments, at least one of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28 is absent. In other embodiments, each of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28 are present. In some embodiments, X20 to X28 and Zi and Z2 are absent. In some embodiments, Xis toX28 and Zi and Z2 are absent. In some embodiments, X10 to X28 and Zi and Z2 are absent. In some embodiments, Xi to X4, X10 to X28 and Zi and Z2 are absent.

[0186] In some embodiments, at least one of Zi and Z2 is absent. In other embodiments, each of Zi and Z2 are absent.

[0187] In some embodiments, one of Zi and Z2 is absent and the other of Zi and Z2 is selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety. In other embodiments, each of Zi and Z2 are independently selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.

[0188] In some embodiments,Xi is absent or is Y, W or F;X2 is absent or is A, S, G, T or P;X3 is absent or Y, V, I, P, A, L, M, F or W;X4 is absent or is Y, W or F;X5is G, S, A, T, P, V, I, L, or M;X6is R, K, H, G, S, A, T, or P;X7is G, S, T, Y, V, I, P, A, L, M, F, or W;X8is G, S, A, T, P, R, K, or H;X9is G, S, A, T, P, Y, V, I, L, M, F, or W;X10is absent or C;X11is absent or is D or E;X12is absent or is Y, V, I, P, A, L, M, F or W;X13is absent or is Y, V, I, P, A, L, M, F, or W;X14is absent or is G, S, A, T, P, Y, V, I, L, M, F, or W;X15is absent or is N, H, Q, C, S or T;X16is absent or is A, G, S, T or P;X17is absent or is R, K or H;X18is absent or is A, G, S, T or P;X19is absent or is R, K or H;X20is absent or is R, K or H;X2i is absent or is G, S, A, T, P, D, or E;X22 is absent or is G, S, A, T, or P;X23 is absent or is R, K, H, N, H, Q, C, S, or T;X24 is absent or is G, S, A, T, P, R, K, or H;X25 is absent or is G, S, A, T, P, N, H, Q, or C;X26 is absent or is R, K, or H;X27 is absent or is G, S, A, T, or P;X28 is absent or is C; andZi and Z2 are independently absent or independently selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.

[0189] In some embodiments,Xi is absent or Y;X2 is absent or T;X3 is absent or I;X4 is absent or W;X5is G, S, A, T, P, V, I, L, or M;X6is R, K, G, S, A, or T;X7is G, S, T, Y, V, I, P, A, L, M, F, or W;X8is G, S, A, T, R, or K;X9is G, S, A, T, Y, V, I, L, M, F, or W;X10is absent or C;X11is absent or D;X12is absent or I;X13is absent or is Y, V, I, A, L, M, F, or W;X14is absent or is G, S, A, T, Y, V, I, L, M, F, or W;X15is absent or N;X16is absent or S;X17is absent or R;X18is absent or G;X19 is absent or K;X20 is absent or R;X21 is absent or is G, S, A, T, D, or E;X22 is absent or is G, S, A, T, or P;X23 is absent or is R, K, N, Q, S, or T;X24 is absent or is G, S, A, T, R, or K;X25 is absent or is G, S, A, T, N, or Q;X26 is absent or is R or K;X27 is absent or is G, S, A, or T;X28 is absent or is C; andZi and Z2 are independently absent or independently selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.

[0190] In some embodiments,Xi is absent or Y;X2 is absent or T;X3 is absent or I;X4 is absent or W;X5 is P or V;Xs is R or G;X7 is L or P;Xs is G or R;X9 is T or M;X10 is absent or C;Xu is absent or D;X12 is absent or I;X13 is absent or is F or L;X14 is absent or is T or V;X15 is absent or N;Xis is absent or S;X17is absent or R;X18is absent or G;X19is absent or K;X20is absent or R;X21is absent or is A or E;X22is absent or is S or P;X23is absent or is K or N;X24is absent or is G or R;X25is absent or is S, G, T, or N;X26is absent or is R or K;X27is absent or is T or A;X28is absent or C; andZi and Z2 are absent.

[0191] In some embodiments: Xi is absent or is Y;X2 is absent or is T;X3 is absent or is I;X4 is absent or is W;X5is P;X6is R;X7is P;X8is R;X9is T;X10 is absent or is C;Xu is absent or is D;X12 is absent or is I;X13 is absent or is F;X14 is absent or is T;X15 is absent or is N;X16is absent or is S;X17is absent or is R;X18is absent or is G;X19is absent or is K;X20is absent or is R;X21is absent or is A;X22is absent or is S;X23is absent or is N;X24is absent or is G;X25is absent or is N;X26is absent or is K;X27is absent or is T;X28is absent or is C; andZi and Z2 are absent.

[0192] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-A):Z1X1X2X3X4MPENX5X6X7X8X9PCDIX13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2(I-A)wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, and Z2are as defined in Formula (I) or any embodiments thereof.

[0193] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-B):Z1X1X2X3X4MPENX5X6X7X8X9PX10X11X12X13X14NSRGKRX21X22X23X24X25X26X27X28Z2(I-B)wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X21, X22, X23, X24, X25, X26, X27, X28, and Z2are as defined in Formula (I) or any embodiments thereof.

[0194] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-C):Z1X1X2X3X4MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25KX27CZ2(1-0wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X27, and Z2are as defined in Formula (I) or any embodiments thereof.

[0195] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-D):Z1YTIWMPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2(I-D)wherein each of Z1, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, and Z2are as defined in Formula (I) or any embodiments thereof.

[0196] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-E):Z1X1X2X3X4MPENX5X6X7X8X9PCDIX13X14NSRGKRX21X22X23X24X25KX27CZ2 (I-E) wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X13, X14, X21, X22, X23, X24, X25, X27, and Z2are as defined in Formula (I) or any embodiments thereof.

[0197] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-F):Z1MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2 (I-F) wherein each of Z1, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, and Z2are as defined in Formula (I) or any embodiments thereof.

[0198] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-Fl):Z1MPENX5X6X7X8X9PCDIX13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2 (I-Fl) wherein each of Z1, X5, X6, X7, X8, X9, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, and Z2are as defined in Formula (I) or any embodiments thereof.

[0199] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-F2):Z1MPENX5X6X7X8X9PX10X11X12X13X14NSRGKRX21X22X23X24X25X26X27X28Z2 (I-F2) wherein each of Z1, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X21, X22, X23, X24, X25, X26, X27, X28, and Z2are as defined in Formula (I) or any embodiments thereof.

[0200] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-F3):Z1MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25KX27CZ2 (I-F3) wherein each of Z1, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X27, and Z2are as defined in Formula (I) or any embodiments thereof.

[0201] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-F4):Z1MPENX5X6X7X8X9PCDIX13X14NSRGKRX21X22X23X24X25KX27CZ2 (I-F4) wherein each of Z1, X5, X6, X7, X8, X9, X13, X14, X21, X22, X23, X24, X25, X27, and Z2are as defined in Formula (I) or any embodiments thereof.

[0202] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-F5):Z1MPENPRPRTPX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2 (I-F5) wherein each of Z1, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, and Z2are as defined in Formula (I) or any embodiments thereof.

[0203] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-G):Z1X1X2X3X4MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20Z2 (I-G) wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, and Z2are as defined in Formula (I) or any embodiments thereof.

[0204] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-Gl):Z1YTIWMPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20Z2 (I-Gl) wherein each of Z1, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, and Z2are as defined in Formula (I) or any embodiments thereof.

[0205] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-G2):Z1X1X2X3X4MPENX5X6X7X8X9PCDIX13X14X15X16X17X18X19X20Z2 (I-G2) wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X13, X14, X15, X16, X17, X18, X19, X20, and Z2are as defined in Formula (I) or any embodiments thereof.

[0206] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-G3):Z1X1X2X3X4MPENX5X6X7X8X9PX10X11X12X13X14NSRGKRZ2 (I-G3) wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, and Z2are as defined in Formula (I) or any embodiments thereof.

[0207] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-G4):Z1YTIWMPENX5X6X7X8X9PCDIX13X14NSRGKRZ2 (I-G4) wherein each of Z1, X5, X6, X7, X8, X9, X13, X14, and Z2are as defined in Formula (I) or any embodiments thereof.

[0208] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-H):Z1MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20Z2 (I-H) wherein each of Z1, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, and Z2are as defined in Formula (I) or any embodiments thereof.

[0209] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-Hl):Z1MPENX5X6X7X8X9PCDIX13X14X15X16X17X18X19X20Z2 (I-Hl) wherein each of Z1, X5, X6, X7, X8, X9, X13, X14, X15, X16, X17, X18, X19, X20, and Z2are as defined in Formula (I) or any embodiments thereof.

[0210] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-H2):Z1MPENX5X6X7X8X9PX10X11X12X13X14NSRGKRZ2 (I-H2) wherein each of Z1, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, and Z2are as defined in Formula (I) or any embodiments thereof.

[0211] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-H3):Z1MPENX5X6X7X8X9PCDIX13X14NSRGKRZ2 (I-H3) wherein each of Z1, X5, X6, X7, X8, X9, X13, X14, and Z2are as defined in Formula (I) or any embodiments thereof.

[0212] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-I):Z1YTIWMPENX5X6X7X8X9PCDIX13X14NSRGKRX21X22X23X24X25KX27CZ2 (I-I) wherein each of Z1, X5, X6, X7, X8, X9, X13, X14, X21, X22, X23, X24, X25, X27, and Z2are as defined in Formula (I) or any embodiments thereof.

[0213] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-J):Z1X1X2X3X4MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19Z2 (I-J) wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, and Z2are as defined in Formula (I) or any embodiments thereof.

[0214] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-Jl):Z1X1X2X3X4MPENPRPRTPX10X11X12X13X14X15X16X17X18X19Z2 (I-J1) wherein each of Z1, X1, X2, X3, X4, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, and Z2are as defined in Formula (I) or any embodiments thereof.

[0215] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-K):Z1X1X2X3X4MPENX5X6X7X8X9PX10X11X12X13X14X15Z2 (I-K) wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0216] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-Kl):Z1X1X2X3X4MPENPRPRTPX10X11X12X13X14X15Z2 (I-Kl) wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0217] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-L):Z1X1X2X3X4MPENX5X6X7X8X9PZ2 (I-L)wherein each of Z1, X1, X2, X3, X4, X5, X6, X7, X8, X9, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0218] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-Ll):Z1X1X2X3X4MPENPRPRTPZ2 (I-Ll)wherein each of Z1, X1, X2, X3, X4, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0219] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-M):Z1MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19Z2 (I-M) wherein each of Z1, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0220] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-Ml):Z1MPENPRPRTPX10X11X12X13X14X15X16X17X18X19Z2 (I-Ml) wherein each of Z1, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0221] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-N):Z1MPENX5X6X7X8X9PX10X11X12X13X14X15Z2 (I-N) wherein each of Zi, Xs, Xs, X7, Xs, X9, X10, X11, X12, X13, X14, X15, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0222] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-Nl):Z1MPENPRPRTPX10X11X12X13X14X15Z2 (I-Nl) wherein each of Z1, X10, X11, X12, X13, X14, X15, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0223] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (1-0):Z1MPENX5X6X7X8X9PZ2 (1-0)wherein each of Z1, X5, X6, X7, X8, X9, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0224] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (1-01):Z1MPENPRPRTPZ2 (1-01)wherein each of Z1, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0225] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by Formula (I-P):Z1X1X2X3X4MPENPRPRTPX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2(I-P)wherein each of Z1, X1, X2, X3, X4, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, and Z2 are as defined in Formula (I) or any embodiments thereof.

[0226] In some embodiments, the proteinaceous molecule of Formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-Fl), (I-F2), (I-F3), (I-F4), (I-F5), (I-G), (I-Gl), (I-G2), (I-G3), (I-G4), (I-H), (I-Hl), (I-H2), (I-H3), (I-I), (I-J), (I-Jl), (I-K), (I-Kl), (I-L), (I-Ll), (I-M), (I-Ml), (I-N), (I-Nl), (1-0), (1-01) and / or (I-P) may be between 8 amino acid residues and 100 amino acid residues in length (and all integer amino acid residues therebetween); between 8 amino acid residues and 50 amino acid residues in length, between 8 amino acid residues and 40 amino acid residues in length, between 8 amino acid residues and 35 amino acid residues in length, between 10 amino acid residues and 100 amino acid residues in length, between 10 amino acid residues and 50 amino acid residues in length, between 10 amino acid residues and 40 amino acid residues in length, between 10 amino acid residues and 35 amino acid residues in length, between 10 amino acid residues and 33 amino acid residues in length, between 10 amino acid residues and 24 amino acid residues in length, or between 10 amino acid residues and 20 amino acid residues in length; especially between 10 amino acid residues and 33 amino acid residues in length; including about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 amino acid residues in length. In some embodiments, the proteinaceous molecule is about 10, 20, 24 or 33 amino acid residues in length.

[0227] In some embodiments, the proteinaceous molecule of Formula (I) is other than a proteinaceous molecule comprising the amino acid sequence of SEQ ID NO: 1. In other embodiments, the proteinaceous molecule of Formula (I) is other than a proteinaceous molecule comprising the amino acid sequence represented by any one of SEQ ID NOs: 31-34.

[0228] In one aspect, the present invention provides a proteinaceous molecule comprising, consisting, or consisting essentially of the amino acid sequence represented by any one of SEQ ID NOs: 1-16:YTIWMPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 1];MPENPRPRTP [SEQ ID NO: 2];WMPENPRPRTP [SEQ ID NO: 3];IWMPENPRPRTP [SEQ ID NO: 4];TIWMPENPRPRTP [SEQ ID NO: 5];YTIWMPENPRPRTP [SEQ ID NO: 6];YTIWMPENPRPRTPCDIFTNSRGK [SEQ ID NO: 7];YTIWMPENPRPRTPCDIFTN [SEQ ID NO: 8];MPENPRPRTPCDIFTNSRGK [SEQ ID NO: 9];MPENPRPRTPCDIFTN [SEQ ID NO: 10];MPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 11];MPENPRPRTPCDIFTNSRGKRASNG [SEQ ID NO: 12];WMPENPRPRTPCDIFTNSRGKRASNGN [SEQ ID NO: 13];IWMPENPRPRTPCDIFTNSRGKRASNGNK [SEQ ID NO: 14];TIWMPENPRPRTPCDIFTNSRGKRASNGNKT [SEQ ID NO: 15]; and NHDYTIWMPENPRPRTPCDIFTNSRGKRASN [SEQ ID NO: 16];or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by any one of SEQ ID NOs: 1-16.

[0229] In some embodiments, the proteinaceous molecule of Formula (I) comprises, consists, or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1, 2, 7 and 8.

[0230] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence YTIWMPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 1] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 1.

[0231] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence MPENPRPRTP [SEQ ID NO: 2] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 2.

[0232] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence WMPENPRPRTP [SEQ ID NO: 3] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 3.

[0233] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence IWMPENPRPRTP [SEQ ID NO: 4] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 4.

[0234] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence TIWMPENPRPRTP [SEQ ID NO: 5] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 5.

[0235] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence YTIWMPENPRPRTP [SEQ ID NO: 6] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 6.

[0236] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence YTIWMPENPRPRTPCDIFTNSRGK [SEQ ID NO: 7] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 7.

[0237] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence YTIWMPENPRPRTPCDIFTN [SEQ ID NO: 8] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 8.

[0238] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence MPENPRPRTPCDIFTNSRGK [SEQ ID NO: 9] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 9.

[0239] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence MPENPRPRTPCDIFTN [SEQ ID NO: 10] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 10.

[0240] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence MPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 11] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 11.

[0241] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence MPENPRPRTPCDIFTNSRGKRASNG [SEQ ID NO: 12] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 12.

[0242] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence WMPENPRPRTPCDIFTNSRGKRASNGN [SEQ ID NO: 13] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 13.

[0243] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence IWMPENPRPRTPCDIFTNSRGKRASNGNK [SEQ ID NO: 14] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 14.

[0244] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence TIWMPENPRPRTPCDIFTNSRGKRASNGNKT [SEQ ID NO: 15] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 15.

[0245] In some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of the amino acid sequence NHDYTIWMPENPRPRTPCDIFTNSRGKRASN [SEQ ID NO: 16] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 16.

[0246] In some embodiments, calculations of sequence similarity or sequence identity between sequences are performed as follows:

[0247] To determine the percent identity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g. gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In some embodiments, the length of a reference sequence aligned for comparison purposes is at least 40%, more usually at least 50% or 60%, and even more usually at least 70%, 80%, 90% or 100% of the length of the referencesequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide at the corresponding position in the second sequence, then the molecules are identical at that position. For amino acid sequence comparison, when a position in the first sequence is occupied by the same or similar amino acid residue (i.e. conservative substitution) at the corresponding position in the second sequence, then the molecules are similar at that position.

[0248] The percent identity between the two sequences is a function of the number of identical amino acid residues shared by the sequences at individual positions, taking into account the number of gaps and the length of each gap, which need to be introduced for optimal alignment of the two sequences. By contrast, the percent similarity between the two sequences is a function of the number of identical and similar amino acid residues shared by the sequences at individual positions, taking into account the number of gaps and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0249] The comparison of sequences and determination of percent identity or percent similarity between sequences can be accomplished using a mathematical algorithm. In certain embodiments, the percent identity or similarity between amino acid sequences is determined using the Needleman and Wunsch, (1970, J. Mol. Biol., 48: 444-453) algorithm which has been incorporated into the GAP program in the GCG software package (Devereaux, et al. (1984) Nucleic Acids Research, 12: 387-395), using either a Blosum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In some embodiments, the percent identity or similarity between amino acid sequences can be determined using the algorithm of Meyers and Miller (1989, Cabios, 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0250] In some embodiments, the proteinaceous molecule is isolated.

[0251] In another aspect, the present invention provides an isolated or recombinant proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence selected from:a) the amino acid sequence:FGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGYISAIKVNGF TCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYPD YHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIW MPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMD GTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVKKREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHV NGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHPLADPSTVFKEGDEAEDF VEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSLMTWCRRANRPESKQRS FGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 31];b) the amino acid sequence:MVPQVLLFVLLLGFSLCFGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFS YMELKVGYISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWK MAGDPRYEESLHNPYPDYHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSG ITVSSTYCSTNHDYTIWMPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLK GACRLKLCGVLGLRLMDGTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVK KREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEI IPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHP LADPSTVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSL MTWCRRANRPESKQRSFGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 32];c) the amino acid sequence:FGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGYISAIKVNGF TCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYPD YHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIW MPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMD GTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVKKREECLDTLESIMTTKSV SFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHV NGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHPLADPSTVFKEGDEAEDF VEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSLMTWC [SEQ ID NO: 33]; andd) the amino acid sequence:MVPQVLLFVLLLGFSLCFGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFS YMELKVGYISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWK MAGDPRYEESLHNPYPDYHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSG ITVSSTYCSTNHDYTIWMPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLK GACRLKLCGVLGLRLMDGTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVK KREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEI IPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHP LADPSTVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSL MTWC [SEQ ID NO: 34],

[0252] In some embodiments, the isolated or recombinant proteinaceous molecule comprises, consists or consists essentially of the amino acid sequence:FGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGYISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYPDYHWLRTVRTTKESLIII SPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIWMPENPRPRTPCDIFTNSRGKRASN GNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMDGTWVAMQTSDETKWCPPDQLVNLHDFRSDE IEHLVVEELVKKREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTW NEIIPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHPLADPS TVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSLMTWCRRANRPESK QRSFGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 31].

[0253] In some embodiments, the isolated or recombinant proteinaceous molecule comprises, consists or consists essentially of the amino acid sequence:MVPQVLLFVLLLGFSLCFGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGY ISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYP DYHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIWMPENPRP RTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMDGTWVAMQTSDETK WCPPDQLVNLHDFRSDEIEHLVVEELVKKREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIF NKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQH MELLESSVIPLMHPLADPSTVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGL VLIFSLMTWCRRANRPESKQRSFGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 32],

[0254] In some embodiments, the isolated or recombinant proteinaceous molecule comprises, consists or consists essentially of the amino acid sequence:FGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGYISAIKVNGFTCTGVVTE AETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYPDYHWLRTVRTTKESLIII SPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIWMPENPRPRTPCDIFTNSRGKRASN GNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMDGTWVAMQTSDETKWCPPDQLVNLHDFRSDE IEHLVVEELVKKREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTW NEIIPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHPLADPS TVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSLMTWC [SEQ ID NO: 33].

[0255] In some embodiments, the isolated or recombinant proteinaceous molecule comprises, consists or consists essentially of the amino acid sequence:MVPQVLLFVLLLGFSLCFGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGY ISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYP DYHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIWMPENPRP RTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMDGTWVAMQTSDETK WCPPDQLVNLHDFRSDEIEHLVVEELVKKREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIF NKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHPLADPSTVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGL VLIFSLMTWC [SEQ ID NO: 34],

[0256] In some embodiments, the proteinaceous molecules of the invention have a primary, secondary or tertiary amide, a hydrazide, a hydroxamide or a free-carboxyl group at the C-terminus and / or a primary amine or acetamide at the N-terminus. In some embodiments, the proteinaceous molecules of the invention are cyclic peptides and, thus, may not comprise N- and / or C-terminal amino acid residues. In preferred embodiments, the proteinaceous molecules of the invention have a primary amide or a free carboxyl group (C-terminal acid) at the C-terminus and a primary amine at the N-terminus, especially a free carboxyl group at the C-terminus and a primary amine at the N-terminus.

[0257] Proteinaceous molecules with high levels of stability may be desired, for example, to increase the half-life of the proteinaceous molecule in a subject. Thus, in some embodiments, the proteinaceous molecules of the invention comprise a stabilising or protecting moiety, for example, when the proteinaceous molecule is acyclic. The stabilising or protecting moiety may be conjugated at any point on the proteinaceous molecule. The stabilising or protecting moiety may be any moiety which delays or prevents substantial degradation of the proteinaceous molecule. A skilled person will be well aware of suitable stabilising or protecting moieties which may be used. Exemplary stabilizing or protecting moieties include, but are not limited to, a peptide or protein such as an albumin including human serum albumin or a fragment or variant thereof, a glycine-rich homo-amino-acid polymer, a PAS sequence comprising a combination of alanine, serine and proline residues, the C-terminal peptide (CTP) of the P subunit of human chorionic gonadotropin or fragment or variant thereof, transferrin or a fragment or variant thereof, an albumin binding moiety, which comprises an albumin binding peptide, a bacterial albumin binding domain, an albumin-binding antibody fragment, or any combinations thereof, or an XTEN polypeptide (an extended length polypeptide with a non-naturally occurring, substantially non-repetitive sequence that is composed mainly of small hydrophilic amino acids, with the sequence having a low degree or no secondary or tertiary structure under physiologic conditions); an Fc region or single chain Fc region comprising a functional neonatal Fc receptor (FcRn) binding partner comprising an Fc domain, variant, or fragment thereof; a polymer such as a polyethylene glycol (PEG), a polysialic acid or a derivative thereof, hydroxyethyl starch or a derivative thereof, ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran or polyvinyl alcohol; a glycan or polysaccharide; a lipid moiety for example, a C6-C20 fatty acyl group; or a capping moiety, including an acetyl group, pyroglutamate or an amino group.

[0258] In some embodiments, the protecting or stabilising moiety is a PEG. The PEG can be of any molecular weight and can be branched or unbranched. In one embodiment, the molecular weight is between about 1 kDa and about 100 kDa for ease in handling and manufacturing. Other sizes can be used, depending on the desired profile (e.g. the duration of sustained release desired, the effects, if any on biological activity, the ease in handling and other known effects of the PEG to a peptide or protein). For example, the PEG can have an average molecular weight of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 kDa.

[0259] In some embodiments, the PEG can have a branched structure.Branched polyethylene glycols are described, for example, in U. S. Pat. No. 5,643,575; Morpurgo etal. (1996. Appl. Biochem. Biotechnol. 56:59-72); Vorobjev et al. (1999. Nucleosides Nucleotides 18:2745-2750); and Caliceti et al. (1999. Bioconjug. Chem. 10:638-646).

[0260] In some embodiments, the protecting or stabilising moiety is a lipid moiety. The lipid moiety may be a lipid moiety comprising 6 to 24 carbon atoms in the alkyl chain (and all integers therebetween); especially 8 to 22 carbon atoms; most especially 10 to 20 carbon atoms (e.g. a C6-C20 fatty acyl group). For example, the lipid moiety may be hexanoyl (Cs), heptanoyl (C7), octanoyl (Cs), nonanoyl (C9), decanoyl (C10), undecanoyl (Cu), dodecanoyl (C12), tridecanoyl (C13), tetradecanoyl (CM), pentadecanoyl (C15), hexadecanoyl (Cis), heptadecanoyl (C17) or octadecanoyl (Cis). In particular embodiments, the lipid moiety is hexanoyl (Cs), octanoyl (Cs), decanoyl (C10), dodecanoyl (C12), tetradecanoyl (CM), hexadecanoyl (Cis) or octadecanoyl (Cis); especially tetradecanoyl, hexadecanoyl or octadecanoyl. While the lipid moiety may be directly conjugated to the proteinaceous molecule, in some embodiments, the lipid moiety is conjugated via a linker to the proteinaceous molecule, such as a PEG linker (e.g. a PEG containing from 4 to 12 ethylene glycol groups).

[0261] In preferred embodiments, the acetyl group and / or pyroglutamate are conjugated to the N-terminal amino acid residue of the proteinaceous molecule. In particular embodiments, the N-terminus of the proteinaceous molecule is a pyroglutamide or acetamide. In some embodiments, the amino group is conjugated to the C-terminal amino acid residue of the proteinaceous molecule. In some embodiments, the proteinaceous molecule of the invention has a primary amide at the C-terminus.

[0262] When present the PEG or lipid moiety may be, for example, conjugated to the N-terminal or C-terminal amino acid residue of the proteinaceous molecule or through the amine of a lysine side-chain, especially through the N-terminal amino acidresidue, such as through the a-amino group or through the amino group of a lysine sidechain (i.e. the e-amino group).

[0263] In particular embodiments, the proteinaceous molecule of the invention has a primary amide or a free carboxyl group (acid) at the C-terminus and a primary amine or acetamide at the N-terminus; especially a C-terminal acid, and an N-terminal amine.

[0264] While the protecting or stabilising moiety may be attached to the N-and / or C-terminus of the proteinaceous molecule, the moiety may also be attached to the proteinaceous molecule through a side-chain of an amino acid residue, such as through the amino group in the side chain of an amine- or amide-containing amino acid residue, such as lysine, arginine, glutamine and asparagine or other suitably modified side chain, especially through a lysine side chain.

[0265] In some embodiments, the proteinaceous molecules of the invention may have one or more disulfide bonds (e.g. 1, 2, 3, 4, 5, 6, 7 or 8 disulfide bonds, depending on the number of cysteine residues present).

[0266] The proteinaceous molecules of the present invention may be, isolated, prepared using recombinant DNA techniques, or prepared by chemical synthesis.

[0267] In some embodiments, the proteinaceous molecules of the present invention are prepared using standard peptide synthesis methods, such as solution synthesis or solid phase synthesis. The chemical synthesis of the proteinaceous molecules of the invention may be performed manually or using an automated synthesizer. For example, the linear peptides may be synthesized using solid phase peptide synthesis using either Boc or Fmoc chemistry, as described in Merrifield (1963) J Am Chem Soc, 85(14): 2149-2154; Schnolzer, et al. (1992) Int J Pept Protein Res, 40: 180-193; Ensenat-Waser, etal. (2002) IUBMB Life, 54:33-36; WO 2002 / 010193 and Cardosa, et al. (2015) Mol Pharmacol, 88(2): 291-303. Following deprotection and cleavage from the solid support, the linear peptides are purified using suitable methods, such as preparative chromatography.

[0268] In other embodiments, the proteinaceous molecules of the invention may be cyclized. Cyclization may be performed using several techniques, for example, as described in Davies (2003) J Pept Sci, 9: 471-501.

[0269] In some embodiments, the proteinaceous molecules of the present invention are prepared using recombinant DNA techniques. For example, the proteinaceous molecules of the invention may be prepared by a procedure including the steps of: (a) preparing a construct comprising a polynucleotide sequence that encodes the proteinaceous molecule of the invention and that is operably linked to a regulatoryelement; (b) introducing the construct into a host cell; (c) culturing the host cell to express the polynucleotide sequence to thereby produce the encoded proteinaceous molecule of the invention; and (d) isolating the proteinaceous molecule of the invention from the host cell. The proteinaceous molecule of the present invention may be prepared recombinantly using standard protocols, for example, as described in Klint, et al. (2013) PLOS One, 8(5): e63865; Sambrook, et al. (1989) Molecular Cloning: A Laboratory Manual (Cold Spring Harbour Press), in particular Sections 16 and 17; Ausubel, et al. (1998) Current Protocols in Molecular Biology (John Wiley and Sons, Inc.), in particular Chapters 10 and 16; and Coligan, et al. (1997) Current Protocols in Protein Science (John Wiley and Sons, Inc.), in particular Chapters 1, 5 and 6.4. Chimeric Molecules

[0270] In another aspect, the present invention provides a chimeric molecule. The chimeric molecule comprises a proteinaceous molecule and at least one ancillary moiety.

[0271] A. Proteinaceous Molecule

[0272] The proteinaceous molecule is any proteinaceous molecule described herein. For example, in some embodiments, the proteinaceous molecule comprises, consists, or consists essentially of an amino acid sequence represented by any one of Formulae (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-Fl), (I-F2), (I-F3), (I-F4), (I-F5), (I-G), (I-Gl), (I-G2), (I-G3), (I-G4), (I-H), (I-Hl), (I-H2), (I-H3), (I-I), (I-J), (I-Jl), (I-K), (I-Kl), (I-L), (I-Ll), (I-M), (I-Ml), (I-N), (I-Nl), (I-O), (1-01) and (I-P), or any embodiment thereof, an amino acid sequence represented by any one of SEQ ID NOs: 1-16 and 31-34, or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by any one of SEQ ID NOs: 1-16 and 31-34.

[0273] B. Ancillary Moiety

[0274] The at least one ancillary moiety is not particularly limited, and may be any moiety that contributes to therapeutic efficacy of the chimeric molecule. Suitable ancillary moieties include, but are not limited to, a polypeptide transport moiety (e.g. a cell-penetrating moiety, a signal peptide moiety that directs secretion of the proteinaceous molecule outside of a cell, a transmembrane peptide moiety that localises the proteinaceous molecule to a synaptic membrane, a receptor binding moiety that binds to a receptor that aids cellular uptake of the proteinaceous molecule and / or a PDZ domain) and a targeting ligand.

[0275] In some embodiments, the at least one ancillary moiety comprises, consists, or consists essentially of a polypeptide transport moiety that facilitates transport of the proteinaceous molecule across a biological membrane. When the at least one ancillary moiety comprises a polypeptide transport moiety, the polypeptide transport moiety may be a cell-penetrating moiety that facilitates entry of the proteinaceous molecule into a cell. For example, the cell-penetrating moiety may be polyarginine (e.g., R9).

[0276] In suitable embodiments, the cell-penetrating moiety is a cellpenetrating peptide. For example, the cell-penetrating peptide may be derived from the transactivator of transcription (TAT) of human immunodeficiency virus (HIV). In some embodiments, the cell-penetrating peptide comprises, consists, or consists essentially of the amino acid sequence YGRKKRRQRRR [SEQ ID NO: 35] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 35. In some embodiments, the cell-penetrating peptide comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 35. In other embodiments, the cell-penetrating peptide comprises, consists, or consists essentially of an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 35. Non-limiting examples of suitable cell-penetrating peptides include basic poly(Arg) and poly(Lys) peptides and basic poly(Arg) and poly(Lys) peptides containing non-natural analogues of Arg and Lys residues, RRRRRRRRR (SEQ ID NO: 17); GRRRRRRRRR (SEQ ID NO: 18); GGRRRRRRRRR (SEQ ID NO: 19); GGGRRRRRRRRR (SEQ ID NO: 20); RRRRRRRR (SEQ ID NO: 21); RRRRRRR (SEQ ID NO: 22); RRRRRR (SEQ ID NO: 23); RRWRRWWRRWWRRWRR (W / R; SEQ ID NO: 36), CWK18(AlkCWK18; SEQ ID NO: 37), K18WCCWK18(Di-CWK18; SEQ ID NO: 38), WTLNSAGYLLGKINLKALAALAKKIL (Transportan; SEQ ID NO: 39), GLFEALEELWEAK (DipaLytic; SEQ ID NO: 40), K16GGCRGDMFGCAK16RGD (K16RGD; SEQ ID NO: 41), K16GGCMFGCGG (P1; SEQ ID NO: 42), K16ICRRARGDNPDDRCT (P2; SEQ ID NO: 43), KKWKMRRNQFWVKVQRbAK (B) bA (P3; SEQ ID NO: 44), VAYISRGGVSTYYSDTVKGRFTRQKYNKRA (P3a; SEQ ID NO: 45), IGRIDPANGKTKYAPKFQDKATRSNYYGNSPS (P9.3; SEQ ID NO: 46), KETWWETWWTEWSQPKKKRKV (Pep-1; SEQ ID NO: 47), PLAEIDGIELTY (Plae; SEQ ID NO: 48), K16GGPLAEIDGIELGA (Kplae; SEQ ID NO: 49), K16GGPLAEIDGIELCA (cKplae; SEQ ID NO: 50), GALFLGFLGGAAGSTMGAWSQPKSKRKV (MGP; SEQ ID NO: 51), WEAK(LAKA)2-LAKH(LAKA)2LKAC (HA2; SEQ ID NO: 52), (LARL)6NHCH3(LARL46; SEQ ID NO: 53), KLLKLLLKLWLLKLLL (Hel-11-7; SEQ ID NO: 54), (KKKK)2GGC (KK; SEQ ID NO: 55), (KWKK)2GCC (KWK; SEQ ID NO: 56), (RWRR)2GGC (RWR; SEQ ID NO: 57),PKKKRKV (SV40 NLS7; SEQ ID NO: 58), PEVKKKRKPEYP (NLS12; SEQ ID NO: 59), TPPKKKRKVEDP (NLS12a; SEQ ID NO: 60), GGGGPKKKRKVGG (SV40 NLS13; SEQ ID NO: 61), GGGFSTSLRARKA (AV NLS13; SEQ ID NO: 62), CKKKKKKSEDEYPYVPN (AV RME NLS17; SEQ ID NO: 63), CKKKKKKKSEDEYPYVPNFSTSLRARKA (AV FP NLS28; SEQ ID NO: 64), LVRKKRKTEEESPLKDKDAKKSKQE (SV40 N1 NLS24; SEQ ID NO: 65), and K9K2K4K8GGK5 (Loligomer; SEQ ID NO: 66); HSV-1 tegument protein VP22; HSV-1 tegument protein VP22r fused with nuclear export signal (NES); mutant B-subunit of Escherichia coli enterotoxin EtxB (H57S); detoxified exotoxin A (ETA); the protein transduction domain of the HIV-1 Tat protein, GRKKRRQRRRPPQ (SEQ ID NO: 67); the Drosophila melanogaster Antennapedia domain Antp (amino acids 43-58), RQIKIWFQNRRMKWKK (SEQ ID NO: 68); Buforin II, TRSSRAGLQFPVGRVHRLLRK (SEQ ID NO: 69); hClock-(amino acids 35-47) (human Clock protein DNA-binding peptide), KRVSRNKSEKKRR (SEQ ID NO: 70); MAP (model amphipathic peptide), KLALKLALKALKAALKLA (SEQ ID NO: 71); K-FGF, AAVALLPAVLLALLAP (SEQ ID NO: 72); Ku70-derived peptide, comprising a peptide selected from the group comprising VPMLKE (SEQ ID NO: 73), VPMLK (SEQ ID NO: 74), PMLKE (SEQ ID NO: 75) or PMLK (SEQ ID NO: 76); Prion, Mouse Prpe (amino acids 1-28), MANLGYWLLALFVTMWTDVGLCKKRPKP (SEQ ID NO: 77); pVEC, LLIILRRRIRKQAHAHSK (SEQ ID NO: 78); Pep-I, KETWWETWWTEWSQPKKKRKV (SEQ ID NO: 79); SynBI, RGGRLSYSRRRFSTSTGR (SEQ ID NO: 80); Transportan, GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 81);Transportan-10, AGYLLGKINLKALAALAKKIL (SEQ ID NO: 82); CADY, Ac-GLWRALWRLLRSLWRLLWRA-cysteamide (SEQ ID NO: 83); Pep-7, SDLWEMMMVSLACQY (SEQ ID NO: 84); HN-1, TSPLNIHNGQKL (SEQ ID NO: 85); VT5, DPKGDPKGVTVTVTVTVTGKGDPKPD (SEQ ID NO: 86); pISL, RVIRVWFQNKRCKDKK (SEQ ID NO: 87); a peptide described in US 20090047272, US 20150266935 or US 20130136742; a peptide described in Neves et al. (2017) ACS Chem Biol, 12: 1257-1268, such as VQQLTKRFSL (PepHl; SEQ ID NO: 88), KLFMALVAFLRFLT (PepH2; SEQ ID NO: 89), AGILKRW (PepH3; SEQ ID NO: 90) or KSKAINVLRGFRKEIGRMLNILN (PepH4; SEQ ID NO: 91); RKKRRRESRKKRRRES (DPV3; SEQ ID NO: 92); GRPRESGKKRKRKRLKP (DPV6; SEQ ID NO: 93); RQIKIWFQNRRMKWKK (penetratin; SEQ ID NO: 94);GRRRRRRRRRPPQ (R9-TAT; SEQ ID NO: 95); RVRVFVVHIPRLT (ARF 19-31; SEQ ID NO: 96); VSALK (Bip4; SEQ ID NO: 97); GIGAVLKVLTTGLPALISWIKRKRQQ (Melittin; SEQ ID NO: 98); or HGLASTLTRWAHYNALIRAF (gH625; SEQ ID NO: 99).

[0277] In some embodiments, the polypeptide transport moiety comprises, consists, or consists essentially of a signal peptide moiety that directs secretion of the proteinaceous molecule outside of a cell. For example, the signal peptide moiety may comprise, consist, or consist essentially of the amino acid sequence MVPQVLLFVLLLGFSLC [SEQ ID NO: 24] or an amino acid sequence having at least 85%(such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 24. In some embodiments, the signal peptide moiety comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 24. In other embodiments, the signal peptide moiety comprises, consists, or consists essentially of an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 24.

[0278] In some embodiments, the polypeptide transport moiety comprises, consists, or consists essentially of a transmembrane peptide moiety that localises the proteinaceous molecule to a synaptic membrane. For example, the transmembrane peptide moiety may comprise, consist, or consist essentially of the amino acid sequence KYVLMTAGAMIGLVLIFSLMTWC [SEQ ID NO: 25] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 25. In some embodiments, the transmembrane peptide moiety comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 25. In other embodiments, the transmembrane peptide moiety comprises, consists, or consists essentially of an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 25.

[0279] In some embodiments, the polypeptide transport moiety comprises, consists, or consists essentially of a receptor binding moiety that binds to a receptor that aids cellular uptake of the proteinaceous molecule. In some embodiments, the receptor binding moiety binds to p75 neurotrophin receptor (p75NTR). For example, the receptor binding moiety may comprise, consist, or consist essentially of the amino acid sequence MTTKSVSFRRL [SEQ ID NO: 26], SHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPS [SEQ ID NO: 27], KGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLL [SEQ ID NO: 28], or MTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHVNG VFFNGIILGPDDHVLIPEMQSSLL [SEQ ID NO: 29], or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by any one of SEQ ID NOs: 26-29. In some embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 26, or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 26. In other embodiments, the receptor binding moietycomprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 27. In some embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 28, or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 28. In some embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 29, or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 29. In some embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 26. In other embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 27. In some embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 28. In some embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 29. In other embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 26. In some embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 27. In some embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 28. In other embodiments, the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 29.

[0280] In some embodiments, the polypeptide transport moiety comprises, consists or consists essentially of a PDZ domain. In other embodiments, the PDZ domain binds to MAST2. For example, the PDZ domain may comprise, consist, or consist essentially of the amino acid sequence RRANRPESKQRSFGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 30] or anamino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 30. In some embodiments, the PDZ domain comprises, consists, or consists essentially of the amino acid sequence of SEQ ID NO: 30. In other embodiments, the PDZ domain comprises, consists, or consists essentially of an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 30.

[0281] In some embodiments, the at least one ancillary moiety comprises, consists or consists essentially of a targeting ligand. As used herein, the term "targeting ligand" refers to a ligand that is prepared synthetically and binds to, or otherwise interacts with, a biological target (e.g., a protein) within a body of a subject. In this manner, the targeting ligand facilitates delivery of the proteinaceous molecule to a particular site within a body of a subject, such as to a neuron or an axon. By way of non-limiting example, the targeting ligand may be any one of the targeted ANS-to-CNS uptake ligands (TACL) set forth in Sellers, D. L. et al. ACS Nano. 2019, 13(10), 10961-10971; a synthetic form of the targeted axonal import (TAxI) peptide described in Sellers, D. L. et al. PNAS 2016, 113(9), 2514-2519; or a peptide described in WO 2013036889 Al, WO 2012167214 Al, or WO 2009006638 A2.

[0282] In some embodiments, the at least one ancillary moiety is directly linked to the proteinaceous molecule, e.g. via a covalent bond. In other embodiments, the at least one ancillary moiety is linked to the proteinaceous molecule via a covalent linker. In some embodiments, when a covalent linker is present, the chimeric molecule may further comprise a spacer linked to the covalent linker and at least one of the proteinaceous molecule and the at least one ancillary moiety. The spacer may provide additional spacing between the at least one ancillary moiety and the proteinaceous molecule to allow for effective delivery of the proteinaceous molecule to a target site. The spacer may be, for example, a peptide spacer such as a peptide of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids in length. It will be appreciated that the covalent linker and / or the spacer may be susceptible to cleavage at a target site within a subject.

[0283] In some embodiments, the at least one ancillary moiety is a plurality of ancillary moieties, such as 2, 3, or 4 ancillary moieties. In such embodiments, at least one of the ancillary moieties is directly linked to the proteinaceous molecule, and at least one of the ancillary moieties is linked to the proteinaceous molecule via a covalent linker. In other embodiments, each of the moieties is directly linked to the proteinaceous molecule. In some embodiments, each of the moieties is linked to the proteinaceous molecule via a covalent linker. Alternatively, a first ancillary moiety may be linked to theproteinaceous molecule and a second ancillary moiety may be linked to the first ancillary moiety, and the like (e.g. the first ancillary moiety is linked to the N-terminus of the proteinaceous molecule and the second ancillary moiety is linked to the N-terminus of the first ancillary moiety).

[0284] In some embodiments, the at least one ancillary moiety is linked to the N-terminus of the proteinaceous molecule. In other embodiments, the at least one ancillary moiety is linked to the C-terminus of the proteinaceous molecule. In some embodiments, when the at least one ancillary moiety is a plurality of ancillary moieties, at least one of the ancillary moieties is linked to the N-terminus of the proteinaceous molecule, and at least one of the ancillary moieties is linked to the C-terminus of the proteinaceous molecule.

[0285] While the ancillary moiety may be attached to the N- and / or C-terminus of the proteinaceous molecule, the moiety may also be attached to the proteinaceous molecule through a side-chain of an amino acid residue, such as through the amino group in the side chain of an amine- or amide-containing amino acid residue, such as lysine, arginine, glutamine and asparagine or other suitably modified side chain, especially through a lysine side chain.5. Expression Vectors, Constructs, and Host Cells

[0286] The invention also contemplates expression vectors, constructs and host cells comprising a nucleic acid sequence that encodes a proteinaceous molecule of the invention.

[0287] Accordingly, in a further aspect, the present invention provides an expression vector comprising a nucleic acid sequence that encodes a proteinaceous molecule as described herein (i.e., a proteinaceous molecule comprising, consisting, or consisting essentially of an amino acid sequence represented by any one of Formulae (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-Fl), (I-F2), (I-F3), (I-F4), (I-F5), (I-G), (I-Gl), (I-G2), (I-G3), (I-G4), (I-H), (I-Hl), (I-H2), (I-H3), (I-I), (I-J), (I-Jl), (I-K), (I-Kl), (I-L), (I-Ll), (I-M), (I-Ml), (I-N), (I-Nl), (1-0), (1-01) and (I-P), or any embodiment thereof, an amino acid sequence represented by SEQ ID NOs: 1-16 or 31-34, or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by any one of SEQ ID NOs: 1-16 and 31-34) or a chimeric molecule as described herein.

[0288] In some embodiments, the expression vector is other than a rabies virus or virion. In other embodiments, the expression vector is a modified rabies virus or virion, a human immunodeficiency virus or virion, or an adenovirus virus or virion. In some embodiments, the expression vector is a modified rabies virus or recombinant non-self-replicating virion capable of delivering the proteinaceous molecule to the brain. An example of such an expression vector is provided in PCT Publication No.W02008 / 054544, the disclosure of which is incorporated herein by reference in its entirety.

[0289] In some embodiments, the nucleic acid sequence is operably connected to a heterologous promoter. Suitable promoters include, for example, a cytomegalovirus promoter, a cytomegalovirus / chicken beta-actin (CBA) hybrid promoter or a synapsin promoter.

[0290] In one aspect, the present invention provides a construct comprising a nucleic acid sequence that encodes a proteinaceous molecule as described herein (i.e., a proteinaceous molecule comprising, consisting, or consisting essentially of an amino acid sequence represented by any one of Formulae (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-Fl), (I-F2), (I-F3), (I-F4), (I-F5), (I-G), (I-Gl), (I-G2), (I-G3), (I-G4), (I-H), (I-Hl), (I-H2), (I-H3), (I-I), (I-J), (I-Jl), (I-K), (I-Kl), (I-L), (I-Ll), (I-M), (I-Ml), (I-N), (I-Nl), (1-0), (1-01) and (I-P), or any embodiment thereof, an amino acid sequence represented by SEQ ID NOs: 1-16 or 31-34, or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by any one of SEQ ID NOs: 1-16 and 31-34) or a chimeric molecule as described herein, operably connected to a heterologous promoter.

[0291] In another aspect, the present invention provides a host cell comprising an expression vector as described herein or a construct as described herein. In some embodiments, the proteinaceous molecules or chimeric molecules of the invention may be produced inside a cell by introduction of one or more expression constructs, such as an expression vector as described herein or a construct as described herein, that comprise a nucleic acid sequence that encodes a proteinaceous molecule described herein or a chimeric molecule described herein.

[0292] The invention contemplates recombinantly producing the proteinaceous molecules or chimeric molecules of the invention inside a host cell, such as a mammalian cell (e.g. Chinese hamster ovary (CHO) cell, mouse myeloma (NSO) cell, baby hamster kidney (BHK) cell or human embryonic kidney (HEK293) cell), yeast cell (e.g. Pichia pastoris cell, Saccharomyces cerevisiae cell, Schizosaccharomyces pombe cell, Hansenula polymorpha cell, Kluyveromyces lactis cell, Yarrowia lipolytica cell or Arxula adeninivorans cell), or bacterial cell (e.g. Escherichia coli cell, Corynebacterium glutamicum or Pseudomonas fluorescens cell).

[0293] As described, for example, in US 5,976,567, the expression of natural or synthetic nucleic acids is typically achieved by operably linking a nucleic acid sequenceencoding a proteinaceous molecule of the invention to a regulatory element (e.g. a promoter, which may be either constitutive or inducible), suitably incorporating the construct into an expression vector and introducing the vector into a suitable host cell. Typical vectors contain transcription and translation terminators, transcription and translation initiation sequences and promoters useful for regulation of the expression of the nucleic acid. The vectors optionally comprise generic expression cassettes containing at least one independent terminator sequence, sequences permitting replication of the cassette in eukaryotes, prokaryotes or both, (e.g. shuttle vectors) and selection markers for both prokaryotic and eukaryotic systems. Vectors may be suitable for replication and integration in prokaryotes, eukaryotes, or both. See, Giliman and Smith (1979), Gene, 8: 81-97; Roberts et al. (1987) Nature, 328: 731-734; Berger and Kimmel, Guide to Molecular Cloning Techniques, Methods in Enzymology, volume 152, Academic Press, Inc., San Diego, Calif. (Berger); Sambrook et al. (1989), Molecular Cloning – a Laboratory Manual (2nd ed.) Vol. 1-3, Cold Spring Harbor Laboratory, Cold Spring Harbor Press, N. Y.; and Ausubel etal., (1994) Current Protocols in Molecular Biology, eds., Current Protocols, a joint venture between Greene Publishing Associates, Inc. and John Wiley & Sons, Inc. (Supplement).

[0294] Expression vectors containing regulatory elements from eukaryotic viruses such as retroviruses are typically used for expression of nucleic acid sequences in eukaryotic cells. SV40 vectors include pSVT7 and pMT2. Vectors derived from bovine papilloma virus include pBV-lMTHA, and vectors derived from Epstein Bar virus include pHEBO, and p2O5. Other exemplary vectors include pMSG, pAV009 / A+, pMTO10 / A+, pMAMneo-5, baculovirus pDSVE, and any other vector allowing expression of proteins under the direction of the SV-40 early promoter, SV-40 later promoter, metallothionein promoter, murine mammary tumor virus promoter, Rous sarcoma virus promoter, polyhedrin promoter, or other promoters shown effective for expression in eukaryotic cells.

[0295] While a variety of vectors may be used, it should be noted that viral expression vectors are useful for modifying eukaryotic cells because of the high efficiency with which the viral vectors transfect target cells and integrate into the target cell genome. Illustrative expression vectors of this type can be derived from viral DNA sequences including, but not limited to, adenovirus, adeno-associated viruses, herpessimplex viruses and retroviruses such as B, C, and D retroviruses as well as spumaviruses and modified lentiviruses. Suitable expression vectors for transfection of animal cells are described, for example, by Wu and Ataai (2000) Curr. Opin. Biotechnol., 11(2): 205-208; Vigna and Naldini (2000) J. Gene Med., 2(5): 308-316; Kay et al.(2001) Nat. Med., 7(1): 33-40; Athanasopoulos et al. (2000) Int. J. Mol. Med., 6(4): 363-375; and Walther and Stein (2000) Drugs, 60(2): 249-271.

[0296] The polypeptide or peptide-encoding portion of the expression vector may comprise a naturally-occurring sequence or a variant thereof, which has been engineered using recombinant techniques. In one example of a variant, the codon composition of a polynucleotide encoding a proteinaceous molecule of the invention is modified to permit enhanced expression of the proteinaceous molecule of the invention in a mammalian host using methods that take advantage of codon usage bias, or codon translational efficiency in specific mammalian cell or tissue types as set forth, for example, in PCT Publication Nos. WO 99 / 02694 and WO 00 / 42215. Briefly, these latter methods are based on the observation that translational efficiencies of different codons vary between different cells or tissues and that these differences can be exploited, together with codon composition of a gene, to regulate expression of a protein in a particular cell or tissue type. Thus, for the construction of codon-optimized polynucleotides, at least one existing codon of a parent polynucleotide is replaced with a synonymous codon that has a higher translational efficiency in a target cell or tissue than the existing codon it replaces. Although it is preferable to replace all the existing codons of a parent nucleic acid molecule with synonymous codons which have that higher translational efficiency, this is not necessary because increased expression can be accomplished even with partial replacement. Suitably, the replacement step affects 5%, 10%, 15%, 20%, 25%, 30%, more preferably 35%, 40%, 50%, 60%, 70% or more of the existing codons of a parent polynucleotide.

[0297] The expression vector is compatible with the cell in which it is introduced such that the proteinaceous molecule of the invention is expressible by the cell. The expression vector is introduced into the cell by any suitable means which will be dependent on the particular choice of expression vector and cell employed. Such means of introduction are well-known to those skilled in the art. For example, introduction can be effected by use of contacting (e.g. in the case of viral vectors), electroporation, transformation, transduction, conjugation or triparental mating, transfection, infection membrane fusion with cationic lipids, high-velocity bombardment with DNA-coated microprojectiles, incubation with calcium phosphate-DNA precipitate, direct microinjection into single cells, and the like. Other methods also are available and are known to those skilled in the art. Alternatively, the vectors are introduced by means of cationic lipids, e.g., liposomes. Such liposomes are commercially available (e.g., Lipofectin®, Lipofectamine™, and the like, supplied by Life Technologies, Gibco BRL, Gaithersburg, Md.).6. Compositions

[0298] In accordance with the present disclosure, the proteinaceous molecules of the present invention (i.e., a proteinaceous molecule comprising, consisting, or consisting essentially of an amino acid sequence represented by any one of Formulae (I),(I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-Fl), (I-F2), (I-F3), (I-F4), (I-F5), (I-G), (I-Gl), (I-G2), (I-G3), (I-G4), (I-H), (I-Hl), (I-H2), (I-H3), (I-I), (I-J), (I-Jl), (I-K), (I-Kl), (I-L), (I-Ll), (I-M), (I-Ml), (I-N), (I-Nl), (1-0), (I-Ol) and (I-P), or any embodiment thereof, an amino acid sequence represented by SEQ ID NOs: 1-16 or 31-34, or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by any one of SEQ ID NOs: 1-16 and 31-34) and the chimeric molecules of the present invention are useful in compositions and methods for the treatment or prevention of a condition involving SARMl-mediated axonal degeneration, such as a neurodegenerative disease. Thus, in some embodiments, the proteinaceous molecules or chimeric molecules may be in the form of a composition (e.g., a pharmaceutical composition), wherein the composition comprises a proteinaceous molecule or a chimeric molecule of the invention and a pharmaceutically acceptable carrier or diluent. In some embodiments, the composition further comprises at least one of a nanoparticle and a liposome. For example, the composition may comprise a nanoparticle. In other embodiments, the composition may comprise a liposome.

[0299] The proteinaceous molecule or chimeric molecule may be formulated into the composition (e.g., pharmaceutical composition) as a neutral or salt form.

[0300] As will be appreciated by those skilled in the art, the choice of pharmaceutically acceptable carrier or diluent will be dependent on the route of administration and on the nature of the condition and subject to be treated. The particular carrier or delivery system and route of administration may be readily determined by a person skilled in the art. The carrier or delivery system and route of administration should be carefully selected to ensure that the activity of the proteinaceous molecule or chimeric molecule is not depleted during preparation of the formulation and the proteinaceous molecule or chimeric molecule is able to reach the site of action intact. The pharmaceutical compositions of the invention may be administered through a variety of routes including, but not limited to, oral, rectal, topical, intranasal, intraocular, transmucosal, intestinal, enteral, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intracerebral, intravaginal, intravesical, intravenous or intraperitoneal administration.

[0301] The pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions and sterile powders for the preparation of sterile injectable solutions. Such forms should be stable under the conditions of manufacture and storage and may be preserved against reduction, oxidation and microbial contamination.

[0302] A person skilled in the art will readily be able to determine appropriate formulations for the proteinaceous molecules of the invention using conventional approaches. Techniques for formulation and administration may be found in, for example, Remington: The Science and Practice of Pharmacy, Adeboye Adejare and Joseph Remington (Ed), Academic Press, London, 23rdEdition, 2021.

[0303] Identification of preferred pH ranges and suitable excipients, such as antioxidants, is routine in the art, for example, as described in Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press). Buffer systems are routinely used to provide pH values of a desired range and may include, but are not limited to, carboxylic acid buffers, such as acetate, citrate, lactate, tartrate and succinate; glycine; histidine; phosphate; tris(hydroxymethyl)aminomethane (Tris); arginine; sodium hydroxide; glutamate; and carbonate buffers. Suitable antioxidants may include, but are not limited to, phenolic compounds such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole; vitamin E; ascorbic acid; reducing agents such as methionine or sulphite; metal chelators such as ethylene diamine tetraacetic acid (EDTA); cysteine hydrochloride; sodium bisulfite; sodium metabisulfite; sodium sulfite; ascorbyl palmitate; lecithin; propyl gallate; and alpha-tocopherol.

[0304] For injection, the proteinaceous molecule or chimeric molecule may be formulated in an aqueous solution, suitably in physiologically compatible buffers such as Hanks' solution, Ringer's solution or physiological saline buffer, such as phosphate buffered saline (PBS). For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0305] The compositions of the present invention may be formulated for administration in the form of liquids, containing acceptable diluents (such as saline and sterile water), or may be in the form of lotions, creams or gels containing acceptable diluents or carriers to impart the desired texture, consistency, viscosity and appearance. Acceptable diluents and carriers are familiar to those skilled in the art and include, but are not restricted to, ethoxylated and nonethoxylated surfactants, fatty alcohols, fatty acids, hydrocarbon oils (such as palm oil, coconut oil, and mineral oil), cocoa butter waxes, silicon oils, pH balancers, cellulose derivatives, emulsifying agents such as nonionic organic and inorganic bases, preserving agents, wax esters, steroid alcohols, triglyceride esters, phospholipids such as lecithin and cephalin, polyhydric alcohol esters, fatty alcohol esters, hydrophilic lanolin derivatives and hydrophilic beeswax derivatives.

[0306] Alternatively, the proteinaceous molecule or chimeric molecule can be formulated readily using pharmaceutically acceptable carriers well known in the art intodosages suitable for oral administration, which is also contemplated for the practice of the present invention. Such carriers enable the proteinaceous molecule or chimeric molecule of the invention to be formulated in dosage forms such as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. These carriers may be selected from sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline and pyrogen-free water.

[0307] Pharmaceutical formulations for parenteral administration include aqueous solutions of the proteinaceous molecule or chimeric molecule in water-soluble form. Additionally, suspensions of the proteinaceous molecule or chimeric molecule may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0308] Sterile solutions may be prepared by combining the proteinaceous molecule or chimeric molecule in the required amount in the appropriate solvent with other excipients as described above as required, followed by sterilization, such as filtration. Generally, dispersions are prepared by incorporating the various sterilized active compounds into a sterile vehicle which contains the basic dispersion medium and the required excipients as described above. Sterile dry powders may be prepared by vacuum- or freeze-drying a sterile solution comprising the active compounds and other required excipients as described above.

[0309] Pharmaceutical preparations for oral use can be obtained by combining proteinaceous molecule or chimeric molecule with solid excipients and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatine, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more therapeutic agents asdescribed above with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g. by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0310] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of particle doses.

[0311] Pharmaceuticals which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

[0312] The proteinaceous molecule or chimeric molecule may be incorporated into modified-release preparations and formulations, for example, polymeric microsphere formulations, and oil- or gel-based formulations.

[0313] In particular embodiments, the proteinaceous molecule or chimeric molecule may be administered in a local rather than systemic manner, such as by injection of the proteinaceous molecule or chimeric molecule directly into a tissue, which is preferably subcutaneous or omental tissue, often in a depot or sustained release formulation. In other embodiments, the proteinaceous molecule or chimeric molecule is systemically administered.

[0314] Furthermore, the proteinaceous molecule or chimeric molecule may be administered in a targeted drug delivery system, such as in a particle which is suitable targeted to and taken up selectively by a cell or tissue. In some embodiments, the proteinaceous molecule or chimeric molecule is contained in or otherwise associated with a vehicle selected from liposomes, including albumin-bound liposomes, micelles, dendrimers, exosomes, biodegradable particles, artificial DNA nanostructure, lipid-based nanoparticles and carbon or gold nanoparticles. In illustrative examples of this type, the vehicle is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol) (PEG), poly(diacetylene) (PDA), PLA-PEG copolymers, PDA-PEG copolymers and combinations thereof.

[0315] In cases of local administration or selective uptake, the effective local concentration of the agent may not be related to plasma concentration.

[0316] It is advantageous to formulate the compositions in dosage unit form for ease of administration and uniformity of dosage. The determination of the novel dosage unit forms of the present invention is dictated by and directly dependent on the unique characteristics of the active material, the particular therapeutic effect to be achieved and the limitations inherent in the art of compounding active materials for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

[0317] While the proteinaceous molecule or chimeric molecule of the invention may be the sole active ingredient administered to the subject, the administration of other active ingredients or therapies concurrently with said proteinaceous molecule or chimeric molecule is within the scope of the invention. For example, in some embodiments, the proteinaceous molecule or chimeric molecule may be administered concurrently with one or more ancillary agents or therapies, such as one or more neurodegenerative disease therapies, SARM1 inhibitors, CaMKII modulators, or inhibitors of brain ageing or neuronal injury. The proteinaceous molecule or chimeric molecule may be therapeutically used after the ancillary agent or therapy or may be therapeutically used together with the ancillary agent or therapy. The proteinaceous molecule or chimeric molecule may be administered separately, simultaneously, or sequentially with the ancillary agent or therapy.

[0318] Accordingly, in another aspect of the invention, there is provided a composition comprising a proteinaceous molecule or chimeric molecule of the invention and an additional therapeutic agent. For example, the present invention also contemplates a composition comprising a proteinaceous molecule or chimeric molecule of the invention and a SARM1 inhibitor or a treatment for a neurodegenerative disease. In some embodiments, the SARM1 inhibitor is a small molecule. Examples of small molecule SARM1 inhibitors are provided in U. S. Patent Application Publication No.2022 / 0008405, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the SARM1 inhibitor is a siRNA. In some embodiments, the SARM1 inhibitor is an antisense oligonucleotide. In some embodiments, the SARM1 inhibitor is a polypeptide. In some embodiments, the SARM1 inhibitor is a peptide fragment. In some embodiments, the SARM1 inhibitor is a nucleic acid. In some embodiments, the SARM1 inhibitor is an antisense oligonucleotide.

[0319] The present invention also contemplates concurrent administration with a treatment for a neurodegenerative disease, such as Parkinson's disease, or Alzheimer's disease, representative examples of which include levodopa (optionally with carbidopa),pramipexole, apomorphine, selegiline, rasagiline, safinamide, entacapone, opicapone, tolcapone, benztropine, trihexylphenidyl, amantadine, istradefyl line, nuplazid, corticosteroids such as prednisone and methylprednisolone, glatiramer acetate, ofatumumab, interferon beta (e.g. interferon beta-la), teriflunomide, dimethyl fumarate, diroximel fumarate, monomethyl fumarate, fingolimod, siponimod, ozanimod, ponesimod, cladribine, natalizumab, ocrelizumab, alemtuzumab, donepezil, galantamine, rivastigmine, memantine, aducanumab, lecanemab, tetrabenazine, deutetrabenazine, haloperidol, fluphenazine, olanzapine, aripiprazole, levitiracetam, clonazepam, citalopram, escitalopram, fluoxetine, sertraline, quetiapine, olanzapine, divalproex, carbamazepine and lamotrigine.

[0320] As previously described, the proteinaceous molecule or chimeric molecule may be compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form. In some embodiments, a unit dosage form may comprise the proteinaceous molecule or chimeric molecule in an amount in the range of from about 0.25 pg to about 2000 mg. The proteinaceous molecule or chimeric molecule may be present in an amount of from about 0.25 pg to about 2000 mg / mL of carrier. In embodiments where the pharmaceutical composition comprises one or more additional active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.7. Methods of Use

[0321] The proteinaceous molecules, chimeric molecules, and compositions (e.g., pharmaceutical compositions) of the invention are useful in methods of treating or inhibiting axonal degeneration, treating a neurodegenerative disease, modulating CaMKII, decreasing a rate of brain ageing, and inhibiting or minimising neuronal injury.

[0322] Accordingly, in another aspect of the invention, there is provided a use of the proteinaceous molecule, the chimeric molecule, or the composition of the invention for therapy, or in the manufacture of a medicament for therapy. The present invention also encompasses a proteinaceous molecule, a chimeric molecule, or a composition of the invention for use in therapy, or for use as a medicament.

[0323] The proteinaceous molecules, chimeric molecules, and compositions of the invention are useful for the inhibition of axonal degeneration (e.g., SARMl-mediated axonal degeneration). Thus, the proteinaceous molecules, chimeric molecules, and compositions of the invention are useful in methods of treating or inhibiting axonal degeneration (e.g., SARMl-mediated axonal degeneration) in a subject. The invention also provides use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention for inhibiting axonal degeneration, a proteinaceous molecule, chimericmolecule, and / or composition of the invention for use in inhibiting axonal degeneration, and a use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention in the manufacture of a medicament for inhibiting axonal degeneration. In some embodiments, the subject experiences at least about a 5% (including about a 5% to about 99% reduction in axonal degeneration and all integer percentages therebetween), at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, at least about a 30%, at least about a 35%, at least about a 40%, at least about a 45%, at least about a 50%, at least about a 55%, at least about a 60%, at least about a 65%, at least about a 70%, at least about a 75%, at least about a 80%, at least about a 85%, at least about a 90%, or at least about a 95%, reduction in axonal degeneration as compared to a subject who is not administered the proteinaceous molecule, chimeric molecule, and / or composition of the invention.

[0324] The proteinaceous molecules, chimeric molecules, and compositions of the invention are useful for treating a neurodegenerative disease (e.g., a SARM1-mediated neurodegenerative disease). Thus, the proteinaceous molecules, chimeric molecules, and compositions of the invention are useful in methods of treating a neurodegenerative disease in a subject. The invention also provides use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention for treating a neurodegenerative disease, a proteinaceous molecule, chimeric molecule, and / or composition of the invention for use in treating a neurodegenerative disease, and a use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention in the manufacture of a medicament for treating a neurodegenerative disease. In some embodiments, the neurodegenerative disease is a SARMl-mediated neurodegenerative disease. By way of non-limiting example, suitable neurodegenerative diseases include amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), dementia (e.g., Alzheimer's disease), Parkinson's disease, multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, Tay-Sachs disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, Guillain-Barre syndrome, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, tauopathy, synucleinopathy, amyloidosis, chemotherapy-induced or diabetes-induced neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Komzweig syndrome, transverse myelitis, motor neuron disease, spinocerebellarataxia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, acute optic neuropathy (AON), Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), autosomal dominant optic atrophy, retinal ganglion degeneration, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, ischemic optic neuropathy, peripheral neuropathy, neuromyelitis optica, Charcot Marie Tooth disease, non-arteritic anterior ischemic optic neuropathy, traumatic brain injury (TBI), traumatic spinal cord injury, traumatic axonal injury, and chronic traumatic encephalopathy (CTE). In some embodiments, the neurodegenerative disease (e.g., SARMl-mediated neurodegenerative disease) is motor neuron disease, dementia (e.g., Alzheimer's disease), Parkinson's disease, multiple sclerosis, traumatic brain injury, traumatic spinal cord injury, glaucoma, peripheral neuropathy, Guillain-Barre syndrome, chemotherapy-induced or diabetes-induced neuropathy, or CTE.

[0325] The proteinaceous molecules, chimeric molecules, and compositions of the invention are useful for treating a neuropathy or axonopathy associated with axonal degeneration. Thus, the proteinaceous molecules, chimeric molecules, and compositions of the invention are useful in methods of treating a neuropathy or axonopathy associated with axonal degeneration in a subject. The invention also provides use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention for treating a neuropathy or axonopathy associated with axonal degeneration, a proteinaceous molecule, chimeric molecule, and / or composition of the invention for use in treating a neuropathy or axonopathy associated with axonal degeneration, and a use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention in the manufacture of a medicament for treating a neuropathy or axonopathy associated with axonal degeneration. In some embodiments, a neuropathy or axonopathy associated with axonal degeneration can be any of a number of neuropathies or axonopathys such as, for example, those that are hereditary or congenital or associated with Parkinson's disease, Alzheimer's disease, herpes simplex virus or varicella zoster virus infection, diabetes, amyotrophic lateral sclerosis, a demyelinating disease, ischemia, stroke, chemical injury, thermal injury, and acquired immunodeficiency syndrome (AIDS). In addition, neurodegenerative diseases not mentioned above as well as a subset of the above mentioned diseases can also be treated with the methods of the present disclosure. Such subsets of diseases can include Parkinson's disease or nonParkinson's diseases (e.g., non-Parkinson's dystonia, non-Parkinson's tremors, etc.), or Alzheimer's disease.

[0326] Neuropathies and axonopathies can include any disease or condition involving neurons and / or supporting cells, such as for example, glia, muscle cells orfibroblasts, and, in particular, those diseases or conditions involving axonal damage. Axonal damage can be caused by traumatic injury or by non-mechanical injury due to diseases, conditions, or exposure to toxic molecules or drugs. The result of such damage can be degeneration or dysfunction of the axon and loss of functional neuronal activity. Diseases and conditions producing or associated with such axonal damage are among a large number of neuropathic diseases and conditions. Such neuropathies can include peripheral neuropathies, central neuropathies, and combinations thereof. Furthermore, peripheral neuropathic manifestations can be produced by diseases focused primarily in the central nervous systems and central nervous system manifestations can be produced by essentially peripheral or systemic diseases.

[0327] Peripheral neuropathies can involve damage to the peripheral nerves, and can be caused by diseases of the nerves or as the result of systemic illnesses. Some such diseases can include diabetes, uraemia, infectious diseases such as AIDS or leprosy, nutritional deficiencies, vascular or collagen disorders such as atherosclerosis, and autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa. Peripheral nerve degeneration can also result from traumatic (mechanical) damage to nerves as well as chemical or thermal damage to nerves. Such conditions that injure peripheral nerves include compression or entrapment injuries such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fracture or dislocated bones; pressure involving superficial nerves (ulna, radial, or peroneal) which can result from prolonged use of crutches or staying in one position for too long, or from a tumour; intraneural haemorrhage; ischaemia; and exposure to cold, radiation, certain medicines or toxic substances such as herbicides or pesticides. In particular, the nerve damage can result from chemical injury due to a cytotoxic anticancer agent such as, for example, taxol, cisplatinin, a proteasome inhibitor, or a vinca alkaloid such as vincristine. Typical symptoms of such peripheral neuropathies include weakness, numbness, paraesthesia (abnormal sensations such as burning, tickling, pricking or tingling) and pain in the arms, hands, legs and / or feet. The neuropathy can also be associated with mitochondrial dysfunction. Such neuropathies can exhibit decreased energy levels, i.e., decreased levels of NAD and ATP.

[0328] A peripheral neuropathy can also be a metabolic and endocrine neuropathy which includes a wide spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include, for example, diabetes mellitus, hypoglycaemia, uraemia, hypothyroidism, hepatic failure, polycythaemia, amyloidosis, acromegaly, porphyria, disorders of lipid / glycolipid metabolism, nutritional / vitamin deficiencies, and mitochondrial disorders, among others. Thecommon hallmark of these diseases is involvement of peripheral nerves by alteration of the structure or function of myelin and axons due to metabolic pathway dysregulation.

[0329] Neuropathies can also include optic neuropathies such as glaucoma; retinal ganglion degeneration such as those associated with retinitis pigmentosa and outer retinal neuropathies; optic nerve neuritis and / or degeneration including that associated with multiple sclerosis; traumatic injury to the optic nerve which can include, for example, injury during tumour removal; hereditary optic neuropathies such as Kjer's disease and Leber's hereditary optic neuropathy; ischemic optic neuropathies, such as those secondary to giant cell arteritis; metabolic optic neuropathies such as neurodegenerative diseases including Leber's neuropathy mentioned earlier, nutritional deficiencies such as deficiencies in vitamins B12or folic acid, and toxicities such as due to ethambutol or cyanide; neuropathies caused by adverse drug reactions and neuropathies caused by vitamin deficiency. Ischemic optic neuropathies also include non-arteritic anterior ischemic optic neuropathy.

[0330] The proteinaceous molecules, chimeric molecules, and compositions of the invention are useful for inhibiting or minimising neuronal injury. Thus, the proteinaceous molecules, chimeric molecules, and compositions of the invention are useful in methods of inhibiting or minimising neuronal injury in a subject. The invention also provides use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention for inhibiting or minimising neuronal injury, a proteinaceous molecule, chimeric molecule, and / or composition of the invention for use in inhibiting or minimising neuronal injury, and a use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention in the manufacture of a medicament for inhibiting or minimising neuronal injury. In some embodiments, the subject experiences at least about a 5% (including about a 5% to about 99% decrease in neuronal injury and all integer percentages therebetween), at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, at least about a 30%, at least about a 35%, at least about a 40%, at least about a 45%, at least about a 50%, at least about a 55%, at least about a 60%, at least about a 65%, at least about a 70%, at least about a 75%, at least about a 80%, at least about a 85%, at least about a 90%, or at least about a 95%, decrease in neuronal injury as compared to a subject who is not administered the proteinaceous molecules, chimeric molecules, and / or compositions of the invention.

[0331] In some embodiments, the neuronal injury involves axonal degeneration. In particular embodiments, the neuronal injury is a neuropathy or axonopathy. Suitable neuropathies and axonopathies are as discussed above.

[0332] The proteinaceous molecules, chimeric molecules, and compositions of the invention are useful for the modulation of CaMKII. Thus, the proteinaceousmolecules, chimeric molecules, and compositions of the invention are useful in methods of modulating CaMKII in a subject. The invention also provides use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention for modulating CaMKII, a proteinaceous molecule, chimeric molecule, and / or composition of the invention for use in modulating CaMKII, and a use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention in the manufacture of a medicament for modulating CaMKII. In some embodiments, modulation of CaMKII results in a reduction of SARMl-mediated axonal degeneration in a subject. In some embodiments, modulation of CaMKII results in treatment of a neurodegenerative disease (e.g., a SARMl-mediated neurodegenerative disease), such as a neurodegenerative disease described herein. In some embodiments, modulation of CaMKII results in inducement of synapse formation in a subject. For example, modulation of CaMKII may result in both a reduction of SARMl-mediated axonal degeneration and inducement of synapse formation in a subject. In some embodiments, the proteinaceous molecules, chimeric molecules, and compositions of the invention activate CaMKII.

[0333] Activation of CaMKII may include, for example, activation of one or more activities of CAMKII, such as enzymatic activity (i.e. kinase activity).

[0334] The proteinaceous molecules, chimeric molecules, and compositions of the invention are useful for inhibiting an activity of SARM1 (e.g., SARMl-mediated axonal degeneration). Thus, the proteinaceous molecules, chimeric molecules, and compositions of the invention are useful in methods of inhibiting an activity of SARM1 in a subject. Accordingly, the invention also provides use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention for inhibiting an activity of SARM1, a proteinaceous molecule, chimeric molecule, and / or composition of the invention for use in inhibiting an activity of SARM1, and a use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention in the manufacture of a medicament for inhibiting an activity of SARM1. In some embodiments, inhibiting an activity of SARM1 results in a reduction of SARMl-mediated axonal degeneration in a subject. In some embodiments, inhibiting an activity of SARM1 results in treatment of a neurodegenerative disease (e.g., a SARMl-mediated neurodegenerative disease), such as a neurodegenerative disease described herein.

[0335] The proteinaceous molecules, chimeric molecules, and compositions of the invention are useful for decreasing a rate of brain ageing. As used herein, "brain ageing" refers to a decline of the brain's capability of generating molecules, such as nicotinamide adenine dinucleotide (NADH), adenosine triphosphate (ATP), and phosphocreatine (PCr), necessary for processes relating to performing complex metal tasks, cognition, learning, memory, attentiveness, focus, etc. Thus, the proteinaceousmolecules, chimeric molecules, and compositions of the invention are useful in methods of decreasing a rate of brain ageing in a subject. The invention also provides use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention for decreasing a rate of brain ageing, a proteinaceous molecule, chimeric molecule, and / or composition of the invention for use in decreasing a rate of brain ageing, and a use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention in the manufacture of a medicament for decreasing a rate of brain ageing. In some embodiments, the subject experiences at least about a 5% (including about a 5% to about 99% decrease in a rate of brain ageing and all integer percentages therebetween), at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, at least about a 30%, at least about a 35%, at least about a 40%, at least about a 45%, at least about a 50%, at least about a 55%, at least about a 60%, at least about a 65%, at least about a 70%, at least about a 75%, at least about a 80%, at least about a 85%, at least about a 90%, or at least about a 95%, decrease in a rate of brain ageing as compared to a subject who is not administered a proteinaceous molecule, chimeric molecule, and / or composition of the invention.

[0336] In some embodiments, neurofilament protein (NfP) levels in blood may be used to characterise axonal degeneration and / or neuronal injury. Elevated NfP levels are known to coincide with neurodegeneration and neuronal injury independent of cause (Yuan, A. and Nixon, R., Front. Neurosci. 2021, 15: 689938). Accordingly, in some embodiments, NfP levels may be monitored in the subject to determine whether axonal degeneration and / or neuronal injury is / are reduced in the subject.

[0337] The proteinaceous molecules, chimeric molecules, and compositions of the invention are useful for inducing synapse formation in a subject. Thus, the proteinaceous molecules, chimeric molecules, and compositions of the invention are useful in methods of inducing synapse formation in a subject. The invention also provides use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention for inducing synapse formation, a proteinaceous molecule, chimeric molecule, and / or composition of the invention for use in inducing synapse formation, and a use of a proteinaceous molecule, chimeric molecule, and / or composition of the invention in the manufacture of a medicament for inducing synapse formation.

[0338] In order that the invention may be readily understood and put into practical effect, particular preferred embodiments will now be described by way of the following non-limiting examples.EXAMPLESEXAMPLE 1 -AXONAL DEGENERATION IN THE PATHOGENESIS OF RABIES

[0339] Rabies virus is a unique neurotropic pathogen that hijacks axonal trafficking and synaptic transmission to spread within the nervous system of its host. In order to investigate the axonal pathogenesis of rabies virus, advanced ex-vivo model systems were developed using primary mouse neurons from the peripheral and central nervous system cultured in a microfluidic chamber system. This model system enabled the separation of neuronal soma and axons, infection with rabies virus at axons similar to natural infections, and investigation of pathological events following axonal uptake and spread of the virus between interconnected neurons in vitro (FIG. IB). Neurons with multiple natural strains of lyssavirus were directly isolated from infected dogs or bats (i.e., rabies isolated from infected dogs in Zimbabwe (Z. DOG) and Thailand (T. DOG), Canadian silver head bat lyssavirus (SHBRV), and Australian bat lyssavirus from a horse (H. ABLV)). With reference to FIGS. 1A and 1C, when neurons were infected with street strain rabies virus, they activated axonal self-destruction, similar to when they are subjected to injury or stress.

[0340] It was also demonstrated that axonal self-destruction induced by rabies infection is dependent on the SARM1 protein. Rabies virus-induced axonal degeneration was significantly delayed (from 24 hours to >4 days) in both cortical and dorsal root ganglion (DRG) neurons derived from SARM1 knockout (SARMl7-) mice compared to wild type mice (WT) (FIG. ID). Using the microfluidic based ex-vivo model system for interconnected neurons, it was subsequently demonstrated that axonal self-destruction resulted in reduced spread of rabies virus between neurons. In contrast, when axonal self-destruction was delayed in SARM1 knockout neurons, increased and unhindered spread of rabies virus resulted (Sundaramoorthy, V. et al., PLoS Pathogens, 2020 el008343).

[0341] Materials and Methods

[0342] Mice: Wild type C57BL / 6J mice were purchased from Animal Resource Centre (Western Australia) or Australian BioResources (New South Wales) and housed at the Small Animal Facility (SAF) of Australian Animal Health Laboratory (AAHL). SARM1 knockout mice on the C57BL / 6 background (Kim, Y. et al., J. Exp. Med. 2007, 204(9):2063-74), were purchased from Jackson Laboratories (USA) (stock number 018069, RRID: IMSR_ JAX:018069). SARM1 knockout (SARMl’ / _) mice were housed and time-mated at SAF-AAHL in the same conditions as wild type mice. Genotyping of SARM1- / -mice was performed following the standard PCR protocol provided by the Jackson Laboratories, using the following primer sequences (5' to 3'); 23149: GGGAGAGCCTTCCTCATACC, 23150: TAAGGATGAACAGGGCCAAG, OIMR6916: CTTGGG TGGAGAGGCTATTC and OIMR6917: AGGTGAGATGACAGGAGATC.

[0343] Viruses: Original lyssavirus strains isolated from infected dog or bat were amplified in suckling mouse brain (Swiss mice) by intracerebral inoculation. The brain homogenates containing the virus were then used to infect Neuro-2a cells for further amplification. The viral strains were subjected to fewer than 3 passages in Neuro-2a cells during amplification. For infection with parental viral stocks, brain homogenates prepared from infected dog brain (PO) or after first passaging in sucking mouse brain (Pl) were used. The brain homogenates were clarified and concentrated using Amicon 10 kDa Ultra centrifugal filters (Merck). The viral titre of cell culture supernatants and clarified brain homogenates were determined by titration assays on BHK-21 cells. All experiments involving viruses were performed in the biosafety level 3 (BSL3) laboratories at AAHL, following protocols approved by AAHL's institutional biosafety committee.

[0344] Primary neuronal culture: Primary cortical neuron cultures were generated from embryonic day 15 (E15) embryos from both wild type and SARMl7-mice, based on previously published protocols (Hilgenberg, L. G. and Smith, M. A., JoVE, 2007(10):e562). Briefly, cortices from E15 embryos were separated under aseptic conditions, chopped into small pieces and digested with 0.125 mg / mL trypsin (Sigma-Aldrich) for 15-20 mins at 37°C. The tissues were then treated with soybean trypsin inhibitor (STI; Sigma-Aldrich) and DNase I (8000 units; ThermoFisher) and homogenised gently to form uniform cell suspensions. Cortical neurons were seeded at 120,000 cells per well on poly-L-ornithine (Sigma-Aldrich) coated glass coverslips (13 mm; Menzel Glaser) in 24 well plates. Primary dorsal root ganglion (DRG) neurons were generated from E13 or E14 embryos. The DRGs were isolated from the embryos and subjected to trypsin digestion and homogenisation as above. Both cortical and DRG neurons were cultured in neurobasal media with B27 supplement, glutamax (ThermoFisher) and gentamicin (Sigma-Aldrich).

[0345] Neuronal culture in microfluidic chamber: Compartmentalized axon chambers: For separating the neuronal cell bodies and axons, cortical and DRG neurons were cultured in xona microfluidic devices (Taylor A. M. et al. Nat. methods, 2005;2(8):599) (XONA Microfluidics, Cat#SND450) mounted on glass coverslips (24 x 40 mm; Menzel Glaser) coated with poly-L-ornithine (Sigma-Aldrich). Approximately 10 pL of cell suspension containing 120,000 cells were added to the cell body panel. The chambers were then incubated at 37°C for 10 min to allow attachment of neurons. Then 200 pL of neuronal culture media was added to the top and bottom wells of cell body panel and 150 pL of media was added to the wells in the axon panel. Approximately halfthe volume of media in each well was replaced with fresh media every two days and the higher volume of media on the cell body panel was maintained.

[0346] Transynaptic microfluidic model: To model synaptically connected ex-vivo neuronal cultures, cortical neurons were extracted as above and seeded on to both the panels of microfluidic device (SND450, XONA microfluidics), each with 10 pL of cell suspension containing 120,000 cells.

[0347] Viral quantification: Viral titres of inocula were determined by direct fluorescent antibody test in BHK cells. Serial 10-fold dilutions of viral suspensions were prepared in cell culture media and were added to 96 well plates (4 replicates each), followed by BHK cell suspensions. The cells were then incubated at 37°C with 5% CO2 for 5-6 days. The plates were fixed with 10% formalin for 30 minutes at room temperature and then stained with FITC conjugated anti-rabies monoclonal antibody (Fujirebio) at 1:10 dilution in 0.5% bovine serum albumin (BSA) / phosphate buffered saline (PBS) with 0.005% Evans blue. Plates were read with an Olympus BX51 inverted microscope and the median tissue culture infectious dose (TCID50) determined (Reed LJ. and Muench H., Am. J. Epidemiol. 1938, 27(3):493-7).

[0348] Viral infection of primary neuron cultures: Primary DRG and cortical neuron cultures were infected after 7-10 days of culture. For infection of neurons cultured in 24 well plates and microfluidic chambers, viral inoculum containing the titre required to infect the neurons at multiplicity of infection (MOI) of 1 (based on the number of neurons originally seeded in each well or panel in microfluidic chamber, i.e. 120,000 cells) were added. For the microfluidic chambers media from the axon panel was removed and viral inoculum was added to the top well of the axon panel and allowed to flow through to the bottom well. Then the appropriate volume of media was added, so the total volume in each well in the axon panel was 150 pL. Then 200 pL of media was added to the cell body panel, so a unidirectional flow of media from the cell body to axon panel was maintained. Similarly, to infect trans-synaptically connected neurons in microfluidic chambers, media from the panel to be inoculated was removed and the viral inoculum added. A unidirectional flow of media from the non-inoculated to inoculated panel was always maintained with higher volume of media in the non-inoculated panel. For mock infection, cell culture supernatant collected from uninfected Neuro-2a cells was added to the wells or chambers.

[0349] Drug treatments: Drug treatments were performed on infected primary cortical neurons cultured on coverslips in 24 well plates. Media from the wells was removed and replaced with fresh media with the appropriate volume of viral inoculum to infect the neurons at MOI of 1. After adding the viral inoculum containing media, appropriate dilutions of NAD (Sigma-Aldrich), egtazic acid (EGTA) (Sigma-Aldrich)or calpain inhibitor III (ABCAM) were added to each well. The stock solution of these compounds was prepared as follows: NAD- 50 mM and 200 mM, dissolved in sterile water; EGTA- 200 mM dissolved in 0.2 M NaOH; Calpain inhibitor III - 20 mM dissolved in dimethylsulfoxide (DMSO). The neurons were fixed at 24 hours post-infection and analysed by immunostaining and confocal imaging.

[0350] Immunocytochemistry: Primary cortical neurons cultured on coverslips were fixed with 4% paraformaldehyde (PFA, Sigma-Aldrich) in 0.05 M PBS for 1 hour at room temperature. The coverslips were washed gently three times with PBS and the cells were permeabilised with 0.1% Triton X-100 (Sigma-Aldrich) in PBS for 5 min and then rinsed with PBS. They were then blocked with 0.5% BSA in PBS for 30 min and incubated overnight at 4°C with primary antibodies diluted in 0.5% BSA in PBS. They were washed three times with PBS and incubated with species-specific fluorescent secondary antibodies (Alexa Fluor, ThermoFisher) diluted at 1:200 in 0.5% BSA in PBS for 1 hour at room temperature. Coverslips were then rinsed twice with PBS, twice with sterile water and then stained with 4',6-diamidino-2-phenylindole (DAPI) for 10 mins, then were washed twice with sterile water and mounted on glass slides (ThermoFisher) with Vectashield mounting medium (Vector Laboratories).

[0351] The following primary antibodies were used at the indicated dilutions: chicken anti-MAP2 (1:1000, ABCAM, cat#ab4674), rabbit anti-rabies nucleoprotein, 1:3000, in-house (Rahmadane I. et al., PLoS Negl. Trop. Dis. 2017, ll(ll):e0006079), mouse pan-axonal neurofilament antibody (SMI-312, 1:1000, BioLegend, cat#837904), Mouse anti-a tubulin (1:1000, Sigma-Aldrich, cat#T6199) and chicken anti-a tubulin (1:1000, ABCAM, cat#ab89984).

[0352] Immunostaining of neurons in microfluidic chambers: Primary cortical and DRG neurons cultured in microfluidic chambers were fixed with 4% paraformaldehyde (PFA) after infection. 200 pL of PFA was added to all four wells in the chamber and allowed to fix for at least an hour. After fixation, immunostaining with primary and secondary antibodies were performed in the microfluidic chamber as above, without disturbing the attachment to glass coverslips. For washing, PBS was added to the top wells first, was allowed to flow through to the bottom wells, was incubated for 10 mins and then repeated three times. Primary and secondary antibodies were appropriately diluted (as above) in 0.5% BSA in PBS and 200 pL was added to each well of the chamber during incubation. After final washes, PBS was added to all the wells in the chamber and stored at 4°C before confocal imaging.

[0353] Confocal and live-cell imaging: Confocal imaging was performed using a ZEISS LSM 800 inverted confocal microscope. To analyse neurite degeneration in MAP2-stained cortical neurons, images were acquired with the 20x objective using tilingfunction, covering an area of 998.28 x 673.84 pM with Z-stacks (20 slices: 19-24 pM), including at least 500 neurons in each image. The images were then stitched and a maximum intensity projection of z-stacks were generated. All the confocal imaging and processing were performed using ZEN 2.5 Blue software (ZEISS).

[0354] For imaging the axon panels of DRG neurons, immunostained microfluidic chambers were placed carefully on the inverted microscope stage. Images of the axon panels were then taken with a 20x objective using tiling function, covering an area of 607.08 x 603.34 pM with Z-stacks (40 slices: 14-18 pM). Similarly, for imaging trans-synaptic neuronal cultures in microfluidic chamber, tile images were taken covering an area of 1.76 mm x 606.77 pM with Z-stacks (40 slices: 34-40 pM).

[0355] Live-cell DIC imaging of rabies infected cortical and DRG neurons were performed using Leica SP5 confocal microscope in BSL3. Neurons were cultured in glass bottom dishes (p-Dish 35 mm high glass bottom, Ibidi), infected with SHBRV lyssavirus at MOI-1 and imaged for 24 hours after infection.

[0356] Image analysis of axonal and dendrite degeneration:Quantification of MAP2-positive dendrites relative to DAPI stained nuclei was performed using stitched tile confocal images, using ImageJ (Schneider C. A. et al., Nat. methods, 2012, 9(7):671. pmid:22930834). Images were binarized, threshold normalized to mock-infected neuron images and the integrated density of MAP2 immunofluorescence was measured. This value was then divided by the total number of DAPI stained nuclei in the same image, counted using particle analyzer plugin with the following parameters: size (inch2)- 0.005-i nfi nity and circularity- 0.00-1.00. " Watershed" function was applied to the DAPI stained images before analysis to avoid counting merged particles.

[0357] The axon degeneration index from tubulin stained confocal images of axons in microfluidic chambers was calculated based on a method described previously (Sasaki Y. et al., J. Neurosci. 2009, 29(17): 5525-35). The tubulin stained axon images were binarized and the total axon area was measured. Then the fragmented axons were quantified using particle analyzer plugin with the following parameters: size (inch2)- 20-15,000 and circularity- 0.00-1.00. Axon degeneration index was then calculated as the ratio of fragmented axon area over total axon area. To quantify axonal degeneration by neurofilament loss in DRG neurons, the integrated density of neurofilament immunofluorescence in DRG axons were quantified from binarized images after normalizing threshold to mock-infected neuron images.

[0358] Statistical significance between two values was determined using a two-tailed t test, analyses of three or more values were performed by one-way ANOVA with Bonferroni's post hoc test using Prism 7 (GraphPad). Data are presented as mean ± standard error of the mean (SEM). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.EXAMPLE 2 - NEUROINVASIVE RABIES STRAIN BLOCKS AXONAL DEGENERATION

[0359] The identification of SARMl-mediated axonal degeneration in rabies infection provided a pathological mechanism causing axonal degeneration in paralytic forms of rabies where there is reduced virus spread. However, this result was inconsistent with furious forms of rabies where there is no evidence of axonal degeneration, or any other neuropathology. To successfully infect a host, rabies virus must initially keep axons healthy, so that it can spread efficiently to the brain and induce behavioural changes, such as aggression, in order to increase the likelihood of transmission to a new host. This cannot be achieved if axonal self-destruction is activated.

[0360] In view of the foregoing, a highly neuroinvasive strain of rabies virus (CVS-11; also referred to herein as "rabies X") was investigated. When neurons were infected with the CVS-11 strain, they did not exhibit axonal self-destruction. Instead, the neurons displayed efficient spread of rabies virus in healthy axons. This suggested that the CVS-11 strain developed an ability to block axonal self-destruction of neurons, thereby enabling the strain to efficiently travel through the nervous system and successfully infect its host.

[0361] To evaluate this theory, two independent in vitro models of axonal selfdestruction, using primary cortical and DRG mouse neurons were investigated (FIGS. 2A-2D). In a first model, cortical neurons were treated with a chemotherapeutic drug, vincristine (VNC). VNC is known to induce axonal self-destruction in neurons. When neurons were treated with vincristine, the neurites degenerated and exhibited severe swelling and a complete loss of dendritic MAP2 protein (FIGS. 2A and 2B). However, neurons infected with the CVS-11 strain of rabies virus displayed significant resistance to VNC-induced degeneration, as evidenced by a significantly higher amount of MAP2-positive neurites in these neurons (FIGS. 2A and 2B).

[0362] In a second model, axonal damage was induced by performing an axotomy of cultured DRG neurons. Degeneration of axons distal to the injury site were observed using live differential interference contrast (DIC) imaging for 24 hours. The axons dissected from uninfected neurons completely disintegrated within about 8 hours. In contrast, the neurons that were previously infected with the CVS-11 strain were able to delay degeneration by up to 24 hours (FIGS. 2C and 2D).

[0363] The findings from each model suggest that the CVS-11 strain of rabies harbors a molecular mechanism that blocks axonal self-destruction in neurons.

[0364] Materials and Methods

[0365] Chemical and injury induced axonal degeneration: To induce axonal degeneration in primary cortical neurons, varying concentrations of vincristine were added. Cortical neurons cultured in 24 well plates were treated with fresh culture media with vincristine (Sigma-Aldrich) dissolved in DMSO (Sigma-Aldrich). One day (i.e., 24 hours) after treatment with vincristine, neurons were fixed, immunostained with MAP2 antibody, and analysed by confocal microscopy. Axonal degeneration was quantified by MAP2 intensity using Image! as described above in Example 1.

[0366] DRG neurons isolated and cultured as described above in Example 1 were used to model axonal degeneration induced by injury. Drop culture of DRG neurons with concentrated cell bodies and distal axons were generated as described in Sasaki, Y. J. Neurosci. 2009, 29(17), 5525-5535. The DRGs were isolated from embryos at gestation day 13-14, as described in Example 1, and seeded on 24 well plates with coverslips coated with laminin and poly-L-ornithine (PLO). 2.5 pL of cell suspension containing approximately 20,000 cells was placed in the centre of a dried well and incubated for 15 minutes. After cell attachment, neurobasal media containing 1 pm 5-fluoro-2'-deoxyuridine (Sigma-Aldrich) and 1 pm uridine (Sigma-Aldrich) was added to each well. After 5 days, 50% of the culture medium was replaced with media lacking 5-fluoro-2'-deoxyuridine and uridine. Axonal injury (axotomy) was performed 14 days after seeding with a micropipette tip. Axons distal from the cell bodies were dissected with the micropipette and the severed axons were imaged to analyse axonal degeneration using live cell and confocal microscopy as described in Example 1.EXAMPLE 3 -RABIES VIRUS-DERIVED PROTEINACEOUS MOLECULE, GP-X, INHIBITS AXONAL DEGENERATION

[0367] Rabies virus is made of five proteins. Among these five proteins, the envelope glycoprotein of rabies virus mediates axonal trafficking and trans-synaptic transmission. Each of the five rabies proteins were expressed individually in primary neurons using a lentivirus expression system. This led to the identification that the rabies glycoprotein is responsible for inhibiting axonal degeneration (FIGS. 3A and 3B).

[0368] Expression of the glycoprotein derived from the highly virulent CVS-11 rabies strain (gp-X;MVPQVLLFVLLLGFSLCFGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGY ISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYP DYHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIWMPENPRP RTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMDGTWVAMQTSDETK WCPPDQLVNLHDFRSDEIEHLVVEELVKKREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIF NKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHPLADPSTVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGL VLIFSLMTWCRRANRPESKQRSFGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 32]) in neurons significantly delayed axonal degeneration in both cortical and DRG neurons when subjected to VNC (100 nM) or axotomy (FIGS. 3A and 3B). Moreover, under these conditions, gp-X-induced axon protection was more efficient than SARM1 gene knockout. Specifically, and with reference to FIG. 3B, wild type neurons expressing gp-X exhibited a lower axonal degeneration index as compared to neurons cultured from SARM1 gene knockout mice subjected to same conditions.

[0369] Materials and Methods

[0370] Lentivirus plasmids: Third generation lentivirus packaging and envelope plasmids, pMD2. G (Addgene ID: 12259) and psPAX2 (Addgene ID: psPAX2), and transfer plasmid pLenti CMV GFP Neo (657-2) (Addgene ID; 17447) were purchased from Addgene. The DNA coding rabies glycoprotein from CVS-11 and Z. DOG strains were synthesised and cloned into the transfer plasmid by a commercial service provider (GenScript Biotech).

[0371] Lentivirus generation and infection: To generate lentivirus, LentiX cells (Takara Bio) were seeded in T75 or T150 flasks at 60% confluency and cultured in Dulbecco's Modified Eagle Medium (DMEM) media (ThermoFisher) with 5% fetal calf serum (FCS). 24 hours after seeding the cells were transfected using Fugene (Promega) transfection reagent at 4 times the concentration of DNA used. PMD2. G, psPAX2, and the transfer plasmid were transfected at a concentration of 0.072, 0.13, and 0.164 pmol / cm2of culture area respectively. 24 hours after transfection, the supernatant in each flask was replaced with fresh media. 48 hours after transfection, the supernatants were collected, centrifuged to remove cell debris, and treated with Lenti-X concentrator (Takara Bio) at 1:3 ratio at 4 °C for a minimum of 12 hours. After incubation, the supernatants were centrifuged at 1500 x g for 45 minutes. The resulting pellets containing concentrated lentiviruses were then resuspended in sterile PBS, aliquoted, and stored at -80 °C. The concentrations of lentivirus stocks were determined using Lenti-X GoStix according to the manufacturer's protocol.

[0372] Primary cortical or DRG neurons were infected with lentiviruses to induce the expression of glycoproteins at days 4-6 post seeding. Lentiviruses infection was performed at MOI: 1-10. An appropriate volume of lentivirus inoculum diluted in 100 pL of neurobasal culture media was added on top of existing culture media in each well of a 24 well plate. 48 hours after infection, the neurons were observed to be expressing glycoproteins and subjected to axonal degeneration assays as described in Example 2.EXAMPLE 4 - GP-X INDUCES SYNAPSE FORMATION

[0373] Gp-X and a corresponding glycoprotein form Z. DOG rabies strain (gp-Y; MVPQALLFVPLLVFSLCFGKFPIYTIPDKLGPWSPIDIHHLSCPNNLVVEDEGCTNLSGFSYMELKVGY ISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPIPDACRAAYNWKMAGDPRYEESLHNPYPD YHWLRTVKTTKESLVIISPSVADLDPYDKSLHSRVFPSGKCSGITVSSTFCSTNHDYTIWMPENPRLG TSCDIFANSRGKRASKGGKTCGFVDERGLYKSLKGACKLKLCGVLGLRLMDGTWVAMQTSDETKW CPPDQLVNMHDFRSDEIEHLVVEELVKKREECLDALESIMTTKSVSFRRLSHLRKLVPGFGKAYTIFN KTLMEADAHYKSVRTWNEIIPSKGCLRVGGRCHPHVNGVFFNGIILGPDGHVLIPEMQSSLLQQHME LLESSVIPLMHPLADPSTVFKDGDEAEDFVEVHLPDVHKQVSGVDLGLPNWGKYVLLSAGTLIALMLI IFLMTCCRRVNRPESTDRSLGGTGRKVSVTSQSGKVISSWESYKSGGETRL [SEQ ID NO: 100]) were expressed in mouse primary cortical neurons. With reference to FIG. 4A, gp-X colocalised with the neuronal membrane and formed numerous dendritic filopodia and spine structures thereon. These dendritic filopodia and spine structures appeared to seek out and form new connections with neighbouring neurons via live-cell confocal imaging (FIG.4B). The gp-X-induced dynamic membrane protrusions varied in length, ranging from 1-2 pm up to 20 pm, and were consistent with dendritic filopodia and spine morphology. In contrast, with reference again to FIG. 4A, gp-Y was localised as short filaments highly concentrated at specific locations on the axonal and dendritic membrane. These observations suggested that gp-X could increase synapse formation between neurons, thereby facilitating efficient trans-synaptic transmission of the rabies virus.

[0374] The number of synapses (synapsin 1 (pre-synaptic) positive puncta) were quantified from high-resolution confocal (airyscan) images. Significantly increased synaptic terminals in neuronal cultures expressing gp-X, as compared to neuronal cultures expressing gp-Y or green fluorescent protein (GFP) tag alone, were observed (FIG. 4D). Many of the gp-X-induced protrusions were also found to be co-localised extensively with pre-synaptic terminals in neighbouring neurons (FIG. 4C, top panel, volumetric rendering). These findings suggest that gp-X increases synapse formation, in addition to blocking axonal degeneration.

[0375] Materials and Methods

[0376] Primary mouse cortical neurons were isolated and cultured as described above in Example 1. Lentivirus carrying GFP tagged gp-X or gp-Y glycoproteins were generated as described above in Example 3 and were used to infect cortical neurons at Day 4-5 post seeding at MOI-1. Glycoprotein expressing neurons were imaged live using 63x objective in Zeiss LSM 800 confocal microscope. For imaging synapses, neurons were fixed, immunostained with anti-synapsin-1 (Synaptic Systems), MAP2 (Abeam), or neurofilament (Abeam) antibodies. Synapsin-1 stained punctate staining was quantified using an Image! particle analyser plugin as described above in Example 1.EXAMPLE 5 - GP-X AND GP-Y MUTANT STUDIES

[0377] Gp-X and gp-Y differ in 19 amino acids distributed throughout the sequence of each proteinaceous molecule. To analyse which of these mutations enabled synapse formation, each of the 19 different amino acids in gp-Y were mutated to match the corresponding residue in gp-X. Lentiviruses were then generated from these 19 different mutant plasmids, and expression of the gp-Y mutants was analysed in mouse cortical neurons (FIGS. 5A and 5B).

[0378] With reference to FIG. 5C, a single serine to proline mutation at residue 207 ([S207P]) in gp-Y changed its localisation profile. Specifically, this mutation enabled gp-Y to form dynamic membrane protrusions involved in synapse formation, similar to gp-X. This effect was not observed with the other mutants. Further analysis revealed that this particular proline is located within a snake venom-like ectodomain of gp-X comprising a 33 amino acid sequence (a proteinaceous molecule referred to herein as the "gp-X peptide"; YTIWMPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 1]).

[0379] Further analysis of this single S207P mutation was performed on the ability of rabies glycoprotein to induce synapse formation. In stem cell-derived human neurons, lentivirus driven expression of gp-X protein was observed to co-localise with both presynaptic (Bassoon) and postsynaptic (Homer) sites on the filopodia structures formed by gp-X (super-resolution, dSTORM imaging, FIGS. 5D and 5E). In addition, the expression of gp-X protein in human neurons increased the number of functional synapses (both bassoon and homer positive sites) and the number of pre- and postsynaptic sites. This was not observed in the neurons expressing gp-Y proteins. The ability to induce synapse formation was restored in gp-Y protein by the introduction of a single S207P mutation (FIGS. 5D and 5E)

[0380] Materials and Methods

[0381] To analyse the functional effects of the mutations in gp-X (compared to gp-Y), each of the 19 single amino acid mutations were introduced in the full-length gp-X glycoprotein lentiviral transfer plasmid using a commercial service provider (GenScript Biotech). The point mutations resulted in the generation of 19 mutant gp-X transfer plasmids, which were used to generate the respective lentiviruses following the protocols described in Example 3 above. Primary cortical neurons were then infected with these lentiviruses and the localisation of the GFP tagged glycoproteins were analysed by confocal microscopy after fixing the cells with 4% PFA as described in Example 1. The human stem cell-derived neurons were generated using protocols described earlier (Sundaramoorthy V. et al., Viruses, 2020, 12, 359). The neurons at over 20 days of differentiation were infected with lentiviruses to express the respective glycoprotein. The neurons were fixed after 48 hours and stained with primary antibodies as described inExample 1. Super-resolution compatible secondary antibodies (Biotium, Fremont, CA, USA) were used and the direct stochastic optical reconstruction microscopy (dSTORM) was preformed using ONI Nanoimager S (ONI, Oxford, UK). The samples were imaged in oxidising mercaptoethylamine (MEA) buffer as described earlier (Gluyshonokv, 0. et al., Scientific Reports, 2018, 8, 8749). The images were quantified using clustering tool in CODI program (ONI, Oxford, UK).EXAMPLE 6 - GP-X INTERACTOME

[0382] To identify the neuronal proteins potentially underlying the observed ability of gp-X to inhibit axonal degeneration and induce synapse formation, the interactome of gp-X and gp-Y was identified via biotin ligase (TurboID)-mediated proximity labelling and conventional GFP tag pull down, followed by mass spectrometry. The neuronal proteins identified are provided in FIG. 6A.

[0383] A comparison of the gp-X and gp-Y interactomes revealed a subset of neuronal proteins that specifically interact with gp-X which could be potentially responsible for inhibiting axonal degeneration and stimulating synapse formation. Both gp-X and gp-Y proteins were found to interact with presynaptic and postsynaptic proteins. However, the gp-X protein showed a significantly higher interaction with synaptic proteins comparted to gp-Y protein (FIG. 6A). In this list of synaptic proteins, Calcium / calmodulin-dependent protein kinase II (CaMKII) was identified as significantly enriched in the gp-X interactome. More specifically, the CaMKIIa and CaMKIip subunits were significantly enriched in both the TurboID and GFP tag analyses of the gp-X interactome. The physical interaction of CaMKII with gp-X was subsequently confirmed through TurboID pull down and western blotting (FIG. 6B).

[0384] CaMKII is a kinase enzyme that controls several downstream signalling pathways, including axon growth, synapse formation, and synaptic plasticity. Typical CaMKII activation is mediated by an increase in calcium ion concentration. This increase in calcium ion concentration is sensed by calmodulin, which then binds and activates CaMKII. Activated CaMKII exerts kinase activity and phosphorylates a number of key proteins activating signalling pathways controlling axon growth and synaptic plasticity (Yasuda, R. et al., Nat. Rev. Neurosci. 2022, 23, 666-682). However, the role of CaMKII in axonal degeneration is presently unclear. While activation of CaMKII can protect against axonal degeneration (Guo, X. et al., Cell 2021, 184(16), P4299-4314. E12), in other conditions, CaMKII can accelerate axonal degeneration (Oka, M. et al., J. Biochem.2017, 162(5), 335-342). This suggests that CaMKII plays a complex role in axonal degeneration. A recent unbiased genetic screen identified that CaMKII activation suppressed a chronic mode of axonal degeneration in a worm. Activation of CaMKII homologue (UNC-43) protected axons via a signalling pathway involving transportinhibitor response 1 (TIR-1; a homologue of SARM1) (Ding, C. et al., eLife 2022, 11, e73557). This uncovered a surprising axon protective role of SARM1 that is regulated by CaMKII. Furthermore, CaMKII directly interacts with SARM1 in worms, controlling SARM1 function in synaptic signalling (Chuang, C-F and Bargmann, C. I., Genes & Dev.2005, 19, 270-281). These previous findings, along with the identification herein that CaMKII interacts with gp-X, suggest that CaMKII may regulate axonal degeneration in mammals by acting upstream of SARM1. Accordingly, and without wishing to be bound by theory, it appears that the ability of gp-X to inhibit axonal degeneration and increase synapse formation may be mediated by its interaction with CaMKII.

[0385] Materials and Methods

[0386] For interactome analysis, neurons expressing either GFP tagged glycoproteins or biotin ligase (TURBOID) tagged glycoproteins were lysed and collected in Radio-Immunoprecipitation Assay (RIPA) buffer (Sigma-Aldrich) with EDTA-free protease inhibitor (Roche). For TURBOID samples, a biotinylation reaction was performed prior to lysate collection, as per the protocol described in Cho, K. F. et al., Nat. Protoc. 2020, 15, 3971-3999. The lysates were then subjected to pull down using GFP trap agarose beads (ChromoTek) or streptavidin magnetic beads (ThermoFisher) per each manufacturer's protocol. The pull-down containing glycoprotein and its interacting proteins were heat inactivated at 56 °C for 1 hour and run on 4-12% SDS PAGE gels (BioRad). The bands in the gel were then excised with the corresponding bands in control samples (GFP alone or untreated). The bands were then dehydrated in 70% ethanol and analysed via mass spectrometry.

[0387] Excised protein bands were de-stained in 100 mM ammonium bicarbonate (Sigma-Aldrich) for 10 minutes and then for 10 minutes with a solution containing a 1:1 ratio of 50 mM ammonium bicarbonate and acetonitrile. These steps were repeated 2-3 times until the coomassie stain disappeared. The bands were then resuspended in 100% acetonitrile by shaking at 37°C for 30 minutes. The proteins were reduced with 200 pL 50 mM dithiothreitol (DTT) for 30 minutes at room temperature and washed again with 200 pL volumes of UA buffer (8 M urea, 0.1 M Tris HCI (pH-8.5), 50 mM dithiothreitol (Sigma-Aldrich)) with centrifugation. To alkylate the cysteine residues, iodoacetamide (50 mM, 100 uL (Sigma-Aldrich)) was applied to the proteins with incubation for 20 minutes at room temperature in the dark. The filter was washed with 200 pL of UA buffer with centrifugation (20,800 x g, 15 minutes). The buffer was exchanged using 50 mM ammonium bicarbonate (pH 8.0) via two consecutive wash / centrifugation steps.

[0388] Sequencing grade porcine trypsin (Promega) was added (0.02 pg / pL, i.e. 4 pg in 200 pL of 50 mM ammonium bicarbonate, 1 mM calcium chloride (Sigma-Aldrich)) to the proteins, followed by incubation for 16 hours at 37 °C in a thermomixer. The digested peptides were then collected following centrifugation (20,800 x g, 10 minutes). The resultant peptides were re-suspended in 200 pL of 0.1% formic acid (FA) and 2 pL (equivalent to ~2 pg of total protein) was analysed by liquid chromatography tandem mass spectrometry (LC-MS / MS).

[0389] Proteolytically digested proteins were analysed with chromatographic separation (4 pL) on an Ekspert nanoLC415 (Eksigent Technologies) directly coupled to the OptiFlow ion source of a TripleTOF 6600 LC-MS / MS (SCIEX). The peptides were desalted for 3 minutes on a Trajan ProteCol C18 (3 pm, 120 A, 10 mm x 0.3 mm) trap column at a flow rate of 10 pL / minute 0.1% FA, and separated on a ChromXP C18 (3 pm, 120 A, 150 mm x 0.3 mm) column at a flow rate of 5 pL / minute at 30 °C. A linear gradient from 3-25% solvent B over 68 min was employed followed by: 5 minutes from 25% B to 35% B; 2 minutes 35% B to 80% B; 3 minutes at 80% B, 80-3% B, 1 minute; and 8 minutes re-equilibration. The solvents were: (A) 5% DMSO, 0.1% FA, 94.9% water; and (B) 5% DMSO, 0.1% FA, 90% acetonitrile, 4.9% water. The instrument parameters were: ion spray voltage 4500 V, curtain gas 30 psi, GS1 30 psi and GS2 30 psi, heated interface 150°C. Data were acquired in information-dependent acquisition (IDA) mode comprising a time-of- flight mass spectrometry (TOF-MS) survey scan followed by 30 tandem mass spectrometry (MS / MS) product ion scans. First stage mass spectrometry analysis was performed in positive ion mode, mass range m / z 400-1250 and 0.25 s accumulation time. Tandem mass spectra were acquired on precursor ions >150 counts / s with charge state 2-5 and dynamic exclusion for 15 s with a 100 ppm mass tolerance.EXAMPLE 7 - PHOSPHOPROTEOME ANALYSIS OF SIGNALLING PATHWAYS INFLUENCED BY RABIES GLYCOPROTEINS

[0390] Since, the gp-X protein showed a stronger interaction with CaMKII compared to gp-Y, whether the gp-X / CaMKII interaction could influence kinase signalling pathways leading to inhibition of axonal degeneration and induction of synapse formation was investigated. A phoshoproteome analysis of neuronal lysates expressing the gp-X, gp-Y proteins as well as the gp-Y [S207P] mutant protein was performed. This analysis revealed a change in multiple kinase signalling pathways involved in synapse formation as well as axonal degeneration / regeneration (FIG. 7). CaMKII kinase signalling was also found to be significantly upregulated in neurons expressing gp-X or the mutant gp-Y S207P protein but not the gp-Y protein (FIG. 7). This finding taken together with the interactome analysis (FIG. 6) implied that the interaction of gp-X with CaMKII significantly increased its kinase activity causing the phosphorylation / activation of multiple signalling proteins leading to inhibition of axonal degeneration and induction of synapse formation. More importantly, the phosphoproteome comparison with gp-Y[S207P] mutant expression also showed that the ability of gp-X to interact and influence CaMKII signalling is reliant on the S207P mutation in the short peptide region within the rabies glycoprotein ectodomain (FIG. 7).

[0391] Materials and Methods

[0392] The phosphoproteome analysis of mouse cortical neurons lysates expressing rabies glycoproteins and the data analysis was performed by Biogenity (Denmark) following their suggested protocols and methods. Neuronal lysates from 4 biological repeats were analysed for each sample. The lysates were prepared in lysis buffer (consisting of 6M guanidinium hydrochloride, 10 mM tris(2-carboxyethyl) phosphine, 40 mM chloroacetamide, 50 mM (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid) (HEPES) pH 8.5). The samples were then heated at 60°C for 1 hour and the protein concentration was determined using a Pierce BCA kit (Thermo Fisher Scientific). Phospho enrichment and peptide detection by mass spectrometry was performed according to manufacturer's protocol (Biogenity). Briefly, peptides were eluted and analyzed on an Exploris 480 instrument (Thermo Fisher Scientific) running in a data-dependent tandem mass spectrometry top-speed mode (3 s cycle time). Full mass spectrometry spectra were collected at a resolution of 60,000, with a normalized automatic gain control target of 300% and automatic maximum injection time, using a scan range of 375-1,500 m / z. The tandem mass spectrometry spectra were obtained at a resolution of 30,000 with the 'turboTMT' functionality enabled, with a normalized automatic gain control target of 100%. Prior to statistical analysis, the data was filtered so that only the phosphorylated peptides that were found in at least 75% of the samples or found in 60% in at least one sample group were included in the analysis. Each expression was tested for normal distribution by Shapiro-Wilk test. If a p-value > 0.05 was obtained (i.e. the expression is exhibiting a normal distribution), the groups were compared using a parametric test such as limma (Ritchie M. E. et al., Nucleic Acids Research, 2015, 43(7), e47) which is a moderated Analysis of Variance (ANOVA) test, followed by a Benjamini Hochberg p-value correction.EXAMPLE 8 - ACTIVATION OF CaMKII WITH GP-X

[0393] To assess whether the interaction of gp-X with CaMKII influenced CaMKII activation to control axonal degeneration and induce synapse formation, a phosphorylated CaMKII antibody that detects kinase-active CaMKII was used. First, a significant increase in phosphorylated CaMKII was observed in neurons expressing gp-X (FIGS. 8A and 8B). Additionally, CaMKII activation in neurons expressing gp-X was unaffected when treated with KN93, a drug that prevents activation of CaMKII via its classical pathway (FIGS. 8A and 8B). Further, gp-Y, having a serine residue at position 207 of its ectodomain as compared to the proline residue of gp-X, was unable to activateCaMKII. This observation potentially explains the inability of gp-Y to induce synapse formation or inhibit axonal degeneration.

[0394] A gp-X mutant, having a serine residue in place of the proline at position 207 of its ectodomain (gp-X P to S mutant), was subsequently tested (FIG. 8C). The gp-X mutant lacked the ability to protect axons against VNC-induced axonal degeneration. Taken together, these observations suggest that a non-classical form of CaMKII activation is mediated by gp-X generally, and the gp-X peptide specifically, to inhibit axonal degeneration and induce synapse formation.

[0395] Materials and Methods

[0396] To inhibit CaMKII activation / phosphorylation, primary cortical neurons expressing gp-X or gp-Y glycoproteins were treated with KN-93 (1 pM (Sigma-Aldrich), 30 minutes). After treatment, neurons were lysed and collected with RIPA buffer (Sigma-Aldrich) and subjected to western blotting with Phospho-CaMKII (Thr286) (D21E4) (Cell Signalling Technology).

[0397] To analyse the effect of the proline residue in the gp-X glycoprotein, the residue was mutated to serine in the lentiviral transfer plasmid by mutagenesis using a commercial service provider (GenScript Biotech). The corresponding lentivirus was generated from this plasmid as described in Example 3 and used to infect primary cortical neurons. Axonal degeneration assays using vincristine treatment were then performed on the neurons using confocal microscopy as described in Examples 1 and 2.EXAMPLE 9 - MODELLING BINDING INTERACTIONS OF GP-X, GP-Y, AND CAMKII

[0398] With reference to FIGS. 9A and 9B, AlphaFold2 was used to model potential interactions between gp-X and CaMKII. The modelling suggests that gp-X can bind to the kinase domain of CaMKII at a site known to be important for its activation (FIGS. 9A and 9B). Moreover, the proline at position 207 of gp-X (and within the gp-X peptide) was identified as the key binding determinant. As set forth above, in gp-Y, the proline at position 207 is replaced with a serine. Without wishing to be bound by theory, the modelling provides further support, along with other Examples provided herein, that gp-X, and the gp-X peptide, activate CaMKII to inhibit axonal degeneration and induce synapse formation.

[0399] Materials and Methods

[0400] To support the cell-based data, predictions of the interaction of rabies virus glycoproteins and CaMKII subunits were generated using Alphafold2 (Jumper, J. et al., Nature 2021, 596, 583-589). The sequences of human CaMKIIa (7-262) and CaMKIIb (8-261) kinase domains were modelled in complex with rabies virus glycoprotein peptides: gp-X (Asnl91-Asn221) (NHDYTIWMPENPRPRTPCDIFTNSRGKRASN[SEQ ID NO: 16]) and gp-Y (Asnl91-Lys221) (NHDYTIWMPENPRLGTSCDIFANSRGKRASK [SEQ ID NO: 101]). The top ranked prediction of CAMKIIa and gp-X (Asnl91-Asn221) generated a complex where the peptide was positioned within the activation site.Analysis of the model using PDBSUM (Laskowski, R. A. et al. Protein Sci. 2018, 27, 129-134) described six hydrogen bonds at the interface. Interestingly, the key residue from experimental cell data and mutagenesis, Pro207, was nestled in a hydrophobic pocket of CAMKIIa, mediated by the residues Phe98 and Tyrl79, with an additional non-bonded contact between Pro207 N and Glul39 OE2 atoms. In comparison to the predicted model for gp-X (Asnl91-Asn221), Alphafold2 was unable to generate a complex of CAMKIIa kinase domain and gp-Y (Asnl91-Lys221), having Ser207. A serine at this position generated a misfolded peptide model with major clashes that could not bind to the kinase domain active site.EXAMPLE 10 - INVESTIGATION OF NEURONAL UPTAKE OF GP-X DERIVED PEPTIDES

[0401] Multiple lines of investigation presented in Examples 1-9 suggested that a short ectodomain region (33 amino acids) within gp-X could be effective in delaying axonal degeneration and inducing synapse formation in neurons. To test this experimentally, synthetic peptides of different lengths (Table 2) were obtained using commercial suppliers. These peptides encompassed the functional serine to proline mutation which was essential for axonal protection and synapse formation. Additionally, the peptides were tagged with a fluorescent FITC molecule at the C-terminus to enable visualisation of peptide localisation using confocal microscopy. In the initial study, the original 33 amino acid long peptide (gp-X-33-FITC) did not appear to be completely taken up by neurons. FIG. 10 shows lack of internal axonal localisation of gp-X-33-FITC in mouse neuronal axons. Hence, a version of the peptide with a cell penetration tag (9R) added at the C-terminus was generated (gp-X-33-9R-FITC, Table 2). This tagging with an additional cell penetration tag enabled the peptide to be taken by neurons as shown in FIG. 10. Shorter versions of the peptide (24 and 20 amino acids long, Table 2) were also generated for functional analysis.TABLE 2PEPTIDE SEQUENCESPeptide Sequence Length SEQ name ID NO: gp-X-33- YTIWMPENPRPRTPCDIFTNSRGKRASNGNKTCGGGRRRRRRRRR 33 amino 102 9R-FITC acids (with {Lys(FITC)} cellpenetration tag (9R) underlined)gp-X-33- YTIWMPENPRPRTPCDIFTNSRGKRASNGNKTC{Lys(FITC)} 33 amino 103 FITC acidsgp-X-24- YTIWMPENPRPRTPCDIFTNSRGK{Lys(FITC)} 24 amino 104 FITC acidsgp-X-20- YTIWMPENPRPRTPCDIFTN{Lys(FITC)} 20 amino 105 FITC acids

[0402] Materials and Methods

[0403] Synthetic peptides comprising the selected ectodomain sequence of gp-X protein were generated by commercial suppliers using solid phase peptide synthesis (GenScript and Auspep). The peptides were dissolved in sterile water and used at 100 nM final concentration in cell culture media for uptake experiments. The primary mouse neurons were cultured in accordance with the method of Example 1.EXAMPLE 11 - RABIES X GLYCOPROTEIN DERIVED PEPTIDES DELAY AXONAL DEGENERATION IN NEURONS

[0404] It was then investigated whether gp-X derived peptides could delay axonal degeneration in mouse primary cortical neurons. A high-throughput axonal degeneration assay in 96 well plates was developed, where axonal degeneration is induced by treatment with microtubule damaging agent vincristine. Three hours after vincristine treatment when visible initial damage to axons is observed (axonal blebbing), the peptides were added at different concentration to investigate whether the peptides could rescue the degeneration of vincristine damaged axons (FIG. 11A). In this analysis, interestingly, the gp-X derived peptides without the cell penetration tag (gp-X-20, gp-X-24 and gp-X-33; Table 2) were most effective in blocking axonal degeneration (FIGS. 11B and 11C). The gp-X-33-9R peptide with the cell penetration tag (Table 2) was least effective in blocking axonal degeneration (FIG. 11C). Across the different concentration the shorter length peptides (gp-X-24 and gp-X-20) were more protective than the longer length gp-X-33 peptide (FIG. 11C). These results implied that the functional region within the gp-X peptide responsible for the axonal protection is shorter than previously predicted. Additionally, the gp-X peptide is not required to be completely taken up by neurons to be able to delay axonal degeneration, suggesting that the peptide may be functioning from the membrane or from the extracellular space.

[0405] Materials and Methods

[0406] Mouse primary cortical neurons were harvested from gestation day 15 mouse embryos in accordance with the method of Example 1. Drop cultures were generated in 96 well plates (optical bottom) coated with poly-D-lysine (0.1 mg / mL; Sigma) and laminin (3 pg / mL). Before seeding, the wells were washed and dried for 10 minutes. The neurons were seeded at 10,000 cells / pL, with 1 pL drop placed in thecentre of the well. After 10 minutes incubation of the cell drops at 37°C, neurobasal media (Thermo Fisher) was added and cultured for 10 days. After 10 days, the neurons were treated with 10 nM vincristine (dissolved in neurobasal medium) for 3 hours. Then neurobasal media containing respective concentration of gp-X peptides were added to the wells. The neurons were then fixed after 24 hours for confocal imaging of axons stained with TUJ1 antibody (Abeam, Catalogue No: ab78078). Axonal degeneration was analysed from confocal images using ImageJ particle analyzer plugin with automated scripts from 10 images from 10 wells for each sample. The experiment was then repeated with at least 3 biological repeats. Statistical analysis was performed using GraphPad software in accordance with the method of Example 1. Synthetic peptides were generated by commercial suppliers using solid phase peptide synthesis (GenScript and Auspep).EXAMPLE 12 - RABIES X GLYCOPROTEIN DERIVED PEPTIDES INTERACT WITH CAMKII IN NEURONS

[0407] Since the shorter gp-X peptides (20 and 24 amino acids long) were significantly effective in protecting axons without cell penetration, the possible mechanism behind the peptide efficacy was then investigated by confocal imaging. Mouse cortical neurons treated with 250 nM of gp-X-20 peptide were imaged and stained with TUJ1 (axonal marker) and CaMKII. In this analysis, it was observed that most of the peptide was distributed on the axonal membrane and this induced clustering of CaMKII close to the membrane where the peptide is localised (FIG. 12A). CaMKII clusters and the gp-X-20 peptide appeared to be interacting at the axonal membrane (FIG. 12A). This implied that the peptide could interact and influence CaMKII signalling from the axonal membrane without entering the cell explaining the protective effect observed in Example 11. This peptide / CaMKII interaction was confirmed by using a biotin tagged version of gp-X peptides which can be co-precipitated with the interacting neuronal proteins using streptavidin beads (FIG. 12B). In this experiment, we included a gp-X peptide that was reduced to 10 amino acids encompassing the functional S207P mutation and the previous GP-X-20 peptide (Table 3). Lysates were collected from primary cortical neurons treated with 250 nM of gp-X-10-biotin and gp-X-20-biotin peptides for 24 hours were subjected to pull down using streptavidin magnetic beads (FIG. 12B). The co-precipitated proteins were then analysed by western blotting and probed with a CaMKII antibody. The blot showed a CaMKII band in both gp-X-10 and gp-X-20 treated lysates confirming the interaction of CaMKII with both peptides (FIG. 12C). This result also showed that the 10 amino acid-long gp-X peptide (gp-X-10) is sufficient to interact with CaMKII in neurons.TABLE 3PEPTIDE SEQUENCESPeptide name Sequence SEQ ID NO: gp-X-20-biotin YTIWMPENPRPRTPCDIFTN{EDA-Biotin} 106gp-X-10-biotin MPENPRPRTP{EDA-Biotin} 107

[0408] Materials and Methods

[0409] Synthetic peptides were generated by commercial suppliers using solid phase peptide synthesis (GenScript and Auspep).

[0410] Primary cortical neurons were treated with 250 nM of gp-X-20 peptide tagged with FITC for 24 hours before fixing and confocal imaging using ZEISS LSM800 microscope with the airyscan high resolution module. Lysates were collected from cortical neurons treated with gp-X-10 or gp-X-20 peptides (Table 3) in radioimmunoprecipitation assay (RIPA) buffer (Sigma) with EDTA free protease inhibitor (Roche). The lysates were then subjected to pull down using streptavidin magnetic beads (Thermo Fisher) as per the manufacturer's protocol. The co-precipitated proteins were then run on a 4-12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels (BioRad) and transferred to western blot (BioRad), probed with anti-CaMKII antibody (1:1000, 6G9, Cell signalling technology).EXAMPLE 13 - RABIES X GLYCOPROTEIN DERIVED 10 AMINO ACID PEPTIDE BLOCKS AXONAL DEGENERATION INDUCED BY VINCRISTINE IN MOUSE NEURONS

[0411] Example 12 showed that the 10 amino acid-long gp-X peptide (gp-X-10) interacts with CaMKII similar to the 20 amino acid-long (gp-X-20) peptide. This indicated that the shorter gp-X-10 peptide could also be effective in protecting axons. Hence, gp-X-10 efficacy was tested against axonal degeneration induced by vincristine treatment (FIG. 13A). The gp-X-10 peptide (Table 3) was added 3 hours after vincristine treatment and the neurons were analysed 24 hours after vincristine treatment (FIG. 13A). In this analysis, the gp-X-10 peptide was observed to be significantly effective in reducing axonal degeneration at all concentrations tested (FIGS. 13B and 13C) with no toxicity observed at higher concentrations (2.5 pM).

[0412] Materials and Methods

[0413] Synthetic peptides were generated by commercial suppliers using solid phase peptide synthesis (GenScript and Auspep).

[0414] The mouse cortical neuron drop cultures and the axonal degeneration assay was performed in accordance with the method of Example 11EXAMPLE 14 - RABIES X GLYCOPROTEIN DERIVED 10 AMINO ACID PEPTIDE BLOCKS AXONAL DEGENERATION INDUCED BY ROTENONE IN MOUSE NEURONS

[0415] The efficacy of the gp-X-10 peptide (Table 3) in an alternate mode of axonal degeneration induced by toxic rotenone treatment was investigated. Rotenone causes axonal degeneration by causing mitochondrial injury and a treatment of 3 hours with 25 pM rotenone is shown to generate damaged axons which will degenerate completely without therapeutic intervention (Hughes R. O. et al., Cell Reports, 2021, 34(1), 108588). This model was used to test whether the gp-X-10 peptide could rescue the rotenone damaged axons of mouse cortical neurons (FIG. 14A). The gp-X-10 peptide was observed to be significantly effective in rescuing rotenone induced axonal degeneration at different concentrations (FIGS. 14B and 14C).

[0416] Materials and Methods

[0417] Synthetic peptides were generated by commercial suppliers using solid phase peptide synthesis (GenScript and Auspep).

[0418] The mouse cortical neuron drop cultures and the axonal degeneration assay was performed in accordance with the method of Example 11. The rotenone treatment was done as previously described (Hughes R. O. et al., Cell Reports, 2021, 34(1), 108588) for 3 hours before treatment with gp-X-10 (Table 3) and the neurons were fixed 16 hours after rotenone treatment.EXAMPLE 15 - RABIES X GLYCOPROTEIN DERIVED 10 AMINO ACID PEPTIDE BLOCKS AXONAL DEGENERATION INDUCED BY VINCRISTINE IN HUMAN MOTOR NEURONS

[0419] Whether gp-X-10 (Table 3) could inhibit axonal degeneration in human neurons and in different type of neurons in addition to forebrain derived cortical neurons was investigated. For this analysis, stem cell-derived human motor neurons previously used in axonal degeneration assays were utilised (Hughes R. O. et al., Cell Reports, 2021, 34(1), 108588). Drop cultures of human motor neurons in 96 well plates were generated and axonal degeneration was induced by treatment with vincristine (40 nM) for 3 hours (FIG. 15A). The efficacy of gp-X-10 peptide (Table 3) was compared with a SARM1 inhibitor drug shown to be effective in inhibiting SARM1 mediated axonal degeneration (Miyamoto T. et al., Journal of Biological Chemistry, 2024, 300(2), 105630). In this analysis, similar to mouse cortical neurons, the gp-X-10 peptide was significantly effective in inhibiting axonal degeneration in human motor neurons (FIGS. 15B and 15C). The gp-X-10 peptide showed similar levels of axonal protection at 125-500 nM concentrations to the SARM1 inhibitor drug used at 10 pM (FIGS. 15B and 15C).

[0420] Materials and Methods

[0421] Synthetic peptides were generated by commercial suppliers using solid phase peptide synthesis (GenScript and Auspep).

[0422] Human iPSC derived motor neurons (catalogue no. C1048) were obtained from Fujifilm Cellular Dynamics. These motor neurons were differentiated following the manufacturer's protocol for 14 days. The drop cultures of motor neurons were generated as described previously (Hughes R. O. et al., Cell Reports, 2021, 34(1), 108588). The differentiated motor neurons on day 14 were treated with 40 nM of vincristine for 3 hours after which the gp-X-10 peptide was added. The SARM1 inhibitor (3-iodo-1H-pyrrolo[2,3-c]pyridine, Sigma) was added at 10 pM final concentration. The motor neurons were fixed 24 hours after vincristine treatment. 10 images of distal axons stained with TUJ1 antibody were taken from 10 wells of each sample and axonal degeneration was measured using ImageJ particle analyser plugin.EXAMPLE 16 - RABIES X GLYCOPROTEIN DERIVED 10 AMINO ACID PEPTIDE BLOCKS AXONAL DEGENERATION INDUCED BY ROTENONE IN HUMAN MOTOR NEURONS.

[0423] Whether gp-X-10 (Table 3) could also inhibit axonal degeneration in human motor neurons induced by rotenone treatment similar to vincristine was analysed. Axonal degeneration was induced in motor neurons by treatment with rotenone (25 pM) for 3 hours and then the neurons were treated with gp-X-10 peptide or SARM1 inhibitor (FIG. 16A). Consistent with previous findings, the gp-X-10 peptide was significantly effective in inhibiting axonal degeneration induced by rotenone in human motor neurons (FIGS. 16B and 16C). The gp-X-10 peptide again showed similar levels of axonal protection at lower concentrations (125-500 nM) when compared to the SARM1 inhibitor drug (10 pM) (FIG. 16C).

[0424] Materials and Methods

[0425] Synthetic peptides were generated by commercial suppliers using solid phase peptide synthesis (GenScript and Auspep).

[0426] Human iPSC derived motor neurons (Catalogue No. C1048) were obtained from Fujifilm Cellular Dynamics. These motor neurons were differentiated following the manufacturer's protocol for 14 days. The drop cultures of motor neurons were generated as described previously (Hughes R. O. et al., Cell Reports, 2021, 34(1), 108588). The differentiated motor neurons were treated with 25 pM of rotenone for 3 hours after which the gp-X-10 (Table 3) was added. The SARM1 inhibitor (3-iodo-1H-pyrrolo[2,3-c]pyridine, Sigma) was added at 10 pM final concentration. The motor neurons were fixed 16 hours after rotenone treatment and the axonal degeneration was measured as described in Example 15.EXAMPLE 17 - RABIES X GLYCOPROTEIN DERIVED 10 AMINO ACID PEPTIDE REDUCES PROGRESSION OF CLINICAL SIGNS SEVERITY IN A MOUSE MODEL FOR FTD / MND.

[0427] The efficacy of the rabies glycoprotein derived 10 amino acid peptide gp-X-10 (MPENPRPRTP; SEQ ID NO: 2) was evaluated in a mice model of motor neuron disease (MND) and frontotemporal dementia (FTD). The hTDP-43-ANLS mouse model is a transgenic mouse that expresses a mutant form of human TDP-43 protein lacking the nuclear localization signal (ANLS) (Walker et al., Acta Neuropathologica, 2015, 130(5), 643-660). In this system, administration of doxycycline (DOX) suppresses transgene expression and removal of DOX induces cytoplasmic accumulation of hTDP-43-ANLS, resulting in progressive neurodegeneration that recapitulates key pathological features of MND and FTD.

[0428] Gp-X-10 was delivered directly to the brain by intracerebroventricular (i.c.v.) infusion in two doses: Low dose: 1 pg / day and High dose: 10 pg / day. While the surgical procedures caused meningitis in all groups including vehicle control, excluding the mice with meningitis revealed a clear therapeutic effect. Gp-X-10 treatment led to a significant reduction in the severity and progression of clinical signs, including tremor (FIG. 17A), hindlimb clasping (FIG. 17B) and impaired grill agility (FIG. 17C). Treatment with gp-X-10 also resulted in decreased levels of neurofilament light chain (NfL), a biomarker of axonal degeneration, in cerebrospinal fluid (CSF) at both high and low doses (FIG. 18A), and in plasma at the low dose (FIG. 18B).

[0429] Western blot analysis of mouse brain lysates demonstrated increased neurofilament levels and decreased synapsin (a synaptic protein) in gp-X-10-treated animals (FIGS. 19A and 19B). Furthermore, gp-X-10 administration was associated with increased phosphorylation of GSK3P, a substrate of CaMKII kinase activity involved in synaptic and axonal protection, indicating potential activation of CaMKII by the peptide (FIGS. 19A and 19B). These findings are consistent with the proposed mechanism of action observed in cultured neurons.

[0430] Materials and Methods

[0431] Synthetic peptides were generated by commercial suppliers using solid phase peptide synthesis (GenScript and Auspep).

[0432] Transgenic rNLS8 mice (mixed male and female) were generated by breeding B6; C3-Tg(tetOTARDBP*)4Vle / J mice expressing mutant hTDP-43-ANLS with B6; C3Tg(NEFH-tTA)8Vle / J mice. Genotype was confirmed by PCR analysis of ear punch DNA prior to randomization. Mice were maintained on a high-dose doxycycline (DOX) diet (200 mg / kg chow) for 10-12 weeks, then switched to standard chow to induce disease.

[0433] Animals were randomly assigned to three groups (n = 16 per group): vehicle control, low dose test article (gp-X-10 peptide in PBS, 1 pg / day), or high dose test article (gp-X-10 peptide in PBS, 10 pg / day). All mice received continuous intracerebroventricular (i.c.v.) infusion via ALZET osmotic pump and cannula, starting at disease induction and continuing for 26 days. Pumps were replaced once at Day 13.

[0434] Clinical assessments (body weight, motor function, tremor, hindlimb clasping / paralysis, grill agility and wellbeing) were performed three times weekly. Grip strength was measured at baseline and study endpoint. Histological analysis of brain sections revealed meningitis potentially due to bacterial infection introduced by surgical procedures in all three groups. Hence, data analysis and presentation was restricted to mice without any histological signs of meningitis (control n = 7, low dose n = 9 and high dose n = 7). Data are represented as the mean ± SEM; ****P<0.0001, ***P<0.001, **P<0.01, **P<0.05.

[0435] At study endpoint, mice were euthanized, and plasma, cerebrospinal fluid (CSF), brain, and spinal cord tissues were collected for biochemical and histological analysis. Lysates for western blot analysis were generated from frozen brains by lysing in 5x v / w radioimmunoprecipitation assay (RIPA) buffer (50 mM Tris, 150 mM NaCI, 1 % NP-40, 5 mM EDTA, 0.5 % sodium deoxycholate, and 0.1 % sodium dodecyl-sulfate (SDS), pH 8.0) containing protease and phosphatase inhibitor cocktails (Sigma). Samples were centrifuged at 4 °C, 100,000g for 30 min and the supernatant taken as the RIPA-soluble fraction which is used for western blotting.

[0436] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

[0437] The citation of any reference herein should not be construed as an admission that such reference is available as " Prior Art" to the instant application.

[0438] Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims.EMBODIMENTS

[0439] Exemplary embodiments include, but are not limited to:1. A proteinaceous molecule comprising, consisting, or consisting essentially of an amino acid sequence represented by Formula (I):Z1X1X2X3X4MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2(I)wherein:X1is absent or is any amino acid residue, preferably an aromatic amino acid residue such as Y;X2 is absent or is any amino acid residue, preferably a small amino acid residue such as T; X3 is absent or is any amino acid residue, preferably a hydrophobic amino acid residue such as I;X4 is absent or is any amino acid residue, preferably an aromatic amino acid residue such as W;X5 is any amino acid residue, preferably a small amino acid residue such as P, or a hydrophobic amino acid residue, preferably an aliphatic amino acid residue such as V; X6is any amino acid residue, preferably a basic amino acid residue such as R, or a small amino acid residue such as G;X7 is any amino acid residue, preferably a hydrophobic amino acid residue, more preferably an aliphatic amino acid residue such as L, or a small amino acid residue such as P;X8is any amino acid residue, preferably a small amino acid residue such as G, or a basic amino acid residue such as R;X9 is any amino acid residue, preferably a small amino acid residue such as T, or a hydrophobic amino acid residue, preferably an aliphatic amino acid residue such as M; X10 is absent or is any amino acid residue, such as C;X11is absent or is any amino acid residue, preferably an acidic amino acid residue such as D;X12 is absent or is any amino acid residue, preferably a hydrophobic amino acid residue such as I;X13 is absent or is any amino acid residue, preferably a hydrophobic amino acid residue including an aromatic amino acid residue such as F, or an aliphatic amino acid residue such as L;X14 is absent or is any amino acid residue, preferably a small amino acid residue such as T, or a hydrophobic amino acid residue, preferably an aliphatic amino acid residue such as V;X15 is absent or is any amino acid residue, preferably a neutral / polar amino acid residue such as N;X16is absent or is any amino acid residue, preferably a small amino acid residue such as S;X17 is absent or is any amino acid residue, preferably a basic amino acid residue such as R;X18is absent or is any amino acid residue, preferably a small amino acid residue such as G;X19 is absent or is any amino acid residue, preferably a basic amino acid residue such as K;X20 is absent or is any amino acid residue, preferably a basic amino acid residue such as R;X21 is absent or is any amino acid residue, preferably a small amino acid residue such as A, or an acidic amino acid residue such as E;X22 is absent or is any amino acid residue, preferably a small amino acid residue such as S or P;X23 is absent or is any amino acid residue, preferably a basic amino acid residue such as K, or a neutral / polar amino acid residue such as N;X24 is absent or is any amino acid residue, preferably a small amino acid residue such as G, or a basic amino acid residue such as R;X25 is absent or is any amino acid residue, preferably a small amino acid residue such as S, G or T, or a neutral / polar amino acid residue such as N;X26 is absent or is any amino acid residue, preferably a basic amino acid residue such as K;X27 is absent or is any amino acid residue, preferably a small amino acid residue such as T or A;X28 is absent or is any amino acid residue, preferably C;Zi and Z2 are independently absent or independently selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.2. The proteinaceous molecule of embodiment 1, wherein at least one of:Xi is Y;X2is T;X3 is I; andX4is W.3. The proteinaceous molecule of embodiment 1, wherein at least one of:Xi is absent;X2is absent;X3 is absent; andX4is absent.4. The proteinaceous molecule of any one of embodiments 1 to 3, wherein X5 is a small amino acid residue.5. The proteinaceous molecule of any one of embodiments 1 to 3, wherein X5 is P.6. The proteinaceous molecule of any one of embodiments 1 to 5, wherein Xs is a basic amino acid residue.7. The proteinaceous molecule of any one of embodiments 1 to 5, wherein Xs is R.8. The proteinaceous molecule of any one of embodiments 1 to 7, wherein X7 is a small amino acid residue.9. The proteinaceous molecule of any one of embodiments 1 to 7, wherein X7 is P.10. The proteinaceous molecule of any one of embodiments 1 to 9, wherein Xs is a basic amino acid residue.11. The proteinaceous molecule of any one of embodiments 1 to 9, wherein Xs is R.12. The proteinaceous molecule of any one of embodiments 1 to 11, wherein X9 is a small amino acid residue.13. The proteinaceous molecule of any one of embodiments 1 to 11, wherein X9 is T.14. The proteinaceous molecule of any one of embodiments 1 to 13, wherein at least one of:X10 is C;Xu is D; andXi2is I.15. The proteinaceous molecule of any one of embodiments 1 to 13, wherein at least one of:Xio is absent;Xu is absent; andX12 is absent.16. The proteinaceous molecule of any one of embodiments 1 to 15, wherein X13 is an aromatic amino acid residue.17. The proteinaceous molecule of any one of embodiments 1 to 15, wherein X13 is F.18. The proteinaceous molecule of any one of embodiments 1 to 17, wherein X14 is a small amino acid residue.19. The proteinaceous molecule of any one of embodiments 1 to 17, wherein X14 is T.20. The proteinaceous molecule of any one of embodiments 1 to 19, wherein X15 is N.21. The proteinaceous molecule of any one of embodiments 1 to 20, wherein at least one of:Xis is S;X17 is R;Xis is G; andX19 is K.22. The proteinaceous molecule of any one of embodiments 1 to 20, wherein at least one of:Xis is absent;X17 is absent;Xis is absent; andX19 is absent.23. The proteinaceous molecule of any one of embodiments 1 to 22, wherein X20 is a basic amino acid residue.24. The proteinaceous molecule of any one of embodiments 1 to 22, wherein X20 is R.25. The proteinaceous molecule of any one of embodiments 1 to 24, wherein X21 is a small amino acid residue.26. The proteinaceous molecule of any one of embodiments 1 to 24, wherein X21 is A.27. The proteinaceous molecule of any one of embodiments 1 to 26, wherein X22 is a small amino acid residue.28. The proteinaceous molecule of any one of embodiments 1 to 26, wherein X22 is S.29. The proteinaceous molecule of any one of embodiments 1 to 28, wherein X23 is a neutral / polar amino acid residue.30. The proteinaceous molecule of any one of embodiments 1 to 28, wherein X23 is N.31. The proteinaceous molecule of any one of embodiments 1 to 30, wherein X24 is a small amino acid residue.32. The proteinaceous molecule of any one of embodiments 1 to 30, wherein X24 is G.33. The proteinaceous molecule of any one of embodiments 1 to 32, wherein X25 is a neutral / polar amino acid residue.34. The proteinaceous molecule of any one of embodiments 1 to 32, wherein X25 is N.35. The proteinaceous molecule of any one of embodiments 1 to 34, wherein X26 is a basic amino acid residue.36. The proteinaceous molecule of any one of embodiments 1 to 34, wherein X26 is K.37. The proteinaceous molecule of any one of embodiments 1 to 36, wherein X27 is a small amino acid residue.38. The proteinaceous molecule of any one of embodiments 1 to 36, wherein X27 is T.39. The proteinaceous molecule of any one of embodiments 1 to 38, wherein X28 is C.40. The proteinaceous molecule of embodiment 1, wherein at least one of Xi, X2, X3, X4, X10, Xu, X12, X13, X14, X15, Xis, X17, Xis, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28 is absent.41. The proteinaceous molecule of embodiment 1, wherein X1, X2, X3, X4, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28are absent.42. The proteinaceous molecule of embodiment 1, wherein X10, Xu, X12, X13, X14, X15, Xis, X17, Xis, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28 are absent.43. The proteinaceous molecule of embodiment 1, wherein Xis, X17, Xis, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28 are absent.44. The proteinaceous molecule of embodiment 1, wherein X20, X21, X22, X23, X24, X25, X26, X27, and X28 are absent.45. The proteinaceous molecule of any one of embodiments 1 to 3 and 14 to 44, wherein Xs is P, Xs is R, X? is P, Xs is R, and X9 is T.46. The proteinaceous molecule of any one of embodiments 1 to 45, wherein each of Zi and Z2 are absent.47. The proteinaceous molecule of any one of embodiments 1 to 45, wherein one of Zi and Z2 is absent and the other of Zi and Z2 is selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.48. The proteinaceous molecule of any one of embodiments 1 to 45, wherein each of Zi and Z2 are independently selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.49. The proteinaceous molecule of any one of embodiments 1 to 48, wherein the proteinaceous molecule is between 10 amino acid residues and 100 amino acid residues in length.50. The proteinaceous molecule of any one of embodiments 1 to 3 and 14 to 49, the proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula (I-P):Z1X1X2X3X4MPENPRPRTPX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2(I-P),wherein each of Zi, Xi, X2, X3, X4, X10, Xu, X12, X13, Xi4, X15, Xie, X17, Xis, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, and Z2 are as defined in any one of embodiments 1 to 3 and 14 to 49.51. The proteinaceous molecule of embodiment 1, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-16:YTIWMPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 1];MPENPRPRTP [SEQ ID NO: 2];WMPENPRPRTP [SEQ ID NO: 3];IWMPENPRPRTP [SEQ ID NO: 4];TIWMPENPRPRTP [SEQ ID NO: 5];YTIWMPENPRPRTP [SEQ ID NO: 6];YTIWMPENPRPRTPCDIFTNSRGK [SEQ ID NO: 7];YTIWMPENPRPRTPCDIFTN [SEQ ID NO: 8];MPENPRPRTPCDIFTNSRGK [SEQ ID NO: 9];MPENPRPRTPCDIFTN [SEQ ID NO: 10];MPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 11];MPENPRPRTPCDIFTNSRGKRASNG [SEQ ID NO: 12];WMPENPRPRTPCDIFTNSRGKRASNGN [SEQ ID NO: 13];IWMPENPRPRTPCDIFTNSRGKRASNGNK [SEQ ID NO: 14];TIWMPENPRPRTPCDIFTNSRGKRASNGNKT [SEQ ID NO: 15]; and NHDYTIWMPENPRPRTPCDIFTNSRGKRASN [SEQ ID NO: 16],52. The proteinaceous molecule of embodiment 51, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1, 2, 7 and 8.53. An isolated or recombinant proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence selected from:a) the amino acid sequence:FGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGYISAIKVNGF TCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYPD YHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIW MPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMD GTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVKKREECLDTLESIMTTKSV SFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHV NGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHPLADPSTVFKEGDEAEDF VEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSLMTWCRRANRPESKQRS FGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 31];b) the amino acid sequence:MVPQVLLFVLLLGFSLCFGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFS YMELKVGYISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWK MAGDPRYEESLHNPYPDYHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSG ITVSSTYCSTNHDYTIWMPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLK GACRLKLCGVLGLRLMDGTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVK KREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEI IPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHP LADPSTVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSL MTWCRRANRPESKQRSFGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 32];c) the amino acid sequence:FGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFSYMELKVGYISAIKVNGF TCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWKMAGDPRYEESLHNPYPD YHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSGITVSSTYCSTNHDYTIW MPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLKGACRLKLCGVLGLRLMD GTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVKKREECLDTLESIMTTKSV SFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHV NGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHPLADPSTVFKEGDEAEDF VEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSLMTWC [SEQ ID NO: 33]; andd) the amino acid sequence:MVPQVLLFVLLLGFSLCFGKFPIYTIPDELGPWSPIDIHHLSCPNNLVVEDEGCTNLSEFS YMELKVGYISAIKVNGFTCTGVVTEAETYTNFVGYVTTTFKRKHFRPTPDACRAAYNWK MAGDPRYEESLHNPYPDYHWLRTVRTTKESLIIISPSVTDLDPYDKSLHSRVFPGGKCSG ITVSSTYCSTNHDYTIWMPENPRPRTPCDIFTNSRGKRASNGNKTCGFVDERGLYKSLK GACRLKLCGVLGLRLMDGTWVAMQTSDETKWCPPDQLVNLHDFRSDEIEHLVVEELVK KREECLDTLESIMTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEI IPSKGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLLQQHMELLESSVIPLMHP LADPSTVFKEGDEAEDFVEVHLPDVYKQISGVDLGLPNWGKYVLMTAGAMIGLVLIFSL MTWC [SEQ ID NO: 34],54. A chimeric molecule comprising the proteinaceous molecule of any one of embodiments 1 to 53 and at least one ancillary moiety.55. The chimeric molecule of embodiment 54, wherein the at least one ancillary moiety comprises a polypeptide transport moiety that facilitates transport of the proteinaceous molecule across a biological membrane.56. The chimeric molecule of embodiment 55, wherein the polypeptide transport moiety comprises a cell-penetrating moiety that facilitates entry of the proteinaceous molecule into a cell.57. The chimeric molecule of embodiment 56, wherein the cell-penetrating moiety comprises polyarginine.58. The chimeric molecule of embodiment 56, wherein the cell-penetrating moiety comprises, consists, or consists essentially of an amino acid sequence represented by SEQ ID NO: 20:GGGRRRRRRRRR [SEQ ID NO: 20].59. The chimeric molecule of embodiment 55, wherein the polypeptide transport moiety comprises a signal peptide moiety that directs secretion of the proteinaceous molecule outside of a cell.60. The chimeric molecule of embodiment 59, wherein the signal peptide moiety comprises, consists, or consists essentially of the amino acid sequenceMVPQVLLFVLLLGFSLC [SEQ ID NO: 24] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 24.61. The chimeric molecule of embodiment 55, wherein the polypeptide transport moiety comprises a transmembrane peptide moiety that localises the proteinaceous molecule to a synaptic membrane.62. The chimeric molecule of embodiment 61, wherein the transmembrane peptide moiety comprises, consists, or consists essentially of the amino acid sequence KYVLMTAGAMIGLVLIFSLMTWC [SEQ ID NO: 25] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 25.63. The chimeric molecule of embodiment 55, wherein the polypeptide transport moiety comprises a receptor binding moiety that binds to a receptor that aids cellular uptake of the proteinaceous molecule.64. The chimeric molecule of embodiment 63, wherein the receptor binding moiety binds to p75 neurotrophin receptor (p75NTR).65. The chimeric molecule of embodiment 64, wherein the receptor binding moiety comprises, consists, or consists essentially of the amino acid sequence MTTKSVSFRRL [SEQ ID NO: 26], SHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPS [SEQ ID NO: 27], KGCLKVGGRCHPHVNGVFFNGIILGPDDHVLIPEMQSSLL [SEQ ID NO: 28], or MTTKSVSFRRLSHLRKLVPGFGKAYTIFNKTLMEADAHYKSVRTWNEIIPSKGCLKVGGRCHPHVNG VFFNGIILGPDDHVLIPEMQSSLL [SEQ ID NO: 29], or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NOs: 26, 27, 28, or 29.66. The chimeric molecule of embodiment 55, wherein the polypeptide transport moiety comprises a PDZ domain.67. The chimeric molecule of embodiment 66, wherein the PDZ domain binds to MAST2.68. The chimeric molecule of embodiment 66, wherein the PDZ domain comprises, consists, or consists essentially of the amino acid sequence RRANRPESKQRSFGGTGGNVSVTSQSGKVIPSWESYKSGGEIRL [SEQ ID NO: 30] or an amino acid sequence having at least 85% (such as from 85% to 99% and all integer percentages therebetween) sequence identity or similarity to the amino acid sequence represented by SEQ ID NO: 30.69. The chimeric molecule of embodiment 54, wherein the at least one ancillary moiety comprises a targeting ligand.70. The chimeric molecule of any one of embodiments 54 to 69, wherein the at least one ancillary moiety is directly linked to the proteinaceous molecule.71. The chimeric molecule of any one of embodiments 54 to 69, wherein the at least one ancillary moiety is linked to the proteinaceous molecule via a covalent linker.72. The chimeric molecule of any one of embodiments 54 to 69, wherein the at least one ancillary moiety is a plurality of ancillary moieties, wherein at least one of the ancillary moieties is directly linked to the proteinaceous molecule, and wherein at least one of the ancillary moieties is linked to the proteinaceous molecule via a covalent linker.73. The chimeric molecule of any one of embodiments 54 to 72, wherein the at least one ancillary moiety is linked to the N-terminus of the proteinaceous molecule.74. The chimeric molecule of any one of embodiments 54 to 72, wherein the at least one ancillary moiety is linked to the C-terminus of the proteinaceous molecule.75. The chimeric molecule of any one of embodiments 54 to 72, wherein the at least one ancillary moiety is a plurality of ancillary moieties, wherein at least one of the ancillary moieties is linked to the N-terminus of the proteinaceous molecule, and wherein at least one of the ancillary moieties is linked to the C-terminus of the proteinaceous molecule.76. An expression vector comprising a nucleic acid sequence that encodes a proteinaceous molecule of any one of embodiments 1 to 53 or a chimeric molecule of any one of embodiments 54 to 75, wherein the vector is other than a rabies virus or virion.77. The expression vector of embodiment 76, wherein the nucleic acid sequence is operably connected to a heterologous promoter.78. A construct comprising a nucleic acid sequence that encodes a proteinaceous molecule of any one of embodiments 1 to 53 or a chimeric molecule of any one of embodiments 54 to 75, operably connected to a heterologous promoter.79. A host cell comprising an expression vector of embodiment 76 or 77 or construct of embodiment 78.80. A composition comprising, consisting, or consisting essentially of a proteinaceous molecule of any one of embodiments 1 to 53 or a chimeric molecule of any one of embodiments 54 to 75, and a pharmaceutically acceptable carrier or diluent.81. The composition of embodiment 80, further comprising at least one of a nanoparticle and a liposome.82. Use of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81, for treating or inhibiting axonal degeneration in a subject.83. The use of embodiment 82, wherein the axonal degeneration is SARM1-mediated axonal degeneration.84. Use of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81, for treating a neurodegenerative disease in a subject.85. The use of embodiment 84, wherein the neurodegenerative disease is motor neuron disease, dementia (e.g., Alzheimer's disease), Parkinson's disease, multiple sclerosis, traumatic brain injury, traumatic spinal cord injury, glaucoma, peripheral neuropathy, Guillain-Barre syndrome, chemotherapy-induced or diabetes-induced neuropathy, or chronic traumatic encephalopathy.86. Use of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81, for modulating CaMKII in a subject.87. Use of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81, for decreasing a rate of brain ageing in a subject.88. Use of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81, for inhibiting or minimising neuronal injury in a subject.89. A method of treating or inhibiting axonal degeneration in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81.90. The method of embodiment 89, wherein the axonal degeneration is SARM1-mediated axonal degeneration.91. A method of treating a neurodegenerative disease in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81.92. The method of embodiment 91, wherein the neurodegenerative disease is motor neuron disease, dementia (e.g., Alzheimer's disease), Parkinson's disease, multiple sclerosis, traumatic brain injury, traumatic spinal cord injury, glaucoma, peripheral neuropathy, Guillain-Barre syndrome, chemotherapy-induced or diabetes-induced neuropathy, or chronic traumatic encephalopathy.93. A method of modulating CaMKII in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81.94. A method of decreasing a rate of brain ageing in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule of any oneof embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81.95. A method of inhibiting or minimising neuronal injury in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81.96. A proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81 for use in treating or inhibiting axonal degeneration in a subject.97. The proteinaceous molecule, chimeric molecule or composition for use of embodiment 96, wherein the axonal degeneration is SARMl-mediated axonal degeneration.98. A proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81 for use in treating a neurodegenerative disease in a subject.99. The proteinaceous molecule, chimeric molecule or composition for use of embodiment 98, wherein the neurodegenerative disease is motor neuron disease, dementia (e.g., Alzheimer's disease), Parkinson's disease, multiple sclerosis, traumatic brain injury, traumatic spinal cord injury, glaucoma, peripheral neuropathy, Guillain-Barre syndrome, chemotherapy-induced or diabetes-induced neuropathy, or chronic traumatic encephalopathy.100. A proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81 for use in modulating CaMKII in a subject.101. A proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81 for use in decreasing a rate of brain ageing in a subject.102. A proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81 for use in inhibiting or minimising neuronal injury in a subject.103. Use of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81 for inducing synapse formation in a subject.104. A method of inducing synapse formation in a subject, comprising administering a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81 to a subject.105. A proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81 for use in inducing synapse formation in a subject.106. Use of a proteinaceous molecule of any one of embodiments 1 to 53, a chimeric molecule of any one of embodiments 54 to 75, or a composition of embodiment 80 or embodiment 81 in the manufacture of a medicament for inducing synapse formation in a subject.

Claims

WHAT IS CLAIMED IS:

1. A proteinaceous molecule comprising, consisting, or consisting essentially of an amino acid sequence represented by Formula (I):Z1X1X2X3X4MPENX5X6X7X8X9PX10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28Z2(I)wherein:Xi is absent or is any amino acid residue;X2 is absent or is any amino acid residue;X3 is absent or is any amino acid residue;X4 is absent or is any amino acid residue;X5 is any amino acid residue;Xs is any amino acid residue;X7 is any amino acid residue;Xs is any amino acid residue;X9 is any amino acid residue;X10 is absent or is any amino acid residue;Xu is absent or is any amino acid residue;X12 is absent or is any amino acid residue;X13 is absent or is any amino acid residue;X14 is absent or is any amino acid residue;X15 is absent or is any amino acid residue;Xis is absent or is any amino acid residue;X17 is absent or is any amino acid residue;Xis is absent or is any amino acid residue;X19 is absent or is any amino acid residue;X20 is absent or is any amino acid residue;X21 is absent or is any amino acid residue;X22 is absent or is any amino acid residue;- Ill -X23 is absent or is any amino acid residue;X24 is absent or is any amino acid residue;X25 is absent or is any amino acid residue;X26 is absent or is any amino acid residue;X27 is absent or is any amino acid residue;X28 is absent or is any amino acid residue;Zi and Z2 are independently absent or independently selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.

2. The proteinaceous molecule of claim 1, wherein:Xi is absent or is an aromatic amino acid residue;X2 is absent or is a small amino acid residue;X3 is absent or is a hydrophobic amino acid residue;X4 is absent or is an aromatic amino acid residue;X5 is a small amino acid residue or a hydrophobic amino acid residue;Xs is a basic amino acid residue or a small amino acid residue;X7 is a hydrophobic amino acid residue or a small amino acid residue;Xs is a small amino acid residue or a basic amino acid residue;X9 is a small amino acid residue or a hydrophobic amino acid residue;X10 is absent or is C;Xu is absent or is an acidic amino acid residue;X12 is absent or is a hydrophobic amino acid residue;X13 is absent or is a hydrophobic amino acid residue;X14 is absent or is a small amino acid residue or a hydrophobic amino acid residue; X15 is absent or is a neutral / polar amino acid residue;Xis is absent or is a small amino acid residue;X17 is absent or is a basic amino acid residue;Xis is absent or is a small amino acid residue;X19 is absent or is a basic amino acid residue;X20 is absent or is a basic amino acid residue;X21 is absent or is a small amino acid residue or an acidic amino acid residue;X22 is absent or is a small amino acid residue;X23 is absent or is a basic amino acid residue or a neutral / polar amino acid residue; X24 is absent or is a small amino acid residue or a basic amino acid residue;X25 is absent or is a small amino acid residue or a neutral / polar amino acid residue; X26 is absent or is a basic amino acid residue;X27 is absent or is a small amino acid residue; and / orX28 is absent or is C.

3. The proteinaceous molecule of claim 1 or claim 2, wherein at least one of: Xi is Y;X2 is T;X3 is I; andX4is W.

4. The proteinaceous molecule of any one of claims 1 to 3, wherein Xs is P.

5. The proteinaceous molecule of any one of claims 1 to 4, wherein Xs is R.

6. The proteinaceous molecule of any one of claims 1 to 5, wherein X7 is P.

7. The proteinaceous molecule of any one of claims 1 to 6, wherein Xs is R.

8. The proteinaceous molecule of any one of claims 1 to 7, wherein X9 is T.

9. The proteinaceous molecule of any one of claims 1 to 8, wherein at least one of:Xu is D; andX12 is I.

10. The proteinaceous molecule of any one of claims 1 to 9, wherein X13 is F.

11. The proteinaceous molecule of any one of claims 1 to 10, wherein X14is T.

12. The proteinaceous molecule of any one of claims 1 to 11, wherein X15 is N.

13. The proteinaceous molecule of any one of claims 1 to 12, wherein at least one of:Xis is S;X17 is R;Xis is G; andX19 is K.

14. The proteinaceous molecule of any one of claims 1 to 13, wherein X20 is R.

15. The proteinaceous molecule of any one of claims 1 to 14, wherein X21 is A.

16. The proteinaceous molecule of any one of claims 1 to 15, wherein X22 is S.

17. The proteinaceous molecule of any one of claims 1 to 16, wherein X23 is N.

18. The proteinaceous molecule of any one of claims 1 to 17, wherein X24 is G.

19. The proteinaceous molecule of any one of claims 1 to 18, wherein X25 is N.

20. The proteinaceous molecule of any one of claims 1 to 19, wherein X26 is K.

21. The proteinaceous molecule of any one of claims 1 to 20, wherein X27 is T.

22. The proteinaceous molecule of claim 1 or claim 2, wherein at least one of Xi, X2, X3, X4, X10, Xu, X12, X13, X14, X15, Xis, X17, Xis, X19, X20, X21, X22, X23, X24, X25, X26, X27, and X28 is absent.

23. The proteinaceous molecule of any one of claims 1 to 22, wherein each of Zi and Z2 are absent.

24. The proteinaceous molecule of claim 1, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-16:YTIWMPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 1];MPENPRPRTP [SEQ ID NO: 2];WMPENPRPRTP [SEQ ID NO: 3];IWMPENPRPRTP [SEQ ID NO: 4];TIWMPENPRPRTP [SEQ ID NO: 5];YTIWMPENPRPRTP [SEQ ID NO: 6];YTIWMPENPRPRTPCDIFTNSRGK [SEQ ID NO: 7];YTIWMPENPRPRTPCDIFTN [SEQ ID NO: 8];MPENPRPRTPCDIFTNSRGK [SEQ ID NO: 9];MPENPRPRTPCDIFTN [SEQ ID NO: 10];MPENPRPRTPCDIFTNSRGKRASNGNKTC [SEQ ID NO: 11];MPENPRPRTPCDIFTNSRGKRASNG [SEQ ID NO: 12];WMPENPRPRTPCDIFTNSRGKRASNGN [SEQ ID NO: 13];IWMPENPRPRTPCDIFTNSRGKRASNGNK [SEQ ID NO: 14];TIWMPENPRPRTPCDIFTNSRGKRASNGNKT [SEQ ID NO: 15]; andNHDYTIWMPENPRPRTPCDIFTNSRGKRASN [SEQ ID NO: 16].

25. The proteinaceous molecule of claim 24, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1, 2, 7 and 8.

26. A chimeric molecule comprising the proteinaceous molecule of any one of claims 1 to 25 and at least one ancillary moiety.

27. The chimeric molecule of claim 26, wherein the at least one ancillary moiety comprises a polypeptide transport moiety that facilitates transport of the proteinaceous molecule across a biological membrane.

28. A composition comprising, consisting, or consisting essentially of a proteinaceous molecule of any one of claims 1 to 25 or a chimeric molecule of claim 26 or claim 27, and a pharmaceutically acceptable carrier or diluent.

29. A method of treating or inhibiting axonal degeneration in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule of any one of claims 1 to 25, a chimeric molecule of claim 26 or claim 27, or a composition of claim 28.

30. The method of claim 29, wherein the axonal degeneration is SARM1-mediated axonal degeneration.

31. A method of treating a neurodegenerative disease in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule of any one of claims 1 to 25, a chimeric molecule of claim 26 or claim 27, or a composition of claim 28.

32. The method of claim 31, wherein the neurodegenerative disease is motor neuron disease, dementia (e.g., Alzheimer's disease), Parkinson's disease, multiple sclerosis, traumatic brain injury, traumatic spinal cord injury, glaucoma, peripheral neuropathy, Guillain-Barre syndrome, chemotherapy-induced or diabetes-induced neuropathy, or chronic traumatic encephalopathy.

33. A method of modulating CaMKII in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule of any one of claims 1 to 25, a chimeric molecule of claim 26 or claim 27, or a composition of claim 28.

34. A method of decreasing a rate of brain ageing in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule of any one of claims 1 to 25, a chimeric molecule of claim 26 or claim 27, or a composition of claim 28.

35. A method of inhibiting or minimising neuronal injury in a subject, comprising administering to the subject an effective amount of a proteinaceous molecule of anyone of claims 1 to 25, a chimeric molecule of claim 26 or claim 27, or a composition of claim 28.

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