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US 2009/0156496 A1 Benowitz Et Al US 20090156496A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0156496 A1 Benowitz et al. (43) Pub. Date: Jun. 18, 2009 (54) METHODS AND COMPOSITIONS FOR (86). PCT No.: PCT/US2007/O11576 TREATING AND PREVENTING PERPHERAL NERVE DAMAGE S371 (c)(1), (2), (4) Date: Nov. 12, 2008 (75) Inventors: Larry I. Benowitz, Newton, MA Related U.S. Application Data (US); Yuqin Yin, Brighton, MA (60) Provisional application No. 60/800,068, filed on May (US) 12, 2006. Correspondence Address: Publication Classification DAVID S. RESNICK (51) Int. Cl. NIXON PEABODY LLP, 100 SUMMER STREET A638/17 (2006.01) BOSTON, MA 02110-2131 (US) (52) U.S. Cl. .......................................................... S14/12 (57) ABSTRACT (73) Assignee: CHILDRENS MEDICAL Disclosed herein is a method for treating and/or preventing CENTER CORPORATION, peripheral nerve damage in a Subject comprising administer INC., Boston, MA (US) ing to the Subject a therapeutically effective amount of onco modulin. Preferably, the subject is a mammal, most prefer (21) Appl. No.: 12/300,591 ably, a human. In preferred embodiments, the oncomodulin may be used in combination with mannose, a mannose deriva (22) PCT Filed: May 14, 2007 tive and/or inosine. Patent Application Publication Jun. 18, 2009 Sheet 2 of 20 US 2009/O156496 A1 +=- WOW+– ?OI(OI)I -W0 (ST30%) HMOONOX NNWW+WSHOHNO?? OI"9IJI s ye won (S19)%) HIMO)NONOX Patent Application Publication Jun. 18, 2009 Sheet 3 of 20 US 2009/0156496 A1 s 35s N See N QS - 5 RN (ST30%) HIMO)NONOX - H + + + + + + i + Q9 + + N + Q5 * * ' N. S. + S2 st c Le 2 3 G (OZIYWNON OTH/SO9) S TAIAS Patent Application Publication Jun. 18, 2009 Sheet 4 of 20 US 2009/O156496 A1 i s 3 (SO4) HAONEO NOX Patent Application Publication Jun. 18, 2009 Sheet 5 of 20 US 2009/0156496 A1 -- Ge. O r w (STO%) HMO)NO NOX -- E o O ce O a ur Y CN y (STO%) HIMO)NONOXV Patent Application Publication Jun. 18, 2009 Sheet 6 of 20 US 2009/O156496 A1 s Patent Application Publication Jun. 18, 2009 Sheet 7 of 20 US 2009/O156496 A1 Se r s o s s er s wn (STO%)HAOSINO NOX i se + se + 2 e - N se -- GY s + i S Se s S + S as (OOOOONNO909 5 T130/39NV8NOSSV) SNEONI8 Patent Application Publication Jun. 18, 2009 Sheet 8 of 20 US 2009/O156496 A1 s A. fe as a e e E s s s o f N us s 33/ONN09 s B RS s C R s -- s S. s I S. 6re e se --N O s. 2 s s o seR O s s s s ae w s us ar sa ma (n") NONISOIOS Patent Application Publication Jun. 18, 2009 Sheet 9 of 20 US 2009/O156496 A1 st S s S s us ra NION NOISINBOld Patent Application Publication Jun. 18, 2009 Sheet 10 of 20 US 2009/O156496 A1 (STO%) HMONSNOX tEH + + s H s -- H : -- H 5 E se re S a e t r na vy s is (STO%) HMO)NOX 2 Patent Application Publication Jun. 18, 2009 Sheet 11 of 20 US 2009/O156496 A1 (SO4) HMOSNOX Patent Application Publication Jun. 18, 2009 Sheet 12 of 20 US 2009/O156496 A1 ONOO NO Patent Application Publication Jun. 18, 2009 Sheet 13 of 20 US 2009/O156496 A1 Patent Application Publication Jun. 18, 2009 Sheet 14 of 20 US 2009/O156496 A1 S2 as 5 NS h Q5 RN SAa 2i NO NN NO N81 ONO) (INIS Patent Application Publication Jun. 18, 2009 Sheet 15 of 20 US 2009/O156496 A1 ***** 29™9IJI 0 09™9IJI Patent Application Publication Jun. 18, 2009 Sheet 16 of 20 US 2009/O156496 A1 a TONO) SO-d/ Patent Application Publication Jun. 18, 2009 Sheet 17 of 20 US 2009/O156496 A1 Q9(9.I.H. SON 18 SN3-ds -- WO Patent Application Publication Jun. 18, 2009 Sheet 18 of 20 US 2009/O156496 A1 (WWI) NOXYS39NO uloool C SNOXY E s 5. E. 2 E A W 5 s s s O S ce e So s us N urloog < SNOXY Patent Application Publication Jun. 18, 2009 Sheet 19 of 20 US 2009/O156496 A1 s A e RS 5 N E e Q5 se N sa ey ass D M l e 2 s ala L NTS NO Patent Application Publication Jun. 18, 2009 Sheet 20 of 20 US 2009/O156496 A1 SLIMN HAST WINS: s S e se se on s WrloodZSLINN3N HLASTN023 US 2009/0156496 A1 Jun. 18, 2009 METHODS AND COMPOSITIONS FOR cally effective amount of oncomodulin, to thereby treat and/ TREATING AND PREVENTING PERPHERAL or prevent peripheral nerve damage in the Subject. The NERVE DAMAGE peripheral nerve damage may be in the Subject's spinal cord. Another aspect of the present invention relates to a method for RELATED APPLICATIONS treating and/or preventing spinal cord injury in a subject comprising administering to the Subject a therapeutically 0001. This application is an International Application, effective amount of oncomodulin to thereby treat and/or pre which claims the benefit of priority under 35 U.S.C. S 119(e) vent spinal cord injury in the Subject. These methods may of U.S. Provisional Application Ser. No. 60/800,068 filed on optionally further comprise a step of selecting a subject in May 12, 2006, the contents of which are incorporated herein need of treatment or prevention of such peripheral nerve by reference in its entirety. damage. In one embodiment, the methods further comprise administering to said subject a cAMP modulator. The cAMP GOVERNMENT SUPPORT modulator can be non-hydrolyzable cAMP analogues, for 0002 This invention was supported, in part, by National Skolin, adenylate cyclase activators, macrophage-derived fac Institutes of Health (NIH) Grant No. EY 05690. The govern tors that stimulate cAMP macrophage activators, calcium ment of the United States may have certain rights to the ionophores, membrane depolarization, phosphodiesterase invention. inhibitors, specific phosphodiesterase IV inhibitors, beta2 adrenoreceptor inhibitors or vasoactive intestinal peptide, or BACKGROUND OF THE INVENTION combinations thereof. In one embodiment, the methods fur 0003 Peripheral neuropathy describes damage to the ther comprise administering mannose or a mannose deriva peripheral nervous system. It can manifest itself as a dysfunc tive to said subject. In one embodiment, the methods further tion of motor, sensory, sensorimotor or autonomic nerves. comprise administering inosine to said subject. The periph 0004. The disorder is associated with a wide variety of eral nerve damage can be the result of diabetic neuropathy, of causes, including genetically acquired conditions, systemic a viral or bacterial infection. The oncomodulin may be disease or exposure to toxic agents. Diabetic neuropathy is administered topically, by local injection. The oncomodulin one example of disease-induced peripheral neuropathy. Neu can be administered to the Subject in a pharmaceutically ropathies can also occur in conditions such as acromegaly, acceptable formulation. The subject of the method may be a hypothyroidism, AIDS, leprosy, Lyme disease, systemic mammal, e.g. a human. lupus erythematosus, rheumatoid arthritis, Sjogren's syn 0012 Another aspect of the present invention relates to an drome, periarteritis nodosa, Wegener's granulomatosis, cra article of manufacture comprising packaging material and a nial arteritis, and sarcoidosis, as well as other conditions. pharmaceutical agent contained within said packaging mate 0005. There is a strong need in the art for treatments of rial, wherein said packaging material comprises a label which peripheral nerve damage (peripheral neuropathy). indicates said pharmaceutical may be administered, for a Sufficient term at an effective dose, for treating and/or pre SUMMARY OF INVENTION venting peripheral nerve damage together with a pharmaceu tically acceptable carrier, wherein the pharmaceutical agent 0006. The present invention provides a method for treating comprises oncomodulin. and/or preventing peripheral nerve damage in a subject com 0013 Another aspect of the present invention relates to a prising selecting a Subject having peripheral nerve damage or pharmaceutical kit for the treatment and/or prevention of in need of prevention of Such damage, and administering to damage to peripheral nerves comprising the combination of the subject a therapeutically effective amount of oncomodu oncomodulin, an axogenic factor, and a cAMP modulator. lin. Preferably, the subject is a mammal, most preferably, a The axogenic factor can be mannose, a mannose derivative or human. inosine. Examples of cAMP modulators are non hydrolyz 0007. In one embodiment, a cAMP modulator and/or an able cAMP analogues, forskolin, adenylate cyclase activa axogenic factor is further administered to the subject. The tors, macrophage-derived factors that stimulate cAMP mac components can be used separately, but administered contem rophage activators, calcium ionophores, membrane poraneously. While not wishing to be bound by a particular depolarization, phosphodiesterase inhibitors, specific phos theory, it is believed that the cAMP modulator and axogenic phodiesterase IV inhibitors, beta2-adrenoreceptor inhibitors factor potentiates the activity of the oncomodulin. or vasoactive intestinal peptide. 0008 Preferably, the cAMP modulator is non-hydrolyz 0014) Another aspect of the present invention relates to the able cAMP analogues, forskolin, adenylate cyclase activa use of oncomodulin in the preparation of a medicament for tors, macrophage-derived factors that stimulate cAMP mac treating and/or preventing peripheral nerve damage in a Sub rophage activators, calcium ionophores, membrane ject. This use is envisioned as described in the methods depolarization, phosphodiesterase inhibitors, specific phos herein. phodiesterase IV inhibitors, beta2-adrenoreceptor inhibitors 0015. Another aspect of the present invention relates to a or vasoactive intestinal peptide. method for inhibiting the axogenic effects of oncomodulin on 0009 Preferred axogenic factors include mannose (some a neuron comprising contacting an inhibitor of oncomodulin times referred to as "AF-1), mannose derivatives and to the neuron.
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