WO2024030951A2 - Mesencephalic astrocyte-derived neurotrophic factor (manf) for preventing and treating peripheral neuropathies - Google Patents

Abstract

Methods for prevention of peripheral neuropathies, including taxane-induced peripheral neuropathies, by administration of MANF or nucleic acids encoding MANF are provided. Methods of treating extant peripheral neuropathies and neuropathy-associated peripheral pain are provided.

Description

MESENCEPHALIC ASTROCYTE-DERIVED NEUROTROPHIC FACTOR (MANF) FOR PREVENTING AND TREATING PERIPHERAL NEUROPATHIES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No. 63/394,770, filed August 3, 2022, the contents of which are hereby incorporated by reference.

BACKGROUND

[0002] The disclosures of all publications, patents, patent application publications and books referred to in this application are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.

[0003] The innate immune system plays an important role in driving neuropathic pain and neurodegeneration in chemotherapy-induced peripheral neuropathy (CIPN) (1-12). Tn particular, macrophages, white blood cells that are sentinels of tissue maintenance and involved in phagocytosis of damaged or foreign cells, are involved in all steps of pain, from onset to resolution (13-15). Macrophages can increase hypersensitivity in response to chemotherapeutics because systemic inhibition of pro-inflammatory macrophage activation and infiltration by minocycline or chemokine MCP-l/CCL-2 neutralizing antibodies protects sensory neurons from developing neuropathic pain and degeneration of peripheral nerves in the skin (1,4,11,12). However, macrophages not only control inflammation but promote subsequent regeneration of tissues by clearing cellular debris, and by promoting angiogenesis, and the extracellular matrix formation (16,17). Inflamed macrophages also contribute to paclitaxel (PTX)-mediated cancer treatment by infiltrating and killing tumors (18-20). As such, the responses of macrophages to chemotherapeutics can alter cellular processes and pain experiences in complex ways. Furthermore, molecular profiles of macrophages change continuously depending on their extracellular environment as they transition from resident to activated states: either pro- inflammatory and pain-producing or anti-inflammatory and analgesic forms (14,17,21-24). Many intermediate forms of activated macrophages exist in-between these two extremes (14,23,25-27), further confounding the potential use of macrophage-based therapies for patients suffering from CIPN. To safely target macrophages for CIPN treatment, it is imperative to better understand how different macrophage activation states contribute to the pathological progression of neuropathic pain. However, how these local macrophages respond to chemotherapeutics and contribute to CIPN is poorly understood.

[0004] The present invention addresses these needs and provides compositions and methods for treating peripheral neuropathies including treatment of taxane-induced peripheral neuropathies.

SUMMARY OF THE INVENTION

[0005] A method of preventing, reducing development of, or treating a peripheral neuropathy in a subject is provided, comprising administering to the subject an amount of a mesencephalic astrocyte-derived neurotrophic factor (MANF), or a nucleic acid encoding therefor, effective to treat a peripheral neuropathy.

[0006] Also provided is a method of reducing taxane-induced macrophage activation in a subject receiving a taxane treatment, or who is to receive a taxane treatment, comprising administering to the subject an amount of a mesencephalic astrocyte-derived neurotrophic factor (MANF), or nucleic acid encoding therefor, effective to treat a peripheral reducing taxane- induced macrophage activation in a subject.

[0007] Also provided is a method of reducing peripheral pain in a subject associated with activated pro-inflammatory macrophages comprising locally administering to the area of peripheral pain an amount of a mesencephalic astrocyte-derived neurotrophic factor (MANF), or nucleic acid encoding therefor, effective to reduce the peripheral pain.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Fig 1. Live imaging of PTX-treated animals reveals the timeline of morphological degeneration in nociceptive neurons in Drosophila. Yellow asterisks (varicosities and fragmentation, quantified as # degeneration in 243x243pm²). Error bars=SD. One-way ANOVA (w/Tukey’s posttest) VC=VehCont, P=PTX 20pM.

[0009] Fig 2. Macrophage-like cell transition in Drosophila models following cellular stress. PM=plasmatocyte, LM=lamellocyte, Green=Eater, Red= MSN, Magenta = integrin [IPS.

[0010] Fig. 3. Macrophage surrounding nociceptive neurons activates and transitions in response to PTX (20pM) insult in a time-dependent manner in larvae. 2nd row: enlarged insets.

[0011] Fig 4. A pilot single-cell Drosophila macrophage quantification in situ surrounding nociceptive neurons showed dose-dependent transition of hemocytes at 48h. Single cell segmentation by an in-house trained deep-learning algorithm. VehCont n=33, PTX 5pM n=182, PTX 20pM n=670 (n= number of hemocytes/ Drosophila macrophages in a nociceptive neuron receptive field tested).

[0012] Fig. 5A-5D. Macrophages are closely localized to nociceptive terminals in Drosophila. 5 A control. Green=nociceptive neurons, Eater; Red=MSN. 5B. Inset shows ruffling (arrowheads) and vacuoles (asterisks). 5C. Transition to LM. 5D. Arrowheads point to neurites wrapping a macrophage cluster.

[0013] Fig. 6. MANF overexpression protects nociceptive terminal morphology from PTX in Drosophila. Chronic treatment (20pM), arrow heads indicate degeneration. Two-way ANOVA (w/ Bonferroni posttest). Error bars = SEM

[0014] Fig. 7. MANF protects PTX-induced toxicity in adult DRG neurons in vitro. PTX 50nM 72h ± MANF (200nM). NF200. Tukey’s box and whiskers. Left: Kruskal -Wallis test (w/Dunn’s posttest), Right: 1-way ANOVA (w/Tukey’s posttest). n=6 ROIs (1.3x1.3mm²) each. Green asterisks= cell bodies.

[0015] Fig. 8. DRG neuron-macrophage co-culture. Compartment microfluidic chamber to study peripheral interaction between axon terminals (green) and macrophages (MP; red and blue). DETAILED DESCRIPTION

[0016] A method of preventing, reducing development of, or treating a peripheral neuropathy in a subject is provided, comprising administering to the subject an amount of a mesencephalic astrocyte-derived neurotrophic factor (MANF), or a nucleic acid encoding therefor, effective to treat a peripheral neuropathy.

[0017] In embodiments, the peripheral neuropathy is a chemotherapy-induced peripheral neuropathy (CIPN).

[0018] In embodiments, the peripheral neuropathy is a taxane-induced peripheral neuropathy.

[0019] In embodiments, the peripheral neuropathy is a paclitaxel-induced peripheral neuropathy.

[0020] In embodiments, the method is of preventing or reducing the reducing development of the CIPN and the MANF, or nucleic acid encoding therefor, is administered prior to the subject receiving chemotherapy.

[0021] In embodiments, the method further comprises administering MANF, or nucleic acid encoding therefor, to the subject during a period of chemotherapy administration.

[0022] In embodiments, the method is of treating an extant CIPN and the MANF, or nucleic acid encoding therefor, is administered during and/or subsequent to the subject receiving chemotherapy.

[0023] In embodiments, the CIPN is acute transient CIPN.

[0024] In embodiments, the CIPN is sub-acute long-lasting CIPN.

[0025] In embodiments, the peripheral neuropathy is an idiopathic peripheral neuropathy.

[0026] In embodiments, the idiopathic peripheral neuropathy is an aging-related idiopathic peripheral neuropathy.

[0027] In embodiments, the peripheral neuropathy is a sensory small fiber peripheral neuropathy.

[0028] In embodiments, the sensory small fiber peripheral neuropathy is a pre-diabetic neuropathy, a diabetic neuropathy, an HIV neuropathy, an amyloid neuropathy, or an inflammatory neuropathy.

[0029] In embodiments, the peripheral neuropathy is a diabetic peripheral neuropathy.

[0030] In embodiments, the subject has type 1 diabetes. [0031] In embodiments, the subject has type 2 diabetes mellitus.

[0032] In embodiments, the MANF, or nucleic acid encoding therefor, is administered locally to a site of the peripheral neuropathy.

[0033] In embodiments, the MANF, or nucleic acid encoding therefor, is locally administered to hands and/or feet of the subject. In embodiments, the MANF, or nucleic acid encoding therefor, is injected into the hands or feet. In embodiments, the MANF, or nucleic acid encoding therefor, is injected into the leg of the subject.

[0034] In embodiments, the subject is not being treated with a non-taxane chemotherapy.

[0035] In embodiments, the methods further comprise diagnosing the subject as suffering from a taxane-induced peripheral chemotherapy or as susceptible to a taxane-induced peripheral chemotherapy, prior to administering the MANF, or nucleic acid encoding therefor, to the subject.

[0036] In embodiments, the methods further comprise diagnosing the subject as suffering from an idiopathic or sensory small fiber peripheral neuropathy or as susceptible to an idiopathic or sensory small fiber peripheral neuropathy, prior to administering the MANF, or nucleic acid encoding therefor, to the subject.

[0037] Also provided is a method of reducing taxane-induced macrophage activation in a subject receiving a taxane treatment, or who is to receive a taxane treatment, comprising administering to the subject an amount of a mesencephalic astrocyte-derived neurotrophic factor (MANF), or nucleic acid encoding therefor, effective to treat a peripheral reducing taxane- induced macrophage activation in a subject.

[0038] Also provided is a method of reducing peripheral pain in a subject associated with activated pro-inflammatory macrophages comprising locally administering to the area of peripheral pain an amount of a mesencephalic astrocyte-derived neurotrophic factor (MANF), or nucleic acid encoding therefor, effective to reduce the peripheral pain.

[0039] In embodiments, the MANF disclosed herein is lyophilized and/or freeze dried and are reconstituted for use. Compositions or pharmaceutical compositions comprising the MANF disclosed herein can comprise stabilizers to prevent loss of activity or structural integrity of the protein due to the effects of denaturation, oxidation or aggregation over a period of time during storage and transportation prior to use. The compositions or pharmaceutical compositions can comprise one or more of any combination of salts, surfactants, pH and tonicity agents such as sugars can contribute to overcoming aggregation problems. Where a composition or pharmaceutical composition of the present invention is used as an injection or infusion, it is desirable to have a pH value in an approximately neutral pH range, it is also advantageous to minimize surfactant levels to avoid bubbles in the formulation which are detrimental for injection into subjects. In an embodiment, the composition or pharmaceutical composition is in liquid form and stably supports high concentrations of M ANH in solution and is suitable for inhalational or parenteral administration. In an embodiment, the composition or pharmaceutical composition is suitable for intravenous, intramuscular, intraperitoneal, intradermal, intraorgan, and/or subcutaneous injection. In an embodiment, the composition or pharmaceutical composition is in liquid form and has minimized risk of bubble formation and anaphylactoid side effects. In an embodiment, the composition or pharmaceutical composition is isotonic. In an embodiment, the composition or pharmaceutical composition has a pH or 6.8 to 7.4.

[0040] Examples of pharmaceutically acceptable carriers include, but are not limited to, phosphate buffered saline solution, sterile water (including water for injection USP), emulsions such as oil/water emulsion, and various types of wetting agents. Preferred diluents for aerosol or parenteral administration are phosphate buffered saline or normal (0.9%) saline, for example 0.9% sodium chloride solution, USP. Compositions comprising such carriers are formulated by well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990; and Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000, the content of each of which is hereby incorporated in its entirety). In non-limiting examples, the can comprise one or more of dibasic sodium phosphate, potassium chloride, monobasic potassium phosphate, polysorbate 80 (e.g. 2-[2-[3,5-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl (E)-octadec- 9-enoate), disodium edetate dehydrate, sucrose, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate dihydrate.

[0041] In an embodiment the composition or pharmaceutical composition comprising the MANF described herein is substantially pure with regard to the MANF. A composition or pharmaceutical composition comprising the MANF described herein is "substantially pure" with regard to the MANF when at least 60% to 75% of a sample of the composition or pharmaceutical composition exhibits a single species of the MANF. A substantially pure composition or pharmaceutical composition comprising the MANF described herein can comprise, in the portion thereof which is the MANF, 60%, 70%, 80% or 90% of the MANF, more usually about 95%, and preferably over 99%. Purity or homogeneity may be tested by a number of means well known in the art, such as polyacrylamide gel electrophoresis or HPLC.

[0042] In an embodiment, the MANF is a recombinantly-produced MANF. In an embodiment, the MANF has the sequence of a human MANF. In an embodiment, the MANF comprises the amino acid sequence set forth in SEQ ID NO: 1.

[0043] In an embodiment the nucleic acid encoding MANF is an mRNA. In an embodiment, the nucleic acid encoding MANF is administered via a lipid nanoparticle composition comprising the mRNA.

[0044] Administration can be local. Administration can be performed in a manner so as to not elicit systemic effects. Administration can be intramuscular or subcutaneous. Administration can be via infusion or injection. Administration can also be direct to an affected body part where peripheral neuropathy symptoms are occurring or expected to occur. Administration can be via local injection. Administration can also be auricular, buccal, conjunctival, cutaneous, subcutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, via hemodialysis, interstitial, intrab dominal, intraamniotic, intra-arterial, intra-articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavernous, intracavitary, intracerebral, intraci sternal, intracorneal, intracoronary, intradermal, intradiscal, intraductal, intraepidermal, intraesophagus, intragastric, intravaginal, intragingival, intraileal, intraluminal, intralesional, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intraepicardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intraorgan, intratympanic, intrauterine, intravascular, intravenous, intraventricular, intravesical, intravitreal, laryngeal, nasal, nasogastric, ophthalmic, oral, oropharyngeal, parenteral, percutaneous, periarticular, peridural, rectal, inhalationally, retrobulbar, subarachnoid, subconjuctival, sublingual, submucosal, topically, transdermal, transmucosal, transplacental, transtracheal, ureteral, uretheral, and vaginal.

[0045] Symptoms of peripheral neuropathy, that can be ameliorated or prevented by the methods herein, include one or more of numbness and tingling in the feet or hands; burning, stabbing or shooting pain in affected areas; loss of balance and co-ordination; muscle weakness, including in the feet or hands [0046] In embodiments, the MANF is administered at a dose of 0.1 pg/kg to 1 pig/kg. In embodiments, the MANF is administered at a dose of 0.5 pg/kg to 5 pg/kg. In embodiments, the MANF is administered at a dose of 1.5 pg/kg to 2.5 pg/kg. In embodiments, the MANF is administered at a dose of 0.5 pg/kg to 500 pg/kg. In embodiments, the MANF is administered at a dose of 0.5mg/kg to 100 mg/kg. In embodiments, the MANF is administered at a dose of 101 mg/kg to 250 mg/kg. In embodiments, the MANF is administered at a dose of 251 mg/kg to 500 mg/kg. In embodiments, the MANF is administered at a dose of 501 mg/kg to 1000 mg/kg. In embodiments, the MANF is administered at a dose of 1001 mg/kg to 2000 mg/kg. In embodiments, the MANF is administered at a dose indicated herein once per day, twice per daily, daily, every other day, weekly, monthly or every three months. In embodiments, the MANF is administered at a dose of 25 to 100 mg twice daily, daily, every other day, weekly, monthly or every three months. In embodiments, the MANF is administered at a dose of 1.5 pg/kg to 2.5 pg/kg twice daily, daily, every other day, weekly, monthly or every three months. In embodiments, the MANF is administered at a dose of 100 to 250 mg twice daily, daily, every other day, weekly, monthly or every three months. In embodiments, the MANF is administered at a dose of 250 to 500 mg twice daily, daily, every other day, weekly, monthly or every three months. In embodiments, the MANF is administered at a dose of 500 to 1000 mg twice daily, daily, every other day, weekly, monthly or every three months. In embodiments, the MANF is administered at a dose of 1000 to 2000 mg twice daily, daily, every other day, weekly, monthly or every three months.

[0047] Another aspect of the invention provides a method for the prevention, treatment or amelioration of a peripheral neuropathy. According to this aspect, the MANF composition as disclosed hereinabove is administered to a subject in need of such a prevention, treatment or amelioration.

[0048] In a preferred embodiment, the method of peripheral neuropathy prevention, treatment or amelioration occurs in a human.

[0049] “And/or” as used herein, for example, with option A and/or option B, encompasses the separate embodiments of (i) option A, (ii) option B, and (iii) option A plus option B.

[0050] All combinations of the various elements described herein are within the scope of the invention unless otherwise indicated herein or otherwise clearly contradicted by context. [0051] Definitions: The terms used in this specification generally have their ordinary meanings in the art, within the context of this invention and the specific context where each term is used. Certain terms are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner in describing the methods of the invention and how to use them. Moreover, it will be appreciated that the same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of the other synonyms. The use of examples anywhere in the specification, including examples of any terms discussed herein, is illustrative only, and in no way limits the scope and meaning of the invention or any exemplified term. Likewise, the invention is not limited to its preferred embodiments.

[0052] The term “subject” as used in this application means a mammal. Mammals include canines, felines, rodents, bovine, equines, porcines, ovines, and primates including humans. Thus, the invention can be used in human medicine or also in veterinary medicine, e.g., to treat companion animals, farm animals, laboratory animals in zoological parks, and animals in the wild. The invention is particularly desirable for human medical applications. In a preferred embodiment the subject is a human.

[0053] The terms “treat”, “treatment” of a disease, and the like refer to slowing down, relieving, ameliorating or alleviating at least one of the symptoms of the peripheral neuropathy, or reversing the disease after its onset.

[0054] The terms “prevent”, “prevention”, and the like refer to acting prior to overt disease or disorder onset, to prevent the disease or disorder from developing or minimize the extent of the peripheral neuropathy or slow its course of development.

[0055] The term “in need thereof’ with regard to a subject would be a subject known or suspected of having or being at risk of developing peripheral neuropathy.

[0056] The terms “therapeutically effective amount” or "amount effective to" encompasses an amount sufficient to ameliorate or prevent a symptom or sign of the medical condition. An effective amount for a particular subject may vary depending on factors such as the condition being treated, the overall health of the patient, the method route and dose of administration and the severity of side effects. An effective amount can be the maximal dose or dosing protocol that avoids significant side effects or toxic effects.

[0057] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system, i.e., the degree of precision required for a particular purpose, such as a pharmaceutical formulation. For example, “about” can mean within 1 or more than 1 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0058] In embodiments of the methods herein, the subject is a human subject.

[0059] In embodiments of the methods herein, the MANF comprises the amino acid sequence as set forth in SEQ ID NO:1 hereinbelow.

[0060] In embodiments of the methods herein, the MANF is administered.

[0061] In embodiments of the methods herein, the nucleic acid encoding MANF is administered. In embodiments of the methods herein, the nucleic acid comprises an mRNA encoding the MANF. In embodiments of the methods herein, the mRNA is administered in the form of a lipid nanoparticle composition comprising the mRNA.

[0062] In an embodiment, the MANF has the sequence of a human MANF. In an embodiment, the MANF comprises the following sequence:

LRPGDCEVCISYLGRFYQDLI<DRDVTFSPATIENELII<FCRFARGI<ENRLCYYIGATDDA ATKIINEVSKPLAHHIPVEKICEKLKKKDSQICELKYDKQIDLSTVDLKKLRVKELKKILD DWGETCKGCAEKSDYIRKINELMPKYAPKAASARTDL (SEQ ID NO: 1).

[0063] In an embodiment, the MANF has the sequence of a human MANF set forth in Uniprot ID P55145. In an embodiment, the MANF is non-glycosylated. EXPERIMENTAL EXAMPLES

[0064] How macrophages transition between pro- and anti-inflammatory status in a

Drosophila CIPN model: Macrophages are one of the major drivers of painful CIPN (2,3,5,12,41), yet how they transition throughout pathological progression is poorly understood. Single-cell RNAseq analyses of Drosophila immune cells (26,27) and our initial results highlight the diversity of activated macrophages after cellular stress. Moreover, there are at least 14 different clusters of Drosophila immune cells that become differentially activated following wasp attack and injury (27). The mechanisms of macrophage activation in the context of sensory neuron pathology in CIPN will be characterized. Targets, such as mesencephalic astrocyte- derived neurotrophic factor (MANF), are identified to locally modulate immune responses (42) in CIPN. In addition, because many genes expressed in Drosophila macrophages are conserved in the mammalian system (43), the study provides an invaluable in vivo model to understand the pathological progression and specific treatment targets for CIPN.

[0065] Paclitaxel (PTX)-induced macrophage activation precedes neuronal degeneration in Drosophila in vivo: A recent study by this laboratory established a timeline of pathological stages in PTX-induced peripheral neuropathy in mouse and Drosophila CIPN models and revealed that intracellular changes precede morphological changes in sensory neuron degeneration. Initial changes in both models include a reduction in motility of recycling endosomes (Rab4⁺) and lysosomes (40) We identified early (24h), intermediate (48h), and late (72h) pathological stages in our Drosophila CIPN model (Fig. 1). Behavioral studies in the literature (24 and 48h) (44) and our preliminary analysis at 72h support an emergence of hypersensitivity to noxious heat during pathological progression.

[0066] Administration of recombinant human MANF proteins protects DRG neurons from PTX toxicity: Due to MANF’s highly conserved role in Drosophila and mammalian models (42,56,59), we tested the protective capacity of MANF in an adult mouse CIPN model optimized in our previous study (40). We administered recombinant human (rh) MANF proteins in DRG culture and compared neuronal integrity and growth to vehicle controls lacking MANF supplementation. Initial results disclosed herein indicate that MANF protects from PTX-induced degeneration and neurite reduction (Fig. 7), supporting a conserved protective role for MANF. Because MANF is directly involved in immune cell differentiation and anti-inflammatory status (42,59,61,74), the effect of the MANF-mediated protection is also directly applicable to macrophages.

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Claims

1. A method of preventing, reducing development of, or treating a peripheral neuropathy in a subject, comprising administering to the subject an amount of a mesencephalic astrocyte-derived neurotrophic factor (MANF), or a nucleic acid encoding therefor, effective to treat a peripheral neuropathy.

2. The method of Claim 1, wherein the peripheral neuropathy is a chemotherapy-induced peripheral neuropathy (CIPN).

3. The method of Claim 1 or 2, wherein the peripheral neuropathy is a taxane-induced peripheral neuropathy.

4. The method of Claim 3, wherein the peripheral neuropathy is a paclitaxel-induced peripheral neuropathy.

5. The method of any of Claims 2-4, wherein the method is of preventing or reducing the development of the CIPN and wherein the MANF, or nucleic acid encoding therefor, is administered prior to the subject receiving chemotherapy.

6. The method of Claim 5, further comprising administering MANF, or nucleic acid encoding therefor, to the subject during a period of chemotherapy administration.

7. The method of any of Claims 2-4, wherein the method is of treating an extant CIPN and the MANF, or nucleic acid encoding therefor, is administered during and/or subsequent to the subject receiving chemotherapy.

8. The method of any of Claims 2-7, wherein the CIPN is acute transient CIPN.

9. The method of any of Claims 2-7, wherein the CIPN is sub-acute long-lasting CIPN. The method of Claim 1 , wherein the peripheral neuropathy is an idiopathic peripheral neuropathy. The method of Claim 10, wherein the idiopathic peripheral neuropathy is an aging-related idiopathic peripheral neuropathy. The method of Claim 11, wherein the peripheral neuropathy is a sensory small fiber peripheral neuropathy. The method of Claim 12, wherein the sensory small fiber peripheral neuropathy is a prediabetic neuropathy, a diabetic neuropathy, an HIV neuropathy, an amyloid neuropathy, or an inflammatory neuropathy. The method of Claim 13, wherein the peripheral neuropathy is a diabetic peripheral neuropathy. The method of Claim 14, wherein the subject has type I diabetes. The method of Claim 14, wherein the subject has type 2 diabetes mellitus. The method of any of Claims 1-16, wherein the MANF, or nucleic acid encoding therefor, is administered locally to a site of the peripheral neuropathy. The method of any of Claims 2-9, wherein the MANF, or nucleic acid encoding therefor, is locally administered to hands and/or feet of the subject. The method of any of Claims 2-9, wherein the subject is not being treated with a non- taxane chemotherapy. The method of any of Claims 1-9, 17, 18 or 19, further comprising diagnosing the subject as suffering from a taxane-induced peripheral chemotherapy or as susceptible to a taxane- induced peripheral chemotherapy, prior to administering the MAW, or nucleic acid encoding therefor, to the subject. The method of any of Claims 1 or 10-19, further comprising diagnosing the subject as suffering from an idiopathic or sensory small fiber peripheral neuropathy or as susceptible to an idiopathic or sensory small fiber peripheral neuropathy, prior to administering the MANF, or nucleic acid encoding therefor, to the subject. A method of reducing taxane-induced macrophage activation in a subject receiving a taxane treatment, or who is to receive a taxane treatment, comprising administering to the subject an amount of a mesencephalic astrocyte-derived neurotrophic factor (MANF) , or nucleic acid encoding therefor, effective to treat a peripheral reducing taxane-induced macrophage activation in a subject. A method of reducing peripheral pain in a subject associated with activated pro- inflammatory macrophages comprising locally administering to the area of peripheral pain an amount of a mesencephalic astrocyte-derived neurotrophic factor (MANF), or nucleic acid encoding therefor, effective to reduce the peripheral pain. The methods of any of Claims 1-23, wherein the subject is a human subject. The methods of any of Claims 1-24, wherein the MANF comprises the amino acid sequence as set forth in SEQ ID NO:1. The method of any of Claims 1-25, wherein the MANF is administered. The method of any of Claims 1-25, wherein the nucleic acid encoding MANF is administered. The method of Claim 27, wherein the nucleic acid comprises an mRNA encoding the MANF.

29. The method of Claims 28, wherein the mRNA is administered in the form of a lipid nanoparticle composition comprising the mRNA.