Using p62 for prevention and treatment of chronic pain

Abstract

A method to alleviate chronic pain in humans and animals is disclosed. It comprises administering to said subject p62 / SQSTM1 polypeptide, p62 / SQSTM1 encoding nucleic acid, or mesenchymal stem cells expressing a p62-encoding vector or pretreated to increase the level of p62 protein encoded by the cell's chromosome or secretome from such cells.

Description

USING P62 FOR PREVENTION AND TREATMENT OF CHRONIC PAIN

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 720,185, filed on November 14, 2024, and incorporated herein by reference in its entirety.INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED AS AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM

[0002] The content of the file “0030-0014WO.xml,” created on January 14, 2026, and sized 6,166 bytes, is incorporated herein by reference in its entirety. In that file, Sequence ID No. 1 is the wild-type nucleic acid sequence of human p62, and Sequence ID No. 2 is the wild-type amino acid sequence of human p62.FIELD OF THE INVENTION

[0003] The disclosure relates to new treatment methods for various types of chronic pain, including methods that use compositions containing p62 / SQSTMl DNA or protein.BACKGROUND

[0004] Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Pain is currently classified as acute, subacute, or chronic. Chronic pain is persistent or recurrent pain that extends beyond the typical healing process, often arbitrarily defined as lasting 3 months. Chronic pain is exceptionally disabling, and assessments of the global burden of disease consistently rank headache and low back pain among the leading causes of global disability. Chronic pain is not only a bothersome symptom but also a disease, an important health issue worldwide that imposes a considerable social and economic burden. More than 30% of adults worldwide are estimated to suffer from pain. In the United States, approximately 20% of adults (52 million people) suffer from chronic pain, creating a substantial personal and societal burden and costing the economy up to $635 billion per year. Chronic pain often leads to other symptoms and conditions, including generalized anxiety disorder, major depressive disorder, fatigue, insomnia, irritability, and mood swings.

[0005] Common types of chronic pain include arthritis or joint pain (e g., knee pain), back pain, headaches, including migraines, cancer pain, neck pain, neuropathic (nerve) pain, fibromyalgia, and chronic skin pain (e.g., dermatitis, psoriasis).

[0006] A range of medications and interventions have been developed to treat chronic pain. However, they provide only limited relief and can cause problems (Table 1). For instance, the most common pain medication, nonsteroidal anti-inflammatory drugs (NSAIDs), while relieving some forms of pain, may cause gastrointestinal problems and, at higher doses, kidney problems (Table 1). More effective pain medications, such as opioids, often lead to addiction, and as a result, opioids currently cause the most prescription medication-related overdose deaths in the US. Many current methods for relieving pain lack solid evidence from long-term, randomized clinical trials. There is no high-quality evidence that patients benefit from many of the surgical procedures prescribed to treat chronic pain, such as dorsal rhizotomies, spinal fusions, and arthroscopies. Orthopedics assumes that correcting tissue anatomy will resolve pain, but in many cases, placebo surgery may be just as effective, and overall cure rates from these procedures remain low. Additionally, these treatments can often cause serious complications. Therefore, there is an urgent need for more effective chronic pain medications with fewer side effects.Medication Work First LineBenefits Side Effects Type Mechanism Option forMild tomoderate pain May cause accompanied nausea, stomach by swelling pain, stomach and bleeding, or When taken asinflammation ulcers Block COX-1 directed,Arthritis pain When taken in and COX-2 generally safeand p high doses, can enzymes ain for short- andNSAIDs resulting from lead to kidney involved in long-term usemuscle sprai problems, fluid pain and nsAvailableand strains, retention, and inflammation without aback and neck high blood prescriptioninjuries, pressure overuse Increased risk of injuries, and side effects for menstrual older adults crampsWhen more than the Thought torecommended blockdose is taken or prostaglandin AvailableMild to when taken with Acetaminophen production in without amoderate pain alcohol, the central prescriptionincreased risk of nervouskidney damage systemand liver failure over timeMedication Work First LineBenefits Side Effects Type Mechanism Option forHeadache and dizziness When taken in high doses, can Rheumatoid As effective aslead to stomach arthritis, NSAIDsbleeding, kidney osteoarthritis, withoutCOX-2 Block COX-2 problems, fluid menstrual damaginginhibitors enzymes retention, high cramps and stomach liningblood pressure, injury-related at regularheart attack, and pain dosesstroke Increased risk of side effects for older adultsDrowsiness Can be used in possible with doses much tricyclic Neuropathic lower than antidepressants pain, chronic what is Can take several Interfere withheadaches, currently used weeks to certainfibromyalgia to treat produce desired Antidepressants chemicalMay be depression effects processes thatconsidered for Side effectscause pain May worsen chronic low generally mild, depression and back pain depending on cause suicidal the type of thoughts in a antidepressant small number of peopleMedication Work First LineBenefits Side Effects Type Mechanism Option forMay cause dizziness, drowsiness, nausea, reduced PostherpeticQuiet pain coordination and neuralgia,Anti-seizure signals from Side effects weight changes diabeticmedications damaged generally mild May worsen neuropathy,nerves depression and fibromyalgiacause suicidal thoughts in a small number of peopleFeeling drowsy, nausea, Blocks opioid Acute pain,itchiness, receptors, such as painconstipation which stop the that followsrelease of surgery or a Powerful relief Tolerance,during shortc dependence, Opioids hemicals that bone fractureperiods ofcause pain misuse,Typically,severe pain addiction and Can stop the prescribed foroverdose, which transmission a few days ormay begin to of pain signals lessdevelop within one week of useTable 1. Pain medications

[0007] Inflammation in the pathogenesis of chronic pain

[0008] Inflammation is associated with pain and multiple disease outcomes and is characterized by five typical signs: redness, swelling, heat, pain, and loss of function. Inflammation can be divided into three types according to the progression of the underlying pathology in the injured tissue: (1) acute inflammation occurs shortly after injury and persists for a few days; (2) chronic inflammation occurs when acute inflammation fails to resolve and may last for several months or even years; and (3) subacute inflammation is a transitional period spanning the acute to the chronic stage, lasting from 2 to 6 weeks.

[0009] Apart from acute inflammation, which is transient and can be beneficial, for instance, in protecting organisms from pathogens, chronic inflammation is maladaptive and often leads to considerable chronic pain. Inflammatory pain disorders include pain caused by inflammation generally elicited by some noxious insult or degeneration, for example, osteoarthritis, autoimmune conditions (e.g., lupus), rheumatoid arthritis, and tissue trauma, where immune cells are recruited and secrete inflammatory mediators that directly cause peripheral sensitization and later central sensitization.

[0010] Overwhelming evidence supports neuroinflammation’s fundamental role in pain; however, its pathogenic mechanisms remain incompletely elucidated. A neuroinflammatory state is characterized by glial cell activation, the generation of pro-inflammatory mediators (cytokines and chemokines, among others), and vascular changes. These changes increase permeability, leukocytic infiltration, and alterations in gene expression.

[0011] During inflammatory responses, macrophages and Schwann cells can release pro-inflammatory cytokines, including IL- 1 and IL-6 (where IL stands for interleukins) and tumor necrosis factor (TNF), as well as anti-inflammatory cytokines, including IL -4 and IL- 10, to regulate the inflammatory process. These factors contribute to chronic neuropathic pain. Given the critical role of inflammation (including neuroinflammation) in the induction and maintenance of chronic pain, it may be practical to directly target inflammation by modulating cytokines, chemokines, and other mediators. However, except for NSAIDs, which have limited efficacy and side effects (Table 1), no other anti-inflammatory drugs are currently approved for chronic pain treatment.

[0012] The musculoskeletal system is a leading source of chronic pain, with osteoarthritis (OA) as the leading cause. As the most prevalent form of arthritis, OA affects over 32.5 million US adults. Worldwide, 240 million individuals live with symptomatic OA, and its prevalence is increasing as the world’s population ages. OA is associated with an increased risk of all-cause mortality, often due to reduced mobility. OA is a multifactorial, mostly slowly progressive degenerative disorder of the synovial joints that is frequently age-related and / or trauma-induced. OA is characterized by degradation of articular cartilage and bone matrix components, leading to loss of cartilage structure and function. Beyond structural deterioration in OA joints, pain is a dominant and probably the most debilitating hallmark of OA pathology. This is the main reason0030-0014WQpatients experience reduced physical mobility. The sources of OA pain include nociceptive, inflammatory, and neuropathic pain, as well as peripheral and central sensitization. Structural features such as bone marrow lesions (BMLs), synovitis, and joint effusion strongly correlate with pain intensity

[0013] Considerable effort has been devoted to OA-related pain research to identify underlying mechanisms, but due to its complexity, no general guidelines for effective treatment have been established. As with other chronic pain conditions, classical treatments for OA include acetaminophen (paracetamol), NSAIDs, and opioids, which cause a plethora of unwanted side effects (Table 1). Despite massive efforts to develop new OA treatments, pain reduction in OA remains relatively unsuccessful. So far, biologies targeting the inflammatory cytokines IL-1, IL-6, and TNF-a have not prevented pain or structural progression of OA.BRIEF SUMMARY

[0014] Chronic pain is a significant health issue worldwide, imposing a considerable social and economic burden. A range of medications and interventions have been developed to treat chronic pain. However, these treatments provide only limited relief and have numerous side effects. Disclosed are methods for treating chronic pain based on the p62 protein, also known as sequestosome 1 (SQSTM1), or on plasmid DNA encoding p62 / SQSTMl. Also disclosed are formulations and treatment protocols for preventing and alleviating chronic pain.

[0015] Disclosed is a method for treating, alleviating, ameliorating, relieving, delaying the onset of, inhibiting the progression of, or reducing the severity of chronic pain in a human or animal subject, comprising administering to the subject p62-encoding nucleic acid or a p62 polypeptide.

[0016] Chronic pain may include arthritis or joint pain, back pain, headaches, migraines, cancer pain, neck pain, neuropathic pain, fibromyalgia, or skin pain.

[0017] The p62-encoding nucleic acid or the p62 polypeptide may comprise one or more domain deletions relative to Sequence ID No. 2.

[0018] The p62-encoding nucleic acid may encode a p62 polypeptide at least 95% identical to Sequence ID No. 2

[0019] The p62 polypeptide may be at least 95% identical to Sequence ID No. 2.

[0020] The p62-encoding nucleic acid may be a plasmid, an RNA, a cosmid, a virus, a viral particle, or a bacterium that comprises a p62 plasmid or a p62 RNA.

[0021] The p62-encoding nucleic acid or the p62 polypeptide may be administered by injection, intramuscularly, orally, topically, subcutaneously, per rectum, intranasally, via a microbiome carrier, intraocularly, subdermally, or by inhalation.

[0022] Disclosed is a method for treating, alleviating, ameliorating, relieving, delaying the onset of, inhibiting the progression of, or reducing the severity of chronic pain in a human or animal subject, comprising administering mesenchymal stem cells (MSCs) to the subject, wherein the MSCs express a p62-encoding vector or are pretreated to increase the level of p62 protein encoded by their chromosomes.

[0023] The methods may further comprise isolating the MSCs from a subject, another human subject, a healthy donor, an umbilical cord, an embryo, or a non-human subject, and transfecting the MSCs with a pharmaceutical formulation comprising a p62-encoding nucleic acid or a p62 polypeptide.

[0024] The methods may further include infecting MSCs with p62-expressing viruses.

[0025] The MSCs may be propagated ex vivo before administration to the subject.

[0026] Disclosed is a method for treating, alleviating, ameliorating, relieving, delaying the onset of, inhibiting the progression of, or reducing the severity of chronic pain in a human or animal subject, comprising administering to the subject a secretome from cells expressing a p62-encoding nucleic acid or from cells pretreated to increase the level of p62 protein encoded by the cells’ chromosomes.

[0027] The secretome may be obtained by transfecting MSCs with a p62-encoding plasmid, RNA, or cosmid, or by infecting MSCs with p62-expressing viruses, propagating the MSCs ex vivo, collecting conditioned medium (secretome) from the MSCs, and administering the secretome to the subject.

[0028] The cells may be obtained from the subject, from another human of the same species, or from a non-human organism.

[0029] The cells may be MSCs.0030-0014WQ

[0030] The methods may further comprise administering a drug, performing a procedure, or applying a method to the subject to prevent, treat, alleviate, ameliorate, relieve, delay the onset of, inhibit the progression of, or reduce the severity of chronic pain.

[0031] Cells or the secretome may be frozen and thawed before administration.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 shows changes in the components of the Canine Brief Pain Inventory (CBPI) scores, namely the pain severity score (PSS; 0-10) and the pain interference score (PIS; 0-10), after treatment with the p62 plasmid.

[0033] Figure 2 shows the dynamics of the CBPI score during treatment with the p62 plasmid.

[0034] Figure 3 shows the Spearman correlation coefficient (p) for each subjective chronic pain assessment parameter (CBPI score) following p62 plasmid treatment.DETAILED DESCRIPTION

[0035] p62 Plasmid Alleviates Chronic Pain in Dogs with Osteoarthritis

[0036] OA in dogs closely resembles human OA and is characterized by clinical signs such as stiffness, lameness, and gait alterations, all associated with chronic pain. A study of the p62 plasmid was conducted in client-owned dogs weighing > 3 kg, of any age, sex, or breed, with a medical history, clinical signs, physical examination findings, and radiographic findings consistent with OA. Radiographic findings, as interpreted by radiologists, include subchondral bone sclerosis, bone remodeling, osteophytes, and irregular or diminished joint space in at least one joint. Only dogs with an OA diagnosis made during screening for the study who had not commenced any treatment (including nutraceuticals, special diets, and over-the-counter supplement-type products) and dogs with a prior OA diagnosis that the owners had elected not to treat are eligible for inclusion in the study. Animals are confirmed to be in good general health based on a general physical examination and routine blood tests.

[0037] Procedures and Outcome Measurement

[0038] The dogs receive EV, 1 mg intramuscularly (IM) once weekly for 10 weeks. Efficacy is assessed weekly by the owners using the Canine Brief Pain Inventory (CBPI). The CBPI comprises three domains: the pain severity score (PSS, 0-10 scale), the pain interference score0030-0014WQ(PIS, 0-10 scale), and the owner’s overall impression of quality of life (QoL, “poor,” “fair,” “good,” “excellent”). To be eligible for the study, an initial PSS > 2 and / or PIS > 2 is required.

[0039] The primary efficacy endpoint is treatment success at 10 weeks, as assessed by the owner using the CBPI. Treatment success was defined as a reduction of more than 1 in PSS (0—10; 0 — no pain, 10 — extreme pain) and > 2 in PIS (0-10; 0 — no pain, 10 — extreme pain), following the CBPI author’s recommendation, compared with pre-treatment (baseline). Secondary efficacy endpoints included CBPI-based treatment success at all other assessed time points, owner-assessed PSS and PIS scores, QoL, and the percentage of dogs classified as having good or excellent QoL at the final time point.

[0040] Patient Characteristics

[0041] Table 2 presents the characteristics of the dogs enrolled in the study. As expected, most dogs with OA are large breeds (e.g., 6 of 17 are Labradors) and relatively old (median age: 9 years), although smaller and younger dogs were also present (e.g., a 5-year-old Spitz, #9, in Table 2). All dogs showed chronic OA on radiographic findings and clinical signs but were otherwise healthy.Dog # Sex Age Weight Breed1 F 11.5 35 Doberman2 M 4.5 34 Akita3 M 8.5 6 Mixed4 M 6.5 50 Beninese Mountain Dog5 F 13.5 49 South Russian Shepherd Dog6 F 13 6 Mixed7 F 11 35 Labrador Retriever8 F 8 35 Labrador Retriever9 M 5 3 Pomeranian Spitz10 F 9.5 35 Labrador Retriever11 F 11.5 32 German Shepherd12 F 11 35 Labrador Retriever13 M 14 40 Labrador Retriever14 M 12 40 Labrador RetrieverDog # Sex Age Weight Breed15 M 6 3.2 Yorkshire Terrier16 F 6 9.5 Beagle17 F 7.5 7.5 Fox TerrierMedian 9 28Range 4-14 3-50Table 2. Patient characteristics

[0042] Efficacy of EV Treatment in Dogs with OA

[0043] The dogs enrolled in the study were treated intramuscularly with 1 mg of p62 plasmid once weekly for 10 weeks. As in previous studies in dogs and humans, no adverse treatment effects were observed. To assess the treatment effect on chronic pain, dog owners administered a standard CBPI test weekly. Changes in the main components of CBPI, the pain severity score (PSS), pain interference score (PIS), and quality of life (QoL), in individual dogs after treatment are presented in Table 3 and Fig. 1.0030-0014WQTable 3. Efficacy of p62 plasmid treatment in dogs with OA

[0044] According to the CBPI assessment, only one dog (#13) shows a slight worsening in CBPI scores, less than 1 unit, and this dog is the oldest in the population (14-year-old LabradorRetriever) (Table 3). Another dog, #9, shows a decline in QoL (from fair to poor), and this is the smallest dog (Pomeranian Spitz). All other dogs show varying degrees of improvement across all three CBPI components, with some (#3 and #8) showing complete resolution of OA symptoms by the end of treatment (Table 1). Thus, EV treatment was effective in 15 of 17 dogs (90%).

[0045] Changes in PSS and PIS scores for all dogs are presented in Fig. 1. Both PSS and PIS scores decreased significantly by the end of treatment. Specifically, the average PSS score decreased from 5.25 to 3.25 (p<0.001), and the average PIS score from 7.0 to 3.17 (p<0.001). A significant improvement in QoL was also observed: while only 6% of dogs had good QoL before treatment, this increased to 53% after treatment (Fig. 1).QoL, p<0.001 Before AfterPoor (0) 1 (5.9%) 1 (5.9%)Fair (1) 15 (88%) 4 (24%)Good (2) 1 (5.9%) 9 (53%)Excellent (3) 0 (0%) 3 (18%)Table 4. Change in QoL of dogs after the treatment with p62 plasmid, n (%)

[0046] The next question is how each of the 10 components of chronic pain (CBPI score) changes before and during treatment in the entire dog population. A positive effect of the treatment on all parameters was observed primarily after 2-4 weeks of treatment, whereas after 5-6 weeks, the parameters reached a plateau (Fig. 2).

[0047] Spearman correlation coefficients are calculated for each subjective assessment to understand the relationship between the duration of injection time and behavioral scores (Fig. 3). The calculations show that for all ten parameters of CBPI scores, there is a clear inverse correlation between scores and the time of treatment, with several parameters (e.g., pain levels) close to -1.0 (Fig. 3). Overall, the correlation of all parameters with the time of treatment demonstrates statistical significance ranging from 4><10‘6to 0.0014 (Fig. 3).

[0048] Treatment with EV significantly improves all 11 chronic pain parameters (CBPI) as well as PSS, PIS, and QoL (Fig. 1, Tables 3-4). Specifically, the mean PSS score decreased from 5.25 to 3.25 (1.6-fold), the PIS score from 7.0 to 3.27 (2.2-fold), and the number of dogs with excellent or good QoL increased from 1 to 12 (Table 3). Overall, the treatment success rate (i.e., a reduction >1 in PSS and >2 in PIS) is 90%. Importantly, as in previous studies with dogs andhumans, no EV-related side effects were observed during the entire treatment period. Based on this data, the p62 plasmid may be considered a safe and effective medicine for OA treatment.

[0049] Embodiment 1

[0050] We administer a p62 / SQSTMl-encoding vector to treat, alleviate, ameliorate, relieve, delay the onset of, inhibit the progression of, and reduce the severity of chronic pain in a human or an animal suffering from chronic pain (for example, types of pain listed and / or mentioned in this disclosure). For example, we administer a plasmid, DNA, RNA, or viral vector encoding p62 and observe prevention and / or alleviation of pain relative to expectations without treatment. The patient feels more comfortable and suffers less. The p62 can be a gene encoding a full-length protein or an isoform lacking one or more domains. Alternatively, it can be gene-altered with codon optimization. It also can be a p62 with one or more amino acid substitutions or deletions. For example, we administer a p62-encoding vector topically at a site of chronic pain or systemically (e.g., intramuscularly, intravenously, subcutaneously, intranasally, intradermally, intraocularly, or per rectum) or topically and systemically in combination with other treatments.

[0051] Embodiment 2

[0052] We treat a human or an animal suffering from chronic pain (for example, a type of pain listed and / or mentioned in this patent). We isolate, propagate, and administer mesenchymal stem cells (MSCs) and / or any other cells transfected with a p62-encoding vector to treat, alleviate, ameliorate, relieve, delay the onset of, inhibit the progression of, or reduce the severity of chronic pain (for example, types of pain listed and / or mentioned in this patent). The cells may be transfected transiently or permanently (transduced) with a plasmid, DNA, RNA, or a viral vector encoding p62. Treatment with p62-expressing MSCs and / or another cell type results in the prevention and / or alleviation of pain compared to what would be expected without the treatment. The patient feels more comfortable and suffers less. For example, we administer p62-transfected / transduced MSCs topically at the site of pain, systemically, or both topically and systemically, in combination with other treatments.

[0053] Embodiment 3

[0054] We administer secretome from mesenchymal stem cells (MSCs) and / or any other cells transfected with a p62-encoding vector to treat, alleviate, ameliorate, relieve, delay the onset of,0030-0014WQinhibit the progression of, and reduce the severity of chronic pain in a human or an animal suffering from chronic pain (for example, types of pain listed and / or mentioned in this patent). The cells may be transfected transiently or permanently (i.e., via transduction) with a plasmid, DNA, RNA, or a viral vector encoding p62. Treatment with secretome collected from p62-expressing MSCs and / or another cell type results in pain prevention and / or alleviation compared to what would be expected without the treatment. The patient feels more comfortable and suffers less. For example, we administer the secretome of p62-transfected or transduced cells topically at the site of pain or systemically, or both topically and systemically, in combination with other treatments.

[0055] Embodiment 4

[0056] We administer p62 / SQSTMl protein to a human or an animal suffering from chronic pain (for example, types of pain listed and / or mentioned in this patent). The protein can be a full-length protein or an isofomi lacking one or more domains. It can also be a p62 with one or more amino acid substitutions or deletions. This treatment results in the prevention and / or alleviation of pain compared to what would be expected without the treatment. For example, we administer p62 / SQSTMl protein topically at the site of pain or systemically, or both topically and systemically, in combination with other treatments.

[0057] Embodiment 5

[0058] Practicing any of Embodiments 1-4 using a pharmaceutical carrier that facilitates (a) delivery to a body of p62-vector, p62-transfected cell, or secretome of p62-transfected cell; (b) penetration into a cell, and / or stability of p62-encoding vector. This treatment alleviates, ameliorates, relieves, delays the onset of, inhibits the progression of, and reduces the severity of chronic pain.

[0059] Embodiment 6

[0060] To prevent and treat chronic pain, practice any of Embodiments 1-5 alongside other treatments, including drugs and procedures. This treatment alleviates, ameliorates, and relieves chronic pain, delays its onset, inhibits its progression, and reduces its severity.

[0061] Embodiment 7

[0062] We treat a human or an animal suffering from chronic pain (for example, types of pain listed and / or mentioned in this patent). We isolate, propagate, and administer mesenchymal stemcells (MSCs) and / or any other cells treated with a method or agent that increases p62 expression in the cell, encoded by the cell's chromosome, to treat, alleviate, ameliorate, relieve, delay the onset of, inhibit the progression of, or reduce the severity of chronic pain (for example, types of pain listed and / or mentioned in this patent). For example, methods may include hypoxia during cell growth, transfection with a nucleic acid or protein that decreases suppression of p62 gene expression, transfection with a nucleic acid or protein that increases p62 gene expression, or transfection with a nucleic acid or protein that decreases p62 protein degradation. Treatment with MSCs and / or another cell type with elevated levels of p62 protein results in pain prevention and / or alleviation compared to what would be expected without the treatment. The patient feels more comfortable and suffers less. For example, we administer p62-transfected or transduced MSCs topically at the site of pain or systemically, or both topically and systemically, in combination with other treatments.

[0063] Embodiment 8

[0064] Practicing any of Embodiments 3 and 7, where the MSC is taken from the organism of a patient and then returned to the same patient (i.e., syngeneic cells), or taken from a different organism of the same species (for example, from another human, i.e., allogeneic cells), or taken from a different organism (for example, MSC taken from a pig, treated, and administered to a human or a dog, i.e., xenogeneic cells).

Claims

0030-0014WQCLAIMS1. A method for treating, alleviating, ameliorating, relieving, delaying the onset of, inhibiting the progression of, or reducing the severity of chronic pain in a human or animal subject, comprising administering to the subject p62-encoding nucleic acid or a p62 polypeptide.

2. A method of claim 1, wherein the chronic pain is arthritis or joint pain, back pain, headaches, migraines, cancer pain, neck pain, neuropathic pain, fibromyalgia, or skin pain.

3. The method of claim 1, wherein the p62-encoding nucleic acid or the p62 polypeptide comprises one or more domain deletions relative to Sequence ID No. 2.

4. The method of claim 1,wherein the p62-encoding nucleic acid encodes a p62 polypeptide at least 95% identical to Sequence ID No. 2, orwherein the p62 polypeptide is at least 95% identical to Sequence ID No. 2.

5. The method of claim 1, wherein the p62-encoding nucleic acid is a plasmid, an RNA, a cosmid, a virus, a viral particle, or a bacterium comprising a p62 plasmid or a p62 RNA.

6. The method of claim 1, wherein the p62-encoding nucleic acid or the p62 polypeptide is administered by injection, intramuscularly, orally, topically, subcutaneously, per rectum, intranasally, by a microbiome carrier, intraocularly, subdermally, or by inhalation.

7. A method for treating, alleviating, ameliorating, relieving, delaying the onset of, inhibiting the progression of, or reducing the severity of chronic pain in a human or animal subject, comprising:administering mesenchymal stem cells (MSCs) to the subject, wherein the MSCs express a p62-encoding vector or are pretreated to increase the level of p62 protein encoded by their chromosomes.

8. The method of claim 7 further comprising:isolating the MSCs from the subject, another human subject, a healthy donor, an umbilical cord, an embryo, or a non-human subject, andtransfecting the MSCs with a pharmaceutical formulation comprising a p62-encoding nucleic acid or a p62 polypeptide.0030-0014WQ9. The method of claim 7 further comprising:infecting MSCs with p62-expressing viruses.

10. The method of claim 7, wherein the MSCs are propagated ex vivo prior to administration to the subject.

11. A method to treat, alleviate, ameliorate, relieve, delay the onset of, inhibit the progression of, or reduce the severity of chronic pain in a human or animal subject, comprising:administering to the subject a secretome from cells expressing a p62-encoding nucleic acid or from cells pretreated to increase the level of p62 protein encoded by the cells’ chromosomes.

12. The method of claim 11, wherein the secretome is obtained by transfecting MSCs with a p62-encoding plasmid, p62-encoding RNA, or p62-encoding cosmid, or by infecting MSCs with p62-expressing viruses, propagating the MSCs ex vivo, collecting conditioned medium (secretome) from the MSCs, and administering the secretome to the subject.

13. The method of claim 11, wherein the cells are obtained from the subject, from another human organism of the same species, or from a non-human organism.14 The method of claim 11 , wherein the cells are MSCs.

15. The method of Claim 11 further comprising administering a drug, procedure, or method to the subject to prevent, treat, alleviate, ameliorate, relieve, delay the onset of, inhibit the progression of, or reduce the severity of chronic pain.

16. The method of Claim 11, wherein the cells or the secretome are frozen and defrosted before the administration.

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