TECHNICAL FIELD

Without limitation, some embodiments comprise methods and/or compositions comprising exosomes derived from mammalian cells and use of same in the research, diagnosis, and/or treatment of sensory and motor dysfunction, abnormal sensitivity, and neurotoxicity, including peripheral neuropathy induced by chemotherapies and to sensitize tumors to chemotherapies.

BACKGROUND

Cancer is a common cause of death worldwide. An unmet need remains for new and effective methods, systems, and compositions for the treatment of cancer and its associated side effects. Chemotherapy is the use of chemical substances to treat disease and in the sense of this invention refers primarily to the use of cytotoxic drugs (called chemotherapeutic drugs) to treat cancer. Chemotherapy in cancer consists of a personalized combination of potent chemotherapy drugs, designed to slow rapid cancer tumor growth, shrink tumors, kill cancer cells, and prevent the spread of cancer. The chemotherapeutic drugs prevent cells from replicating in the typical, out-of-control manner in which cancer cells divide. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common, serious side effects that can lead to dose reductions or early discontinuation of chemotherapy, reducing the efficacy of cancer treatments. It can cause debilitating symptoms and also significantly impacts the patient's quality of life. An estimated 30 to 40 percent of cancer patients treated with chemotherapy experience CIPN.

The peripheral nervous system (PNS) consists of sensory neurons running from stimulus receptors that inform the central nervous system (CNS) of the stimuli, and motor neurons running from the spinal cord to the effectors that take action. In CIPN, an anticancer drug could impair both sensory and motor functions. “Neuropathic pain” is defined by the International Association For The Study Of Pain (IASP) as “pain initiated or caused by a primary lesion or dysfunction in the nervous system” (IASP, Classification of chronic pain, 2ndEdition, IASP Press (2002), p. 210). For the purpose of this invention included under this heading or to be treated as synonymous is “Neurogenic Pain” which is defined by the IASP as “pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral or central nervous system”. In regards to this invention, the neuropathic pain treated according to this invention is restricted to the neuropathic pain resulting from chemotherapy, meaning being caused by the administration and use of a chemotherapeutic drug in chemotherapy. The most likely cause of this is neurotoxicity of the chemotherapeutic drug, especially peripheral neurotoxicity.

Patients will often experience symptoms usually starting in the hands and/or feet and creep up the arms and legs. Patients may in addition or alternatively experience symptoms ranging from a shooting and/or burning pain or sensitivity to temperature, for example, include sharp, stabbing pain. CIPN symptoms can also include hearing loss, blurred vision and change in taste. CIPN can make it difficult to perform normal day-to-day tasks like buttoning a shirt, sorting coins in a purse, or walking. In addition, the motor neuron dysfunction can manifest as cramps, difficulty with fine motor activities (e.g. writing or dialing a phone), gait disturbances, paralysis, spasms, tremors and weakness.

Peripheral neuropathy is a common complication of several classes of chemotherapeutic agents including taxanes (paclitaxel and docetaxel), platinum-based compounds (carboplatin, cisplatin, and oxaliplatin), and vinca alkaloids (vincristine and vinblastine). Because these agents are used to treat several prevalent cancers, chemotherapy-induced peripheral neuropathy (CIPN) is common in patients treated with chemotherapy. CIPN is manifested by the development of paresthesias, dysesthesias, loss of joint and vibration sense, and loss of deep tendon reflexes. The onset of symptomatic CIPN usually leads to reductions in dose(s) and/or interruptions of therapy, which can negatively impact cancer-related outcomes.

There are few effective pharmacological options to treat symptoms due to CIPN. Analgesics (i.e., opioids and nonsteroidal anti-inflammatory agents) are only modestly effective in treating symptoms from neuropathy. Tricyclic antidepressants (e.g., nortriptyline and amitriptyline) have been suggested as therapeutic options for neuropathy; however, there are few data to support their use in CIPN. One randomized trial evaluated nortriptyline for therapy of CIPN symptoms; this agent was found to be ineffective. Compared to other neuropathies or neuropathic pain syndromes, there is a resemblance to diabetic neuropathy with similar glove and stocking distribution and other symptoms, such as pain, paresthesias, and dysesthesias. However, treatments for diabetic neuropathies are not necessarily helpful for preventing or treating neuropathies associated with chemotherapy.

Given the prevalence of CIPN, and that it can be dose-limiting for several cytotoxic drugs, symptom control studies have been conducted looking at ways to prevent or alleviate established CIPN. The identification of alternate treatment strategies would be a welcome development for patients afflicted with CIPN. Outside of clinical trials, CIPN symptoms are commonly managed in a manner similar to other types of nerve pain, that is, with a combination of physical therapy, complementary therapies such as massage and acupuncture, and medications that can include steroids, antidepressants, anti-epileptic drugs, and opioids for severe pain. But these therapies have not demonstrated true efficacy for CIPN, and virtually all of the drugs to treat peripheral neuropathy carry side effects of their own.

The actual causes of CIPN, on the cellular and tissue level, is still largely a matter of speculation. Oxidative stress may play a key role in CIPN. It was found that antioxidant machinery (e.g. plasma glutathione (GSH) and α- and γ-tocopherol concentrations) of cancer patients with chemotherapy decreased and the GSH redox state became more oxidized. In a rat model of painful oxaliplatin-induced neuropathy, oxidative stress was found to be an important component that mediates pain. In the plasma of oxaliplatin-treated rats, the increase in carbonylated protein and thiobarbituric acid reactive substances in the sciatic nerve and the spinal cord indicated the resultant protein oxidation and lipoperoxidation in these locations, respectively. Oxidative imbalance manifests itself as a mediator of inflammatory pain as well. Use of the anticancer drug cisplatin results in severe cell death of sensory neurons derived from dorsal root ganglia following increase in oxidative stress. Oxidative stress is also found to impair the autonomic nervous system and manifests itself in symptoms such as hearing loss. The results from antioxidants also support a key role of oxidative stress in mediating CIPN. The antineuropathic effect of antioxidant silibinin or α-tocopherol shows as about 50% oxaliplatin-induced behavioral alterations. Administration of anticancer drug bortezomib or oxaliplatin, which elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyllysine, a by-product of oxidative stress. Short-term systemic treatment with either antioxidants could completely prevent hypersensitivity if administered before the cytotoxic drug. The findings highlight a key role for early activation/sensitization of TRPA1 by oxidative stress by-products in producing CIPN. For preventing the onset of CIPN, further clinical testing of many antioxidative stress agents, such as glutathione, acetyl-L-carnitine and α-lipoic acid has been suggested.

Another mechanism underlying CIPN is excitotoxicity where increased release of glutamate forces N-methyl D-aspartate (NMDA) receptors to remain open, allowing increased calcium flux into neurons, resulting in overexcitation and eventually neuronal rupture. The end result of this process is pain without a painful stimulus, also known as neuropathic pain. N-Acetyl-aspartyl-glutamate (NAAG) is an abundant neuropeptide widely distributed in the central and peripheral nervous system which is physiologically hydrolyzed by the enzyme glutamate carboxypeptidase into N-Acetyl-aspartyl (NAA) and glutamate. Glutamate carboxypeptidase inhibition could reduce the severity of chemotherapy-induced peripheral neurotoxicity in rat.

As there are no proven treatments, there is a need for new compositions and methods to properly treat neurotoxicity, for example, peripheral neuropathy, such as chemotherapy-induced peripheral neuropathy or radiation-induced peripheral neuropathy. The present invention provides compositions and methods for the treatment of sensory and motor dysfunction, abnormal sensitivity, and neurotoxicity, including peripheral neuropathy induced by chemotherapies and radiation therapies, for example, CIPN and also providing the unexpected effect of further sensitizing tumor cells to chemotherapeutics.

