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WO 2017/049252 Al 23 March 2017 (23.03.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/049252 Al 23 March 2017 (23.03.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/5513 (2006.01) A61P 25/14 (2006.01) kind of national protection available): AE, AG, AL, AM, C12N 15/861 (2006.01) A61P 25/28 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61P 3/04 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/US2016/052384 KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 17 September 2016 (17.09.201 6) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/220,077 17 September 2015 (17.09.2015) US kind of regional protection available): ARIPO (BW, GH, 62/220,087 17 September 2015 (17.09.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: SWITCH BIO, INC. [US/US]; c/o Cooley TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, LLP, 500 Boylston Street, Boston, Massachusetts 021 16- DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 3736 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors: GREENBERG, Kenneth P.; 240 The Up GW, KM, ML, MR, NE, SN, TD, TG). lands, Berkeley, California 94705 (US). DAVID, Nath¬ aniel; 2946 California Street, San Francisco, California Declarations under Rule 4.17 : 941 15 (US). FINER, Mitchell H.; 150 Whitman Street, — as to applicant's entitlement to apply for and be granted a Stow, Massachusetts 01775 (US). patent (Rule 4.1 7(H)) (74) Agents: BRUKMAN, Alia K. et al; Cooley LLP, 1299 — as to the applicant's entitlement to claim the priority of the Pennsylvania Avenue, NW, Suite 700, Washington, Dis earlier application (Rule 4.1 7(in)) trict of Columbia 20004 (US). [Continued on nextpage] (54) Title: COMPOSITIONS AND METHODS FOR TREATING NEUROLOGICAL DISORDERS FiG. 1 2. Activate 'switch" with 1. Genetically insert bio-Inert molecule to therapeutic 'switch' silence nerve into peripheral nerves sarv Spinal cord o (57) Abstract: The present invention generally provides vectors, compositions, and methods of using the same for treating neurolo o gical disorders, including managing pain. The compositions and methods include the use of G protein-coupled receptors and ligand- gated ion channels to treat neurological indications including pain, epilepsy and satiety disorders. The compositions and methods o further include the use of synthetic ligands to activate the G protein-coupled receptors and ligand-gated ion channels in the treatment of neurological disease. w o 2017/049252 Al III III II II III I IIII II II III! I II I I il II I II Published: — with sequence listing part of description (Rule 5.2(a)) — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) COMPOSITIONS AND METHODS FOR TREATING NEUROLOGICAL DISORDERS [0001] This application claims priority to and benefit of U.S. Provisional Patent Application No. 62/220,077, filed on September 17, 2015 and of U.S. Provisional Patent Application No. 62/220,087, filed on September 17, 2015. The contents of both these applications are herein incorporated by reference in their entirety. DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY [0002] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: SWCH_004_01WO_SeqList_ST25.txt, date recorded: September 16, 2016, file size 14.6 kilobytes). TECHNICAL FIELD [0003] The present invention generally relates to viral vectors encoding receptors, compositions, and related methods of use for treating neurological disorders, including managing pain. BACKGROUND OF THE INVENTION [0004] Hundreds of millions of people worldwide are affected by neurological disorders. It is currently estimated that there are over 600 different neurological disorders that affect people. Approximately 6.2 million people die because of stroke each year with over 80% of deaths in low- and middle-income countries. More than 50 million people suffer from epilepsy worldwide. It is estimated that there are globally 35.6 million people with dementia with 7.7 million new cases every year. Alzheimer's disease is the most common cause of dementia and may contribute to 60-70% of cases. The prevalence of migraine is more than 10% worldwide. More than 110 million Americans alone suffer from chronic pain. The financial burden of neurological disorders is significant. In the United States alone, the cost to treat neurological disorders is estimated to be over $800 billion a year. The global cost of treating neurological disorders is estimated to exceed $6 trillion by the year 2030. [0005] Chronic pain is one type of neurological disorder. Unrelieved chronic pain is a critical health problem in the US and worldwide. A report by the Institute of Medicine estimated that 116 million Americans suffer from pain that persists for weeks to years, with resulting annual costs exceeding $560 million. There are no adequate long-term therapies for chronic pain sufferers, leading to significant cost for both society and the individual. Pain often results in disability and, even when not disabling, it has a profound effect on the quality of life. Pain treatment frequently fails even when the circumstances of care delivery are optimal, such as attentive, well-trained physicians; ready access to opioids; use of adjuvant analgesics; availability of patient-controlled analgesia; and evidence-based use of procedures like nerve blocks and IT pumps. [0006] The most commonly used therapy for chronic pain is the application of opioid analgesics and nonsteroidal anti-inflammatory drugs, but these drugs can lead to addiction and may cause side effects, such as drug dependence, tolerance, respiratory depression, sedation, cognitive failure, hallucinations, and other systemic side effects. Despite the wide usage of pharmaceuticals, there is a strikingly low success rate for its effectiveness in pain relief. A large randomized study with various medications found only one out of every two or three patients achieving at least 50% pain relief (Finnerup et al, 2005). A follow-up study using the most developed pharmacological treatments found the same results, indicating that there was no improvement in the efficacy of medications for pain (Finnerup et al., Pain, 150(3):573-81, 2010). [0007] More invasive options for the treatment of pain include nerve blocks and electrical stimulation. A nerve block is a local anesthetic injection usually in the spinal cord to interrupt pain signals to the brain, the effect of which only lasts from weeks to months. Nerve blocks are not the recommended treatment option in most cases (Mailis and Taenzer, Pain Res Manag. 17(3): 150-158, 2012). Electrical stimulation involves providing electric currents to block pain signals. Although the effect may last longer than a nerve block, complications arise with the electrical leads itself: dislocation, infection, breakage, or the battery dying. One review found that 40% of patients treated with electrical stimulation for neuropathy experienced one or more of these issues with the device (Wolter, 2014). [0008] The most invasive, and least preferred, method for managing pain is complete surgical removal of the nerve or section thereof that is causing the pain. This option is only recommended when the patient has exhausted the former and other less invasive, treatments and found them ineffective. Radiofrequency nerve ablation uses heat to destroy problematic nerves and provides a longer pain relief than a nerve block. However, one study found no difference between the control and treatment groups in partial radiofrequency lesioning of the DRG for chronic lumbosacral radicular pain (Geurts et al., 2003). Other surgical methods for surgically removing the pain nerves suffer from similar shortcomings and have serious side effects long-term, including sensory or motor deficits, or cause pain elsewhere. [0009] Methods for treating neurological disorders should be safe, efficient and cost- effective. Gene therapy could provide non-invasive treatment options for a variety of neurological diseases, including managing pain. However, to date, gene therapy methods have not found widespread use in the treatment of neurological diseases. The key to gene therapy is selecting safe and highly efficient gene delivery systems that can deliver therapeutic genes to overexpress or suppress relevant targets in specific cell types. [0010] However, few delivery systems have been shown to be safe and efficient; thus, the promise of gene therapy for treating neurological disorders, including managing pain, has yet to be realized. SUMMARY OF THE INVENTION [001 1] The present invention provides polynucleotides, vectors, and related compositions for use in the gene therapy of neurological disorders and diseases. In one embodiment, the neurological disorder is pain (e.g., chronic or acute pain).
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