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WO 2016/115632 Al 28 July 2016 (28.07.2016) W P O P C T

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WO 2016/115632 Al 28 July 2016 (28.07.2016) W 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 2016/115632 Al 28 July 2016 (28.07.2016) W P O P C T (51) International Patent Classification: (72) Inventors: TARNOPOLSKY, Mark; 309-397 King C12N 5/ 0 (2006.01) C12N 15/53 (2006.01) Street West, Dundas, Ontario L9H 1W9 (CA). SAFDAR, A61K 35/12 (2015.01) C12N 15/54 (2006.01) Adeel; c/o McMaster University, 1200 Main Street West, A61K 9/51 (2006.01) C12N 15/55 (2006.01) Hamilton, Ontario L8N 3Z5 (CA). C12N 15/11 (2006.01) C12N 15/85 (2006.01) (74) Agent: TANDAN, Susan; Gowling WLG (Canada) LLP, C12N 15/12 (2006.01) C12N 5/071 (2010.01) One Main Street West, Hamilton, Ontario L8P 4Z5 (CA). (21) International Application Number: (81) Designated States indicated, PCT/CA20 16/050046 (unless otherwise for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 2 1 January 2016 (21 .01 .2016) 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, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/105,967 2 1 January 2015 (21.01.2015) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/1 12,940 6 February 2015 (06.02.2015) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 62/21 1,3 12 28 August 2015 (28.08.2015) us (84) Designated States (unless otherwise indicated, for every (71) Applicant: EXERKINE CORPORATION [CA/CA]; kind of regional protection available): ARIPO (BW, GH, Room 2H26, McMaster University Medical Centre, 1200 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Main Street West, Hamilton, Ontario L8N 3Z5 (CA). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, [Continued on nextpage] (54) Title: METHOD FOR TREATING MITOCHONDRIAL DISEASE (57) Abstract: A method of treating a mitochondrial disease in a mammal is provided, wherein the mitochondrial disease results from a mutation in nuc leic acid encoding a mitochondrial product, The method comprises admin istering to the mammal a therapeutic ally effective amount of non-naturally occurring exosomes engineered to comprise total mammalian mitochon drial RNA, nucleic acid encoding the mitochondrial product, or the function al mitochondrial product. w o 2016/115632 A i III II II 11 I Illlll 111 III III lllll lllll lllll lllll 11 11 llll 11llll DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ , LT, Published: LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, — with international search report (Art. 21(3)) SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). METHOD FOR TREATING MITOCHONDRIAL DISEASE Field of the Invention [0001] The present invention generally relates to treatment of mitochondrial disease, and more particularly relates to a method of treating mitochondrial disease using exosomes. Background of the Invention [0002] Mitochondria are intracellular organelles that have a variety of functions. They are best known for their ability to produce ATP from reducing equivalents derived from fat, protein and carbohydrates. The reducing equivalents, FAD¾ and NADH+H+, are delivered to the respiratory chain and used to pump a proton from the matrix of the mitochondria to the inter- membrane space. Through a series of oxidation/reduction reactions, the electrons are transported from complex I and II to coenzyme Q10 and then on to complex III, cytochrome c and complex IV where oxygen is reduced to molecular water. The flow of electrons leads to the pumping of the proton complex I, III and IV. The build-up of protons in the inter-membrane space leads to a proton motive force where the electrons flow through complex V and re-phosphorylate ADP to ATP. In addition to the function as an aerobic source of ATP, the mitochondria are also involved in other cellular processes including: calcium buffering, apoptosis, oxidative stress, telomere maintenance, and activation of inflammatory pathways such as the inflammasome. [0003] The mitochondria are thought to have their origin as bacteria that took on a symbiotic relationship with a proto-eukaryotic cell 1.5 billion years ago. Throughout evolution the approximate 1500 genes that are required for mitochondrial biogenesis and maintenance have been transferred to the nuclear DNA, whilst the human mitochondrial DNA retains 37 of these 500 genes in a small circular piece of DNA called mitochondrial DNA (mtDNA). This circular DNA resembles bacterial DNA (likely from its origin) and undergoes polycistronic replication. Most of the mitochondrial DNA contains exons and the repair mechanisms are not as sophisticated as those in the nuclear DNA. This is associated with an increased propensity for mutagenesis in mtDNA verses nuclear DNA. [0004] Mitochondrial diseases can be caused by genetic defects in many of the mitochondrial (mtDNA) or nuclear DNA (nDNA) genes that encode a mitochondrial localized protein or NA species (mtDNA only). Mutations in mtDNA can affect any of the 2 ribosomal RNAs (rRNA), 22 of the transfer R As (tRNA) or 13 protein-coding subunits (N = 7 complex I, N = 1 complex III, N = 3 complex IV and N= 2 complex V). Mitochondrial DNA is maternally inherited. nDNA mutations can affect genes involved in mitochondrial DNA replication or maintenance or structural components. The nuclear mutations can be inherited in an autosomal recessive, autosomal dominant or X-linked recessive manner, Dysfunction of the mitochondria leads to anaerobic ATP generation with an increased reliance on anaerobic pathways. This leads to inefficient energy generation and the production of lactic acid (through glycolysis). The role of mtDNA mutations (both sporadic and familial) and mitochondrial dysfunction is becoming increasingly apparent in broad range of metabolic and degenerative diseases, cancer, and aging. [0005] The first mutations were found in mtDNA in the late 1980s, including Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) resulting from the mutation, 3243A>G; Leber Hereditary Optic Neuropathy (LHON) resulting from the mutation, 11778G>A; as well as large scale deletions that result in Kearn-Sayre- Syndrome (KSS). Subsequently, many hundreds of mtDNA mutations have been described (http://www.mitomap.org/MITOMAP) . Many nuclear mutations have now been discovered including; NDUF mutations in Leigh syndrome, SC02 mutations in infantile cardiomyopathy, POLG mutations (mutations in gene that codes for DNA polymerase gamma) in many disorders such as SANDO (sensory ataxic neuropathy, dysarthria, and ophthalmoparesis), ataxia and Alper Syndrome, SPG7 mutations in hereditary spastic paraparesis, MFN2 mutations in peripheral neuropathy, and others fhttp://www.mitomap.org/MITOMAP . Mitochondrial diseases are heterogeneous and often multi-systemic due to the fact that mitochondria are present in all tissues in the human body with the exception of mature red blood cells. Because the mitochondrion provides much of the energy for the cell, mitochondrial disorders preferentially affect tissues with high energy demand, including the brain, muscle, and heart, although any organ (including liver, pancreas, bone marrow, etc.) can be affected. Consequently, mitochondrial defects are implicated in forms of blindness, deafness, movement disorders, dementias, cardiomyopathy, myopathy, renal dysfunction, and aging. At the molecular level, in addition to energy crisis, mitochondrial dysfunction can also lead to telomere shortening, oxidative stress, apoptosis and inflammasome activation. [0006] Although the identification of the first mtDNA mutations occurred over 20 years ago, treatment of mitochondrial diseases has been largely supportive (i.e., anti-seizure medications, nutrition, spasticity control, etc.). Minimal success has been achieved using nutraceuticals, such as coenzyme Q10, alpha lipoic acid, creatine monohydrate and riboflavin, that target the cellular consequences of mitochondrial dysfunction. Synthetic anti-oxidants, such asidebenone and other CoQlO-like substances, as well as compounds that enhance mitochondrial biogenesis, and lower lactic acidosis, have also been used to treat individuals with mitochondrial disease. However, all of the above options are supportive measures at best and far from curative. [0007] Thus, there is a need to develop improved methods of treating mitochondrial dysfunction. Summary of the Invention [0008] It has now been determined that exosomes may be effectively used as a vehicle to deliver a mitochondrial product to a mammal to treat pathological conditions such as a mitochondrial disease resulting from a deficiency of a functional mitochondrial product. [0009] Thus, in one aspect of the invention, exosomes are genetically modified to incorporate a functional mitochondrial product and/or nucleic acid encoding a functional mitochondrial product. [0010] In another aspect, a method of increasing the amount of a mitochondrial product in mitochondria in a mammal is provided, comprising administering to the mammal exosomes that are genetically modified to incorporate a functional mitochondrial product and/or nucleic
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