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WO 2017/083750 Al 18 May 20 17 (18.05.2017) 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 2017/083750 Al 18 May 20 17 (18.05.2017) W P O P C T (51) International Patent Classification: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, C07K 14/52 (2006.01) A61K 48/00 (2006.01) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, A61K 38/16 (2006.01) C12N 15/62 (2006.01) 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, (21) International Application Number: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, PCT/US20 16/06 1668 ZW. (22) International Filing Date: (84) Designated States (unless otherwise indicated, for every 11 November 2016 ( 11. 1 1.2016) kind of regional protection available): ARIPO (BW, GH, (25) Filing Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (26) Publication Language: English TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (30) Priority Data: DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 62/254,139 11 November 2015 ( 11. 11.2015) 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, (71) Applicant: INTREXON CORPORATION [US/US]; GW, KM, ML, MR, NE, SN, TD, TG). 20358 Seneca Meadows Pkwy, Germantown, Maryland 20876 (US). Declarations under Rule 4.17 : — as to applicant's entitlement to apply for and be granted a (72) Inventors: PATEL, Dimld S.; 20358 Seneca Meadows patent (Rule 4.1 7(H)) Pkwy, Germantown, Maryland 20876 (US). PATEL, Amit N.; 1040 Chartwell C , Salt Lake City, Utah 84103 (US). — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.1 7(in)) (74) Agent: GIRINATH, Prashant; Wilson Sonsini Goodrich & Rosati, 650 Page Mill Road, Palo Alto, California 94304 Published: (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — before the expiration of the time limit for amending the kind of national protection available): AE, AG, AL, AM, claims and to be republished in the event of receipt of AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, amendments (Rule 48.2(h)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, — with sequence listing part of description (Rule 5.2(a)) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (54) Title: COMPOSITIONS AND METHODS FOR EXPRESSION OF MULTIPLE BIOLOGICALLY ACTIVE POLY PEPTIDES FROM A SINGLE VECTOR FOR TREATMENT OF CARDIAC CONDITIONS AND OTHER PATHOLOGIES FIG. 1 (57) Abstract: The present invention provides compositions and methods useful for treating disorders amenable to therapy via intro - duction of multigenic expression vectors. More particularly, the invention provides vectors and polynucleotides encoding poly peptides for treatment of cardiac disorders wherein said polypeptides may comprise a cytokine, a chemokine, and/or an angiogenic polypeptide, or functional derivatives thereof. Also provided, as compositions of the invention, are linkers useful for connecting and expressing functional (biologically active) polypeptides from single, multigenic-expression constructs. COMPOSITIONS AND METHODS FOR EXPRESSION OF MULTIPLE BIOLOGICALLY ACTIVE POLYPEPTIDES FROM A SINGLE VECTOR FOR TREATMENT OF CARDIAC CONDITIONS AND OTHER PATHOLOGIES CROSS-REFERENCE TO RELATED APPLICATION [0001] The present application claims the benefit of U.S. provisional Patent Application No. 62/254,139, filed November 11, 2015, which is hereby incorporated by reference in its entirety. REFERENCE TO SEQUENCE LISTING [0002] The present application contains a Sequence Listing which has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 11, 2016, is named INX00339WO_20161111_SL.txt and is 271,843 bytes in size. FIELD OF THE INVENTION [0003] The present invention provides novel nucleic acids and vectors, and polypeptides encoded by same, for multigenic therapeutic treatment of diseases, disorders and pathologic conditions. More particularly, the present invention provides novel nucleic acids, vectors, polypeptides and methods for multigenic treatment and prevention of cardiac diseases and disorders. Moreover, the present invention provides novel nucleic acids and polypeptide linkers, which provide advantageous protein expression from nucleic acids and vectors, useful for multigenic therapeutic treatment of diseases, disorders and pathologic conditions. BACKGROUND OF THE INVENTION [0004] Cardiac disease represents a significant unmet medical need; with some estimates indicating at least 25 million patients worldwide. Moreover, according to the United States of America (U.S.) government’s Centers for Disease Control and Prevention (CDC) “Heart Failure Fact Sheet” as of 2013, over 5 million people in the U.S. have heart failure conditions. [0005] Heart failure has been estimated to cause 1 in 9 deaths with as many as 825,000 new cases each year. The average survival rate 5 years after diagnosis is at about 40% and represents the highest hospital readmission rate among any diagnosis-related group. The cost in the U.S. has been estimated to be as high as $32 billion per year. Heart failure treatment options include medications, invasive devices, and heart transplant. [0006] Congestive heart failure (CHF) describes the inability of the heart to provide sufficient cardiac output to supply the metabolic demand of the body. There are more than 22 million people worldwide currently diagnosed with CHF and over 5 million patients in the US. Because the incidence and severity of heart disease increases with age, the overall incidence is expected to rise in the future due to the aging population. The prognosis for patients with CHF remains poor, with a five year mortality rate of 50%. According to the American Heart Association (AHA), cardiovascular disease claimed 810,000 lives in the United States in 2013, which accounts for ~1 in every 3 reported deaths. Pharmacological management of end stage heart failure focus on three goals as follows: 1) improvement of morbidity and mortality (ACE inhibitors, angiotensin II type I receptor antagonists, selected β-blockers, and aldosterone antagonists); 2) control of symptoms (diuretics (eventually thiazide plus loop diuretic), digitalis (low dose); temporary inotropes, and selected anti-arrhythmics); and 3) palliation (opioids, antidepressants, anxiolytics, oxygen and continuous inotropes). However, as disease progresses, therapeutic options become limited to cardiac resynchronization therapy (CRT); considering implantable cardioverter-defibrillator (ICD); heart transplantation and ventricular assist devices (VAD), which are used both as a bridge to transplantation and increasingly as destination therapy due to the lack of donor hearts. Although the overall 5-year survival is 70–80% in heart transplantation patients receiving triple immunosuppressive therapy, heart transplantation as a treatment option is limited by the continuing shortage of donor hearts, the increasing number of transplant candidates and the very high yearly cost over $100,000 per year. Data collected by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), showed that between June 23, 2006 and June 30 2013, 12,335 patients received an FDA approved durable mechanical circulatory support (MCS) device, with a rate of accrual that has continued at a pace of 2,000 patients per year. [0007] There is an increasing study of cell and gene therapies for the treatment of CHF, but with limited results due to issues with biologic effect, cell retention, timing of delivery, and lack of mechanism or limited single gene effect. Even so, many clinical gene therapy trials have demonstrated modest effects at one year. Although gene therapy has a defined mechanism of action, single genes used to improve angiogenesis, stem cell homing, or inotropy have not been sufficient to treat CHF. Because CHF is multifactorial in terms of scarring, decreased contractile function and cell loss, a multigenic approach may better address these individual factors while keeping these extremely sick patients safe. [0008] Traditionally, vectors for gene therapy are single gene. An increasing demand for more complex multigene vectors has arisen in recent years. In particular, this demand is stimulated by the need of combination therapies for cancer and antiviral treatment. Combination gene therapy is medicine’s best attempt to prevent mutation and resistance in cancer. By combining two or three agents a more complete and effective response may be obtained. INCORPORATION BY REFERENCE [0009] All publications, patents, and patent applications herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event of a conflict between a disclosure herein and a disclosure in an incorporated reference, the disclosure herein controls. SUMMARY OF THE DISCLOSURE [0010] An increasing number of patients with congestive heart failure (CHF) continue to have limited therapeutic options. For example, a common CHF treatment results in placement of a destination left ventricular assist device (LVAD)). Accordingly, a different approach involving biologic options to promote recovery from CHF are needed. [0011] A single gene-based approach to treating cardiac disorders is reasonable in patients with unique genetic mutations, i.e. Troponin I or Heavy chain myosin. However, in most patients with cardiac pathology, the end- stage disease is due to multiple factors. Therefore, in such cases a single gene approach is unlikely to work. Cardiac patients usually have scar tissue requiring positive remodeling via cell recruitment and/or angiogenesis. They usually also require an increase in inotropic function via calcium or other pathways.
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