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(12) STANDARD PATENT (11) Application No. AU 2014217615 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title Method of producing microparticles (51) International Patent Classification(s) A61K 31/711 (2006.01) A61PA 25/28 (2006.01) A61K 35/30 (2006.01) CC12N 5/0797 (2010.01) A61P 9/00 (2006.01) C12NC 5/10(2006.01) A61P 11/00 (2006.01) (21) Application No: 2014217615 (22) Date of Filing: 2014.02.12 (87) WIPO No: WO14/125277 (30) Priority Data (31) Number (32) Date (33) Country 1302468.2 2013.02.12 GB 1317888.4 2013.10.09 GB (43) Publication Date: 2014.08.21 (44) Accepted Journal Date: 2018.11.15 (71) Applicant(s) ReNeuron Limited (72) Inventor(s) Sinden, John;Stevanato, Lara;Corteling, Randolph (74) Agent / Attorney Spruson & Ferguson, GPO Box 3898, Sydney, NSW, 2001, AU (56) Related Art KELLER S ET AL, "CD24 is a marker of exosomes secreted into urine and amniotic fluid", KIDNEY INTERNATIONAL, NATURE PUBLISHING GROUP, LONDON, GB, (2007-11-01), vol. 72, no. 9, doi:10.1038/SJ.KI.5002486, ISSN 0085-2538, pages 1095-1102 KELLER S ET AL, "CD24 is a marker of exosomes secreted into urine and amniotic fluid", KIDNEY INTERNATIONAL, NATURE PUBLISHING GROUP, LONDON, GB, (2007-11-01), vol. 72, no. 9, doi:10.1038/SJ.KI.5002486, ISSN 0085-2538, pages 1095-1102 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization lllllllllllllllllllllllllllllllll International Bureau (10) International Publication Number (43) International Publication Date WO 2014/125277 Al 21 August 2014 (21.08.2014) WIPO I PCT (51) International Patent Classification: (74) Agents: GOODFELLOW, Hugh Robin et al.; Carpmaels A61K 31/711 (2006.01) A61P9/00 (2006.01) & Ransford LLP, One Southampton Row, London WC1B C12N 5/0797 (2010.01) A61K35/30 (2006.01) 5HA (GB). A61P 25/28 (2006.01) C12N 5/10 (2006.01) (81) Designated States (unless otherwise indicated, for every A61P11/00 (2006.01) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, PCT/GB2014/050412 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, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 12 February 2014 (12.02.2014) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (25) Filing Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (26) Publication Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (30) Priority Data: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 1302468.2 12 February 2013 (12.02.2013) GB ZW. 1317888.4 9 October 2013 (09.10.2013) GB (84) Designated States (unless otherwise indicated, for every (71) Applicant: RENEURON LIMITED [GB/GB]; 10 Nugent kind of regional protection available): ARIPO (BW, GH, Road, Surrey Research Park, Guildford, Surrey GU2 7AF GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (GB). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors: SINDEN, John; Reneuron Limited, 10 Nugent EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, Road, Surrey Research Park, Guildford, Surrey GU2 7AF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, ~~ (GB). STEVANATO, Lara; Reneuron Limited, 10 Nugent TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Road, Surrey Research Park, Guildford, Surrey GU2 7AF KM, ML, MR, NE, SN, TD, TG). (GB). CORTELING, Randolph; Reneuron Limited, 10 Nugent Road, Surrey Research Park, Guildford, Surrey Published: = GU2 7AF (GB). — with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a)) Al (54) Title: METHOD OF PRODUCING MICROPARTICLES (57) Abstract: The invention is based on the finding that microparticles can be produced by conditionally- immortalised cells. The 2014/125277 conditionally-immortalised cells may be stem cells. The Examples show the successful harvest of microparticles from conditionally immortalised neural stem cells and CD34+ cells. Conditional immortalisation provides a constant supply of clonal cells that produce microparticles such as exosomes. The conditionally immortalised cells are useful as "producer cells" for microparticles such as exo - somes, which are typically harvested or isolated from the conditionally-immortalised cells. WO WO 2014/125277 PCT/GB2014/050412 1 Method of Producing Microparticles Field of the Invention This invention relates to microparticles produced by cells, their use and production thereof. 5 Background of the Invention Stem cells have the ability to self-renew and to differentiate into functionally different cell types. They have the potential to be a powerful tool in the growing field of Regenerative Medicine, in particular regenerative therapy requiring tissue replacement, regeneration or repair (Banerjee et 10 al. 2011). However, there are drawbacks to the use of stem cells in therapy: there is a need for a consistent and substantial supply of stem cells with functional and phenotypic stability and the associated high costs and time delay caused by cell generation, storage, transport and handling; there is a requirement for immunological compatibility to avoid rejection of the stem cells by the recipient; and there are complex regulatory issues related to potential safety risks of 15 tumour or ectopic tissue formation. Further, despite the therapeutic efficacy of stem cell transplantation, there is no convincing evidence for a direct long-term effect of the transplanted stem cells, for example through engraftment and differentiation into reparative or replacement cells. 20 Neural stem cells (NSCs) are self-renewing, multipotent stem cells that generate neurons, astrocytes and oligodendrocytes (Kornblum, 2007). The medical potential of neural stem cells is well-documented. Damaged central nervous system (CNS) tissue has very limited regenerative capacity so that loss of neurological function is often chronic and progressive. Neural stem cells (NSCs) have shown promising results in stem cell-based therapy of 25 neurological injury or disease (Einstein et al. 2008). Implanting neural stem cells (NSCs) into the brains of post-stroke animals has been shown to be followed by significant recovery in motor and cognitive tests (Stroemer et al. 2009). It is not completely understood how NSCs are able to restore function in damaged tissues but it is now becoming increasingly recognised that NSCs have multimodal repairing properties, including site-appropriate cell differentiation, pro- 30 angiogenic and neurotrophic activity and immunomodulation promoting tissue repair by the native immune system and other host cells (Miljan & Sinden, 2009, Horie et al., 2011). It is likely that many of these effects are dependent on transient signalling from implanted neural stem cells to the host milieu, for example NSCs transiently express proinflammatory markers when implanted in ischaemic muscle tissue damage which directs and amplifies the natural pro- 35 angiogenic and regulatory immune response to promote healing and repair (Hicks et al., unpublished data). In chronic stroke brain, NSCs also have a substantial neurotrophic effect. For example, they promote the repopulation of the stoke-damaged striatal brain tissue with host WO 2014/125277 PCT/GB2014/050412 2 brain derived doublecortin positive neroblasts (Hassani, O’Reilly, Pearse, Stroemer et al., PLoS One. 2012;7(11)). Furthermore, on the basis of a large body of NSC restorative effects in animal models with 5 chronic stroke, a clinical trial using neural stem cells is being carried out by ReNeuron Limited (Surrey, UK), to trial the treatment of disabled stroke patients using its “CTX0E03” conditionally- immortalised cortex-derived neural stem cells (Clinicaltrials.gov Identifier: NCT01151124). Mesenchymal stem cells (MSCs) are lineage-restricted stem cells which have the potential to 10 differentiate into mesenchymal cell types only, namely of the adipocytic, chondrocytic and osteocytic lineages (Pittenger et al 1999; Ding et al. 2011). MSCs (also referred to as Mesenchymal Stromal Cells and Mesenchymal Progenitor Cells) are derived from a variety of sources including bone marrow, blood, adipose and other somatic tissues. The therapeutic potential of MSCs, however, is more directed towards the application of their pro-angiogenic 15 and immune modulating properties as undifferentiated cells. Production of human MSCs is limited by the inability of these cells to expand in numbers stably beyond approximately 15-20 population doublings. Mesenchymal stem cell-conditioned medium (MSC-CM) has a therapeutic efficacy similar to 20 that of MSCs themselves, suggesting a paracrine mechanism of MSC-based therapy (Timmers et al. 2007). WO-A-2009/105044 discloses that particles known as exosomes, secreted by MSCs, comprise at least one biological property of the MSCs and suggests the use of these MSC particles in therapy, while Thery et al. 2011 provides a general review of exosomes and other similar secreted vesicles. Whereas some of the drawbacks of using stem cells directly as 25 therapeutic agents are overcome by using the mesenchymal stem cell-derived exosomes (e.g. storage, transport and handling), the problem remains of providing a consistent and substantial supply of functionally and phenotypically stable stem cells to produce the exosomes. For therapeutic use, the exosomes preferably need to be produced on a large scale. In the absence of a stem cell line, replenishment of the cells through repeated derivation from a 30 source of stem cells is required, which incurs recurring costs for testing and validation of each new batch. Furthermore, the diseases and disorders that can be treated by MSCs may be limited. There remains a need for improved stem cell-based therapies.
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    Supplementary Data

    Supplementary Fig. 1 A B Responder_Xenograft_ Responder_Xenograft_ NON- NON- Lu7336, Vehicle vs Lu7466, Vehicle vs Responder_Xenograft_ Responder_Xenograft_ Sagopilone, Welch- Sagopilone, Welch- Lu7187, Vehicle vs Lu7406, Vehicle vs Test: 638 Test: 600 Sagopilone, Welch- Sagopilone, Welch- Test: 468 Test: 482 Responder_Xenograft_ NON- Lu7860, Vehicle vs Responder_Xenograft_ Sagopilone, Welch - Lu7558, Vehicle vs Test: 605 Sagopilone, Welch- Test: 333 Supplementary Fig. 2 Supplementary Fig. 3 Supplementary Figure S1. Venn diagrams comparing probe sets regulated by Sagopilone treatment (10mg/kg for 24h) between individual models (Welsh Test ellipse p-value<0.001 or 5-fold change). A Sagopilone responder models, B Sagopilone non-responder models. Supplementary Figure S2. Pathway analysis of genes regulated by Sagopilone treatment in responder xenograft models 24h after Sagopilone treatment by GeneGo Metacore; the most significant pathway map representing cell cycle/spindle assembly and chromosome separation is shown, genes upregulated by Sagopilone treatment are marked with red thermometers. Supplementary Figure S3. GeneGo Metacore pathway analysis of genes differentially expressed between Sagopilone Responder and Non-Responder models displaying –log(p-Values) of most significant pathway maps. Supplementary Tables Supplementary Table 1. Response and activity in 22 non-small-cell lung cancer (NSCLC) xenograft models after treatment with Sagopilone and other cytotoxic agents commonly used in the management of NSCLC Tumor Model Response type
  • Stroke Genetics and Genomics

    Stroke Genetics and Genomics

    Faculdade de Medicina da Universidade de Lisboa Unidade Neurológica de Investigação Clínica PhD Thesis Stroke Genetics and Genomics Tiago Krug Coelho Host Institution: Instituto Gulbenkian de Ciência Supervisor at Instituto Gulbenkian de Ciência: Doctor Sofia Oliveira Supervisor at Faculdade de Medicina da Universidade de Lisboa: Professor José Ferro PhD in Biomedical Sciences Specialization in Neurosciences 2010 Stroke Genetics and Genomics A ciência tem, de facto, um único objectivo: a verdade. Não esgota perfeitamente a sua tarefa se não descobre a causa do todo. Chiara Lubich i Stroke Genetics and Genomics ii Stroke Genetics and Genomics A impressão desta dissertação foi aprovada pela Comissão Coordenadora do Conselho Científico da Faculdade de Medicina de Lisboa em reunião de 28 de Setembro de 2010. iii Stroke Genetics and Genomics iv Stroke Genetics and Genomics As opiniões expressas são da exclusiva responsabilidade do seu autor. v Stroke Genetics and Genomics vi Stroke Genetics and Genomics Abstract ABSTRACT This project presents a comprehensive approach to the identification of new genes that influence the risk for developing stroke. Stroke is the leading cause of death in Portugal and the third leading cause of death in the developed world. It is even more disabling than lethal, and the persistent neurological impairment and physical disability caused by stroke have a very high socioeconomic cost. Moreover, the number of affected individuals is expected to increase with the current aging of the population. Stroke is a “brain attack” cutting off vital blood and oxygen to the brain cells and it is a complex disease resulting from environmental and genetic factors.