C0f1 Novocell Stem Cell Therapy For Diabetes

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  • 1. COMPANY PROFILE For reprint orders, please contact: reprints@futuremedicine.com Novocell, Inc. Alan J Lewis†, Novocell, Inc. is a stem cell engineering company creating, delivering and commercializing Melissa Carpenter, cell and drug therapies for diabetes and other chronic diseases. The use of human Allan Robins & embryonic stem cells provides a scalable source of any differentiated lineage that has Emmanuel Baetge potential for cell replacement therapy, as well as tools for drug discovery to create †Author for correspondence regenerative medicines. Novocell, Inc., 3550 General Atomics Court, Building 2, Drug discovery Throughout the 1960s and 1970s, the pharma- Room 503, San Diego, CA ceutical industry focused almost exclusively on Novocell is developing defined media conditions 92121, USA Tel.: +1 858 455 3708 small-molecule drugs to treat diseases. The for the growth and expansion of cancer stem cells Fax: +1 858 455 3962 1980s and 1990s witnessed the era of genetic (CSCs). These CSCs are being used to identify spe- E-mail: alewis@novocell.com engineering, resulting in the development of cific druggable targets for cancer treatment. Novo- innovative biologics such as monoclonal anti- cell is also developing drug discovery assays for bodies and recombinant proteins, as well as the regenerative medicine and for drug ADME/toxicity development of new tools to identify small mol- prediction using liver and intestinal cells. ecule drugs. These transformational technologies Novocell: a history helped start the biotechnology industry. As we enter the ‘Century of the Cell’, the advent of Novocell was formed in August 1999 by acquiring stem cell engineering offers the potential to pro- all of the assets and liabilities of Neocrin Company, duce cellular replacement disease-modifying including key licenses to cell encapsulation tech- treatments and potential cures for many debili- nology invented by Jeffrey Hubbell and assigned to tating, degenerative disorders, including diabetes the University of Texas, USA. In August 2004, and cancer. To embrace this revolution Novocell Novocell merged with CyThera, Inc., San Diego, has three primary technology platforms, CA, USA to combine the delivery technology with discussed below. a potential for renewable islet cell sources derived from stem cells. CyThera, focused on developing Stem cell-directed lineage human stem cells for the treatment of human Novocell is the first company to efficiently degenerative disease, merged in July 2004 with engineer human embryonic stem cells (hESCs) Bresagen, Inc., Athens, GA, USA. Bresagen is one into definitive endoderm (DE), the gatekeeper of the few suppliers of ‘presidentially approved’ cells that differentiate into pancreas, liver, lung hESC lines and has access to NIH-funds to distrib- and many other cells, tissues and organs. This ute and characterize these lines. Novocell’s primary provides a platform to create cell therapies, therapeutic target is diabetes and our proprietary develop drug discovery opportunities in regen- technology platform has the potential to provide a erative medicines, and assays for ADME/toxic- renewable supply of functional human insulin-pro- ity, as well as find therapies that target key ducing cells for the treatment of diabetes, thereby cancer stem cells. overcoming the major obstacle of islet supply. Cell encapsulation Novocell’s unique accomplishments Novocell utilizes a biocompatible polyethylene • Demonstrated, in small and large animal stud- glycol (PEG) conformal coating that enables ies, that encapsulated cells are protected from transplanted cells to survive and function by immune rejection after implantation, protecting them from immune rejection. It is enabling the development of a new therapy designed to eliminate the need for continuous for major diseases such as diabetes. immunosuppressant drugs that are necessary for allograft transplants. The technology is • Demonstrated preliminary evidence of safety being used in the current proof-of-principle and function in a Phase I/II proof-of-principle primary islet transplant Phase I/II clinical trial clinical trial in patients with Type 1 diabetes part of in Type 1 diabetics. using encapsulated primary islets. 973 Regen. Med. (2007) 2(6), 973–977 10.2217/17460751.2.6.973 © 2007 Future Medicine Ltd ISSN 1746-0751
  • 2. COMPANY PROFILE – Lewis, Carpenter, Robins & Baetge • Established six human ESC lines, including a engraftment of human primary islets can provide clinical-grade line. relief from daily insulin therapy and lead to nor- malization of blood glucose with predicted long- • Developed DE cells from hESCs. term amelioration of diabetes-related complica- • Developed insulin-producing cells from hESC- tions. All Type I and insulin-requiring Type II derived DE. diabetics (up to 40% of Type II patients) are can- didates for islet cell transplantation. Neverthe- Differentiation of hESCs to endoderm less, there remains a severe shortage of functional A unique property of hESCs obtained from the primary human islet cells for these proven trans- inner cell mass of blastocysts is their ability to plantation treatments. One possible means for differentiate into all the cell types that comprise alleviating this paucity of transplantable insulin- the human body. producing cells would be to produce such cells The generation of fully differentiated cells from hESCs, which are functionally immortal throughout the body occurs by a series of develop- and are considered to have the potential to gen- mental stages. The first stage, known as gastrula- erate every cell type found in the human body. tion, results in the generation of the three somatic hESCs are unique amongst stem cells with lineages (Figure 1): the ectoderm, mesoderm and regard to these properties. endoderm. The endoderm subsequently gives rise Novocell’s milestones for its stem cell engi- to a number of therapeutically important struc- neering programs include: tures including the lungs, liver, thyroids, thymus, • Establishment of hESC lines according to intestine, stomach, bladder and pancreas. clinical standards for application to cell- The development of cell therapies involving replacement therapies such as diabetes; these organs has been hampered by the inability to • Development of ways to efficiently differen- control and direct differentiation of hESCs to tiate hESCs into functioning insulin-produc- DE. The Novocell team accomplished this ing cells that can ultimately be implanted ground-breaking feat by developing a reproduc- into humans; ible and efficient protocol [1–4] that has been repli- • Application of the company’s encapsulation cated in numerous laboratories around the world. technology to allow delivery of cells without This work provided a solution that now opens the immunosuppression in diabetic patients; door to generation of the endoderm-derived • Development of methods to scale-up mature cell types, such as insulin-producing cells production of cells to allow efficient and hepatocytes. commercialization of the technology; • Identification of targets for the discovery of Diabetes program novel anticancer agents to treat those cancers Novocell’s encapsulation and stem cell technolo- linked to endoderm organs such as pancreas, gies have the potential to treat many human cellu- colon and lung. lar degenerative diseases and disorders. The first application of these technologies uses proprietary Novocell’s strategy for the generation of func- cell encapsulation of insulin-producing cells to tional insulin-producing cells is to guide the treat diabetes. The product will be biocompatible hESCs through a step-by-step process that mimics and allows subcutaneous implantation without early embryological development of the pancreas. requirement for long-term immunosuppression. The differentiation of hESCs to insulin-produc- Diabetes is the fifth leading cause of death by ing cells occurs through a series of specifying and disease in the USA alone. According to the Ameri- patterning events whereby hESCs transition can Diabetes Association (ADA) the total annual through mesendoderm, endoderm and foregut economic cost of diabetes in 2002 for the USA was endoderm to form pancreatic endoderm and estimated to be US$132 billion. According to the endocrine precursor cells. We observe the tempo- International Diabetes Federation (IDF), it is esti- ral expression of the principal markers specifying mated that currently some 194 million people each transition including HNF1B, HNF4a, worldwide, or 5.1% in the adult population, have HNF6, PDX1, PTF1A, HLXB9, NKX6.1, diabetes and that this will increase to 333 million, NKX2.2, PAX4, PAX6, NEUROD1, ISL1 and or 6.3%, by 2025. IAAP. As a result of this directed differentiation The efforts of James Shapiro and colleagues, strategy Novocell has generated cell populations creators of the Edmonton Protocol for islet in which the principal islet hormones, including transplantation, demonstrate that hepatic insulin, glucagon, ghrelin, pancreatic polypeptide 974 Regen. Med. (2007) 2(6) future science group
  • 3. Novocell, Inc. – COMPANY PROFILE Figure 1. hESC differentiate into endoderm lineages that have enormous potential for cell therapy and drug discovery. CSC: Cancer stem cells; hESC: Human embryonic stem cells. and somatostatin, are expressed at the mRNA and The biocompatible substance, PEG, can be protein levels. The cells generated have many of effectively and evenly applied to the surface of the properties of fetal pancreatic islets. A manu- islets, allowing insulin and glucose to pass freely script detailing these results has been recently in and out of the capsule while preventing the published [5]. Novocell is currently working on body’s immune system from destroying the islets scale-up technologies to generate sufficient quan- within (Figure 2). tities of insulin-producing cells for clinical entry. After definitive nonhuman primate studies evaluating encapsulated primary islets in experi- Cell encapsulation mentally induced diabetes were successfully While there have been many different completed, an Investigational New Drug (IND) approaches to encapsulating cells, including was submitted to the FDA requesting a com- insulin-producing islets, none of these have been bined Phase I/II clinical trial. The FDA successful in humans to date. approved the IND and trial design and a Phase Novocell’s conformally coated islet allografts I/II trial began in patients with insulin-requiring make the technology clinically and commercially diabetes in December 2005. The islets used in relevant [6]: this trial were sourced from approved procure- ment agencies and donors in collaboration with • Content of biodegradable-PEG other islet isolation facilitates in the USA. A total • Conformal coating (25–50 µm) of two Type 1 diabetic patients were transplanted • Immunologically nonreactive and no significant adverse events have been • Adjustable lifespan and permselectivity observed to date (12 months post-transplant). 975 www.futuremedicine.com future science group
  • 4. COMPANY PROFILE – Lewis, Carpenter, Robins & Baetge Figure 2. PEG encapsulated human islet is biocompatible, permeable to nutrients including glucose but not large molecules and immune cells Complement O2 PEG INSULIN C-peptide Amylin Human GLUCOSE Ghrelin islet Glucagon 25–50 µm Nutrients Immune cells PEG: Polyethylene glycol. In summary, this study has shown: Novocell has discovered a novel cell surface molecule on these cells that is believed to be • No safety concerns to date involved in the self renewal of CSCs. This mol- • No evidence of autoimmune destruction or ecule represents a good target for future drug allograft rejection to date – no apparent development for cancer treatment and Novocell induction of autoantibodies and no precipi- is currently developing monoclonal antibodies tous loss of islet function to this cell surface molecule. • Evidence of function – C-peptide responses to Novocell believes that CSCs represent novel oral glucose tolerance testing without immun- targets for the development of cancer treatments osuppression for more than 12 months and envisions a change in the way cancer is treated. This will involve both agents that target Drug discovery CSC in addition to chemotherapeutic regimens Cancer stem cells that target normal tumor cells making up the CSCs have recently been identified as self- bulk of a tumor. renewing, immortal cells that are thought to be Hepatocytes & ADME/TOX applications for responsible for initiating cancerous tumor drug discovery growth and promoting metastasis. CSCs have been isolated from a number of different tumor The liver hepatocyte is one of the principal epi- types and it is now thought that successful treat- thelial cells arising from the ventral foregut ment of various cancers will require targeting of DE. Currently, the supply of human liver CSCs. While these CSCs have been isolated hepatocytes required for drug metabolism and from a number of tissues, growing and expand- toxicology testing is quite limited. The ing them in vitro has proved problematic. Novo- pharmaceutical need for replenishable and reli- cell has expertise in the production of defined able sources of normal human hepatocytes for media and has developed two proprietary media drug metabolism and toxicity testing is for the growth of stem and progenitor cells [7]. considerable [8]. This market need could be One of these proprietary media has been further met with hepatocytes derived from licensed to Invitrogen, who launched the prod- hESCs having different genetic backgrounds uct in August 2007. Novocell is using its media (i.e., Caucasian European, North American, development expertise to formulate media for Asian, Indian, Arabic, and so on). Drug metab- the expansion of CSCs. olism by liver hepatocytes occurs with different In addition, Novocell has isolated a stable propensities in different genetic populations hESC variant known as BG01v, which is tri- and therefore it would be of value to stratify somic for chromosomes 12 and 17. These same the hepatocyte genotypes produced. We see the trisomies are found in many solid tumors. production of human hepatocytes as the most 976 Regen. Med. (2007) 2(6) future science group
  • 5. Novocell, Inc. – COMPANY PROFILE practical way to leverage our know-how in the that can result from expanding Novocell’s plat- endoderm area to produce cells for product form technologies into new products for the sales on a nontherapeutic R&D basis. treatment of diverse human diseases and disor- ders and for substantial R&D markets with spe- Drug screening & endoderm neogenesis cialized human cell sources for drug screening Neogenesis and survival assays for screening and toxicology testing. small molecules to identify compounds to regen- Financial & competing interests disclosure erate pancreatic islet cells, liver cells, lung cells and other cell types are of paramount impor- All authors are employees of Novocell, Inc. The authors have tance. Novocell is currently interested in devel- no other relevant affiliations or financial involvement with oping assays to identify small molecules/drugs any organization or entity with a financial interest in or and biologics for cell survival and regeneration. financial conflict with the subject matter or materials dis- In summary, in addition to the use of hESC- cussed in the manuscript apart from those disclosed. derived β cells for the treatment of diabetes, No writing assistance was utlilized in the production of there are many potentially important products this manuscript. Principal officers Senior Executive Officers Alan J Lewis, PhD President & Chief Executive Officer E Edward Baetge, PhD Chief Scientific Officer Allan Robins, PhD Chief Technical Officer Melissa Carpenter, PhD VP of Research & Development Xiaojie Yu, PhD Sr Director of Biomaterials Science Anne Sandan, CPA Controller, Sr Director of Corp. Admin. Liz Bui JD, PhD Director of Intellectual Property Board of Directors Fred Middleton Managing Director of Sanderling & Novocell’s Chairman of the Board Alan J Lewis, PhD President & Chief Executive Officer Donald J Elmer Managing General Partner of Pacific Horizon Ventures Franklin Johnson Founding Partner of Asset Management Co. Asish K Xavier, PhD Vice President, Venture Investments, Johnson & Johnson Development Corp. Orville G Kolterman, MD Senior Vice President, Clinical & Regulatory Affairs of Amylin Pharmaceuticals Scientific Advisory Board Matthias Hebrok, PhD Associate Professor, Diabetes Research Center, Department of Medicine, University of California, San Francisco, USA Mike German, MD Professor, Diabetes Center, University of California, San Francisco, USA Jeffrey A Hubbell, PhD Director of the Institute for Biomedical Engineering and Biotechnology, Lausanne, Switzerland Marc R Montminy, MD, PhD Professor, Salk Institute for Biological Studies (Affiliate Membership), Biomedical Sciences Graduate Program, University of California, San Diego, USA Didier YR Stainier, PhD Professor, Department of Biochemistry and Biophysics, University of California, San Francisco, USA James M Wells, PhD Assistant Professor Division of Developmental Biology, Children’s Hospital Research Foundation, Cincinnati, OH, USA Jeffrey A Bluestone, MD AW Clausen Distinguished Professor, UCSF Diabetes Center, University of California, San Francisco, USA Alberto Hayek, MD Professor of Pediatrics, UCSD School of Medicine, Whittier Institute for Diabetes, La Jolla, CA, USA James Shapiro, MD, PhD Director, Clinical Islet Transplant Program University of Alberta, Canada 977 www.futuremedicine.com future science group
  • 6. COMPANY PROFILE – Lewis, Carpenter, Robins & Baetge Bibliography Stanier D: No stem cell is an islet(yet). Clinic. Halberstadt CR, Emerich DF (Eds). 4. D’Amour KA, Agulnick AD, Eliazer S, Kelly N. Eng. J. Med. 354, 521–523 (2006). Academic Press, 135–153 (2007). 1. OG, Kroon E, Baetge EE: Efficient D’Amour KA, Bang AG, Eliazer S et al.: Wang L, Schulz TS, Sherrer ES et al.: Self 5. 7. differentiation of human embryonic stem Production of pancreatic hormone- renewal of human embryonic stem cells cells to definitive endoderm. Nat. Biotechnol. expressing endocrine cells from human requires insulin-like growth factor-1 and 23, 1534–1541 (2005). embryonic stem cells. Nat. Biotechnol. 24, ERBB2 receptor signaling. Blood (2007) Dalton S: It’s endoderm…definitively! 1392–1491 (2006). (In Press). 2. Regenerative Med. 1, 381–383 (2006). Scharp DW: Encapsulated human islet Pouton CW, Haynes JM: Embryonic stem 6. 8. Semb H: Definitive endoderm from allografts: providing safety and efficacy. In: cells as a source of models for drug discovery. 3. embryonic stem cells. Regenerative Med. 1, Cellular Transplantation from Laboratory to Nat. Rev. Drug Discov. 6, 605–616 (2007). 489–492 (2006). 978 Regen. Med. (2007) 2(6) future science group