PRINT THIS PAGE Israel at forefront of stem-cell research
19/09/2007. Source:IVCJ (Israel Venture Capital & Private Equity Journal).
Israeli companies are hoping to capitalize on the discoveries emanating from its world class stem-cell research. In this IVCJ article, Wendy Elliman looks at the accomplishments of Israel’s leading research institutes along with commercial efforts that are on the horizon. The market is out there and its value is in the billions of dollars. CellCure Neurosciences of Jerusalem, for example, estimates its forthcoming stem-cell-based therapy for Parkinson’s disease need penetrate no more than three percent of Parkinson’s patients to achieve blockbuster status of $1 billion in annual sales. Jerusalem’s Gamida Cell Therapy Technologies is similarly confident that it, too, has an upcoming blockbuster – a stemcell- based therapy for blood cancer that will reach the market within three years. And Pluristem Life Systems of Haifa sees a potential $5 billion market for the stem-cell technology it is developing to make bone marrow transplantation simple, safe and successful. Even conservative forecasters talk of a global market of some $40 billion for therapeutic products based on stem-cells.
While Israel’s medical research institutes and 10 young stem-cell start-ups estimate several years of further development before companies in Israel – or anywhere – are ready to tap into this market, “stem-cell therapy should no longer be perceived as futuristic,” according to Dr. Yael Margolin, Gamida Cell’s CEO. “It will be here in less than five years. And in 10 to 15 years, I believe it will be a standard treatment.”
Aiming to cure the incurable by replacing diseased or malfunctioning cells with healthy ones tailor-made from flexible young stem-cells that are essentially a genetic blueprint, stem-cell therapy is expected to revolutionize medicine, and tow in its wake cosmic commercial opportunities.
Despite its relatively modest research budgets – governmental, institutional, private and industrial – Israel is on the frontline of this revolution. Among therapeutic stem-cell technologies that Israeli companies anticipate bringing into clinical practice are procedures to reverse heart failure, enable diabetics to produce insulin, allow Parkinson’s sufferers to manufacture dopamine, and radically ease and improve the outcome of bone marrow transplantation to vanquish blood cancers.
Israeli scientists record stem-cell “firsts”
Several factors have propelled Israel to the vanguard of stem-cell research. One is its long history with stem-cells. Over 40 years ago, Leo Sachs of the Weizmann Institute of Science in Rehovot was the first to show that stem-cells – the building blocks for all human tissue – can be grown in culture. In 1998, Joseph Itzkovitz-Eldor of the Technion’s Rambam Medical Center was the first to isolate stem-cells from human embryos, and two years later Benjamin Reubinoff, at the Hadassah-Hebrew University Medical Center, became the first person to derive neural cells in culture from human embryonic stem-cells. That same year, developmental geneticist Nissim Benvenisty of the Hebrew University of Jerusalem, together with US researchers, made history by describing the differentiation of human embryonic stem-cells in culture. The year following, Reubinoff was first to report genetic modification of the cells.
“The fact that so many first steps were taken in Israel created a platform on which stem-cell research has developed here,” says Prof. Dov Zipori, director of the Kimmel Institute for Stem- Cell Research at Weizmann, who is known worldwide for identifying a unique chemical signaling between stem-cells and bone marrow.
Few restrictions give Israel step up
Israel’s long history of stem-cell research is combined with talented, brilliant researchers, working unfettered by the restrictions placed on research into embryonic stem-cells in the US and several other Western countries. While stem-cells derived from human embryos (rather than from adults or umbilical cord-blood) have, thus far, proven the most fruitful in developing stem-cell therapies, removing stem-cells from embryos is morally fraught, particularly for those who consider life to begin with fertilization. Because embryos stop developing after removal of their stem-cells, those who view these pinhead-sized cell-clusters as human beings see this harvesting as human experimentation. Hence US President Bush’s 2001 decision that while federal funding for research on 64 existing stem-cell lines would continue, no new lines could be created with government monies. This decision, Bush explained, was made “with great care…because embryonic stem-cell research holds great promise, but also the potential of great evil.”
In Israel, however, the focus is firmly on the “great promise” of healing. Israeli law, informed by Jewish belief which dates the start of life 40 days after fertilization, permits research for therapeutic purposes on stem-cells withdrawn from early stage embryos.
All this has taken Israel to the front of the field. In 2002, Israel was named a world leader in stemcell research by Science Magazine. In 2005, figures from Germany’s Research Center Jülich showed that since 2000 Israeli scientists had published more stem-cell research articles per capita than those anywhere else – an impressive 113 articles per million Israelis.
Promising developments
What, then, is happening with stem-cells in Israel? In the laboratory of Prof. Yair Reisner, head of Weizmann’s Immunology Department, nothing less than growing replacement organs. Reisner, who leads one of 10 stem-cell research groups at Weizmann, has grown kidneys in mice. His group implanted stem-cell clusters from early pig and human embryos into the kidney capsules of mice, where they grew into complete, functional kidneys that produce urine.
With an estimated 400,000 Americans alone in treatment for kidney disease each year, the Weizmann team has an impatient market, though Reisner is unwilling to give a timeframe. Still to be solved, he says, are issues of how to grow organs in a bioreactor rather than in an animal, immunological rejection, and timing (if stem-cells are too old, they are rejected; too young and they develop into disorganized, non-kidney tissue, such as bone, cartilage and muscle). But, “if all goes well, we may be able to grow new kidneys for patients in need,” he says.
Hearts are the focus of a team at the Technion’s Rappaport Institute – specifically, replacement cardiac tissue for failing hearts. “Adult heart tissue can’t regenerate,” says Dr. Lior Gepstein, head of Rappaport’s Cardiovascular Research Laboratory. “When a heart attack destroys cardiac cells, the scar tissue it leaves can’t contract and heart efficiency diminishes. The heart failure that results causes more hospitalizations than all cancers combined, and half of all patients with heart failure will die within five years. The only existing solution for patients with end-stage heart failure is heart transplantation.” To circumvent the many problems of heart transplantation, Gepstein’s team is working to replace scar tissue with healthy tissue derived from embryonic stem-cells. “Several years ago, we succeeded in directing the differentiation of embryonic stem-cells into cardiac cells,” says Gepstein.
Left alone, embryonic stem-cells differentiate chaotically into any of the body’s 220 organtypes, with only a few in every hundred becoming cardiac cells. The Haifa team maximized culture conditions, and derived cells which are uniquely cardiac in structure. They express cardiac-specific genes, display cardiac electrical activity and, when given adrenalin, beat faster. More still: when these tiny clumps of up to 2,000 laboratory-grown beating cells are introduced into heart tissue, they propagate activity, generating pace-making to the whole one-billion-cell heart. Most recently, the team has developed cardiac tissue complete with blood vessels, an important step toward successful implantation.
Other clinical applications are foreseen for these lab-grown cells. “One is making them into a kind of biological pacemaker to treat cardiac arrhythmias,” says Gepstein. “Another is using them to screen the effect of experimental drugs on human tissue.” The impact of drugs on the heart (think Vioxx….) is the single most important reason for their withdrawal from the market.
Promising as this is, there’s a long road ahead. “We’re still trying to identify what turns embryonic stem-cells into cardiac cells, and thus increase the percentage generated in the lab,” says Geptstein. “We also need to know more about their development once they’ve become cardiac cells – what makes them ventricular, pacemaking and other types of heart cell.”
Other major hurdles are shared by everyone working with stem-cells: immunological rejection, survival of implanted cells, amplifying production of cells, and ensuring a pure population for implantation. “We have at least five to 10 years’ work ahead of us before clinical application,” says Gepstein.
Parkinson’s disease, Alzheimer’s, ALS and multiple sclerosis are among the bleak neurodegenerative diseases which Benjamin Reubinoff believes can be cured with stem-cells. Director of the Human Embryonic Stem-Cell Research Center at Hadassah, his group was the first anywhere to derive neural precursor cells from embryonic stem-cells. As with Gepstein’s cardiac cells, the differentiation was initially spontaneous, but last year the Hadassah team managed to control the process and develop these primitive brain cells in sufficient quantities for clinical application.
“We’re now trying to turn these early neural cells into specific types of nerve cell,” he explains. “Our first goal is directing them to become dopamine-producing cells, and to create a treatment for Parkinson’s patients.” Four million people in the developed world suffer this progressive neurodegenerative disease. Current pharmaceutical treatments for Parkinson’s have an estimated combined annual market of $4 billion.
Reubinoff’s team was first to show that the condition of Parkinsonian rats can be improved even by primitive neural cells, as yet uncommitted to producing dopamine. “Complete recovery wasn’t achieved, probably because the cells differentiated spontaneously,” he says. “But it was a landmark accomplishment because this was the first time that stem-cells grown in the lab from human embryonic stem-cells were made to develop into a specific cell-type and, when transplanted into animal models, improved Parkinson’s. We’re now trying to increase the number of dopamine-producing cells that regenerate in Parkinson animal models after transplant to achieve their complete recovery.”
Cells suitable for Phase 1 clinical trials may be ready within five years, he says, “though that’s a very loose prediction.” He expects this work to lead to treatments for other neurodegenerative illnesses. “The same general principal should be applicable to, say, creating myelin-producing cells to heal multiple sclerosis.”
Start-ups seek to commercialize innovations
To attract funding for developing and marketing these new therapies, the Hadassah team, like other Israeli teams, has established a start-up to commercialize use of its human embryonic technology. CellCure Neurosciences was founded in March 2006, with an exclusive license for ES Cell International’s intellectual property in neurodegenerative diseases, including a patent on deriving neural cells from human embryonic stem-cells. Among its directors is Alan Coleman, a creator of Dolly the sheep.
“We’re developing preparations of neural cells in suspension to be injected into the striatum of Parkinson’s patients,” says CellCure CEO, Dr. Charles Irving. “We’re currently in the pre-clinical stage and hope to perform clinical studies by 2009/10. We expect our product to slow or eliminate the disease in moderately affected patients, and to stabilize it in the severe.”
Parkinson’s disease is also the target of Israeli start-up BrainStorm Cell Therapeutics. Based on the work of neurologist Eldad Melamed of the Rabin Medical Center and cell biologist Daniel Offen of Tel Aviv University’s Felsenstein Medical Research Center, Brainstorm is working with adult stem-cells derived from bone marrow. Using proprietary technology, it sorts and accurately implants those that produce the protein GDNF, which improves symptoms in Parkinsonian rats by 60 percent.
Combined with Brainstorm's success in producing dopaminergic cells, this gives the company a two-pronged, synergistic approach to developing long-term alternatives for treating Parkinson's and other debililtating disorders, according to Brainstorm management.
Israeli start-up Gamida Cell is predicting a 2009 launch for its flagship product, StemEx, a technology that expands the number of stem-cells produced in the laboratory. StemEx received FDA orphan drug designation in 2005 for blood cancer patients.
“Everyone working with stem-cells struggles with their small numbers because, when grown in culture, nature links proliferation of these cells to their differentiation,” says Gamida Cell’s Yael Margolin. “We, however, have patented enabling technologies which allow expansion of cord-blood stem-cells that maintain stem-cell characteristics.”
Cord-blood transplants have been performed for 20 years, and help treat over 70 disorders – but are largely limited to infants because of the limited number of stem-cells. With its stem-cell expansion technologies Gamida Cell can create therapeutic doses for both adolescents and adults.
With a $25 million investment from Teva Pharmaceutical, positive results from a Phase I/II clinical trial for hematological malignancies and, in October 2006, receipt of an SPA for the clinical protocol, Gamida Cell is now preparing a pivotal, international, multi-center study of StemEx. If successful, they see their first regenerative cellbased medicine on the market in two to three years – and plan to follow it up with stem-cell-based products to regenerate cardiac, vascular and neurological tissue.
Another primary focus for Israeli researchers is bettering bone marrow transplantation. While it is the most commonly performed stem-cell therapy, used for decades to treat patients with cancer and other blood and immune system disorders, bone marrow transplantation remains imperfect and challenging, with an estimated 100,000 patients dying each year because of difficulties in obtaining or receiving bone marrow.
Pluristem Life Systems, a start-up based on work done at the Weizmann Institute and the Technion, believes it can make the procedure significantly easier and more certain. It has developed what it believes to be the safest, most efficient way of growing cord-blood-derived stemcells for bone marrow transplantation.
“We’ve created a ‘green’ system, a threedimensional structure that mimics nature’s bone marrow microstructure without adding any nonnatural substances,” says Pluristem CEO Zami Aberman. Patented in 2004, it is known as the 3-D PluriX™ bioreactor.
Since then, Pluristem has again broken new ground by developing a method to cull stem-cells from placentas. “With 40,000 births in Israel each year, this neglected spongy tissue is an easily available source for therapeutic use,” says Aberman. “The placenta is a unique micro-environment where maternal cells find an equilibrium in which to live with fetal cells. We’ve already proved pre-clinically that adding placental stemcells to cord-blood stem-cells improves the engraftment of bone marrow.”
In January 2007, Pluristem presented the FDA with an IND application for its placental stem-cell technology, and hopes to begin clinical studies this year. “That 100-page proposal cost us $1.5 million,” says Aberman. “We expect to show that injecting placental cells into patients with acute AML and ALL, four hours prior to transplant with umbilical cord-blood, is both safe and reduces engraftment time from seven weeks to less than three, restoring healthy blood-producing cells – and opening up a multimillion dollar market.”
With its record of trailing in later-stage life sciences development and manufacturing, Israel is increasingly making the business-academic combinations that underpin start-ups such as Pluristem, Gamida Cell, Brainstorm and CellCure, to finance costly medical expertise and clinical trials. According to Red Herring magazine, Israel’s 10 stem-cell-oriented companies have raised a total of $75 million, mostly from pharmaceutical companies and venture capital firms.
“It requires a basic shift in thinking for industry and government to invest more money in basic research,” says Benjamin Reubinoff. “But that’s what is needed if we’re to write the prologue to a new medical era in which hitherto incurable illnesses are healed by regenerative therapies.”
.This article appeared in the Israel Venture Capital & Private Equity Journal (IVCJ). IVC Research Center publishes the Israel Venture Capital & Private Equity Journal, a quarterly review of trends and developments in the Israeli-related venture capital industry. IVCJ, distributed worldwide, is dedicated to provide wide-range coverage of Israel's venture capital industry. For more information please visit www.ivc-online.com
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