Dr. Irit Arbel wants to be modest. She knows that the technology being developed by her Israeli start-up Pluristem Life Systems has the potential to save the lives of thousands of people who undergo bone marrow transplants every year.
On the other hand, she also knows that biotechnology is a risky business, and that it is very early days yet for her tiny 12-man company.
Arbel is not alone in being excited by the promise that Pluristem holds out. The company has developed a unique technology platform for the expansion of stem cells, T-cells, and other blood related cells.
At present, the company is focusing specifically on the expansion of hematopoietic stem cells (HSC) from umbilical cord blood, which can be used for bone marrow transplantations.
Cord blood is now considered by many doctors as a more efficient source of HSC than adult bone marrow, the source of most HSCs used in transplants today. The cord blood cells are easier to match than adult stem cells because you do not need a 100 percent fit, they are less likely to be contaminated with common viral pathogens, and are well tolerated by the patient’s body, leading to less problems with rejection.
The snag, however, is that today only limited quantities of HSC (about 100ml) can be collected from each umbilical cord. These amounts are only enough to treat a young child, whose weight is less than 45 kilos. Attempts have been made to pool the cells from different umbilical cords, but every attempt up to now has failed.
Pluristem’s device, the PluriX bioreactor, promises to be able to expand umbilical cord blood by 10, 20 or even 40 times without differentiation, so that adults can also take advantage of the benefits of transplants using cord blood stem cells.
Any technology that can improve the success rate of bone marrow transplants will be welcomed warmly by the medical community. Bone marrow transplants are considered the last hope for many people suffering a range of diseases like cancer, leukemia, lymphoma, aplastic anemia, and other diseases of the immune or blood systems.
About 50,000 people undergo a bone marrow transplant every year around the world. Of these, 50% – that’s 25,000 people – will not survive the process. For people who undergo the operation while suffering from active leukemia, only 20% survive. These are shocking statistics, but for those who have no other option, the operation still offers some hope, even if that hope is small.
At present, there are two main options for patients seeking a bone marrow transplant. The first is to take HSCs from the bone marrow of the patient himself, clean them of malignant cells, and then return them to the patient’s body. This is the best treatment because it ensures that there will be no problems of immune rejection. Unfortunately, it is difficult to ensure that every malignant cell has been removed, and the return of only one or two malignant cells to the body, will lead to a new outbreak of the disease.
The second treatment is to find a matching donor. This is difficult and time-consuming. Only one in three patients will find a suitable donor.
While a bone marrow transplant is relatively simple, most problems occur in the recovery period afterwards when the patient’s immune system starts to rebuild. At this point, the patient is extremely vulnerable to disease, and even a slight infection can kill him.
Patients must also wait to see if the new HSCs will accept or reject their new host. If they reject it, the HSCs attack the patient’s vital organs in a process known as Graft versus Host Disease (GvHD).
“This is one of the most terrible things to witness,” admits Arbel. “Something is destroying all the systems from the inside, and the patient ends up dying.” Cord blood transplants have a noticeable lack of serious GvHD, she adds.
While attempts have been made to “grow” stem cells in Teflon bags or culture flasks, until now, they have not been able to promote stem cell self-renewal, or to prevent them from differentiating. Once a cell has differentiated it cannot be used in a transplant.
The PluriX bioreactor is a 3D plug-flow bioreactor system that uses stromal cells to create an artificial environment that closely resembles the natural bone marrow environment. HSCs are introduced into this environment alongside minerals and oxygen, and start to grow and reproduce, much as they would if they were inside the human body. By keeping the HSCs enclosed within the 3D stromal cell environment, the HSCs maintain their original form and proliferate without differentiating.
Initial results indicate that PluriX can expand HSCs by as much as 40 times, but Arbel points out that even if the bioreactor can only double the number of stem cells, it will be enough to carry out a bone marrow transplant on a person weighing up to 90 kilograms. Arbel believes that if all patients use HSC from cord blood, the patient survival rate could rise from 50% to 75%.
At present, Arbel says the expansion process takes about four to six weeks, but she believes this can be speeded up as new developments and technologies continue to emerge.
Pluristem is currently at the pre-clinical phase, but it expects to begin animal trials at the Weizmann Institute of Science sometime over the next few weeks. These will last between six to 12 months. Once these are completed, the company plans to start clinical trials in the US. These could begin in a year. If all goes well, Arbel says the PluriX bioreactor could be on the market in about three and a half years.
Pluristem was founded by Dr. Shai Meretzki in 2002, and grew out of his five years of Ph.D. research at the Technion Israel Institute of Technology, in cooperation with the Weizmann Institute. In July 2003, Pluristem carried out a complicated reverse merger with A1 Software, a NASDAQ traded shell company, entering Wall Street by the back door. The company raised $1.3 million during the merger, and today, even though Pluristem is still very much a start-up, the company is traded on Nasdaq.
In January, Pluristem raised a further $1.5m. from individual and institutional investors. Arbel admits that this round of fund-raising was primarily to help the company fund a further private placement effort now underway in Israel. Pluristem intends to raise between $3-5m. from a number of local and international venture capital investors. The company is also considering a further round of fund-raising in the US, in about six to nine months.
Arbel has many plans for this money. Aside from continuing the development of the PluriX bioreactor and seeing it through animal model and preclinical trials, she also plans to start exploring new potential products. There are also acquisition plans in the pipeline. In March, the company announced that it was initiating an aggressive M&A plan targeting cord blood storage banks in the US.
There are over 20 core blood banks in the US, and Pluristem is in negotiations with more than one. The company hopes to complete its first purchase this year. Arbel admits that a purchase like this would fit well with the company’s business plan, offering a synergistic business that could put money in the bank while Pluristem continued development of the bioreactor.
The idea of purchasing a cord blood bank is not new. Boston biotech company, ViaCell, one of Pluristem’s biggest rivals, owns a cord blood bank subsidiary called Viacord. Pluristem’s other main competitor is Gamida-Cell, a private Israeli company working in the same field. Gamida-Cell has fast tracked plans to commence a Phase I/II clinical study in 2004, and has garnered a great deal of attention over the years. The company has raised $20m. in financing, and shareholders include Motti Zisser, Teva Pharmaceuticals, and Biomedical Investments.
Arbel believes, however, that Pluristem is the only company offering a technology that can increase the number of HSCs without causing differentiation of the cells.
“Even if another company will reach the market first I believe we have a very unique and successful technology,” says Arbel. “I estimate that within six months of entering the market, we will take a 15% market share.”
Though Arbel admits that she is first and foremost a businesswoman, she also acknowledges that she and her staff derive immense satisfaction from knowing that they are creating a technology that may one day save many lives. “If we can save some patients with our technology, then most of all will believe that we are doing the right thing,” she says. “It’s important to be cautious, but we really hope that one day we can bring real profit to humanity.”