Target Cells Derived From Stem Cells Can Save Millions of Lives

When biochemist, Prof. Michel Revel, retired from the Weizmann Institute after 40 years, during which he won the Israel Prize for medicine, he did not think for a moment to relax at home with his tea with lemon and the old books, to quote the lyrics of an old song. Instead, he founded Kadimastem, which specializes in developing cell therapies based on pluripotent stem cells. The company has developed a technology for differentiating embryonic stem cells into active target cells, nervous system supporting cells (a.k.a astrocytes) and insulin secreting cells for the treatment of ALS (Amyotrophic lateral sclerosis) and diabetics. These are the two main directions in which Kadimastem is currently focusing and in which it has already made impressive achievements.

"ALS is a very serious neurological disease, in which the nerve cells, known as motoneurons, in the brain and spinal cord that transmit the signals to activate the body's muscles die. The mechanism of mortality is unknown to this day. We do know that there are about 15 genes whose mutations can lead to this disease," explains Prof. Revel about the disease that kills patients usually within three to five years from onset, the patient gradually gets completely paralyzed, eventually leading to death mostly due to respiratory failure.

"Studies show that one of the causes of the disease - possibly the main one - is that the brain and spinal cord have not only nerve cells (neurons) but also support cells (astrocytes), whose job is to keep neurons alive. Studies show that in ALS patients, there is damage to the support cells. They don't function properly and not only don't they support motor neurons survival, they even become toxic and release chemicals that cause their death."

And that's where Kadimastem comes in?
"Yes. Our idea was to use embryonic stem cells to make healthy and functioning support cells (AstroRx®) for the neurons and in this way to prevent the neurons from dying. It is impossible to revive cells that have died, but it is possible to prevent further mortality and improve the cells that begin to sustain damage. In animal experiments, where we implanted the cells in the spinal fluid, we saw significant improvement. The injection itself is not a complicated thing; it's a simple medical procedure."

"In a clinical trial conducted by the company in Israel, we saw that the injection does produce a clear medical improvement, but not a permanent one. After few months, the disease continues to progress. We realized that it was probably necessary to give an injection every three months, and planned a clinical trial accordingly. This trial program has was approved by the FDA. The regulatory file we submitted for this clinical trial was quickly approved, in just a month, March 2023. The clinical protocol has been approved by the FDA and the trial is expected to take place in several medical centers in the United States, with emphasis on Boston, which is the global center for the treatment of ALS. The director of the division there is a world-renowned researcher in the field, and she is very enthusiastic about our results so far. We're currently working on raising funds to carry out the clinical trial."

What do the interim results show?
"They are very encouraging. First, there were no side effects or complications from injecting AstroRx® cells into the spinal fluid. The deterioration of patients is measured using the ALSFRS-R score; we compare the state of the patients three months before injection with a follow-up of one year after the intrathecal injection. In the low dose (about 100 million cells), the deterioration was -0.88 per month before the injection, and after the injection, the deterioration slowed to -0.3 (0.039>P). In patients with higher dose (250 million cells) similar effect was obtained dropping from -1.43 to -0.78 (P=0.0023). The improvement lasted for three months after the injection justifying repeated injections in our upcoming FDA approved clinical trial."

What's next?
"In light of these encouraging results, in the next clinical trial, we will inject AstroRx® cells every three months. We expect significant improvement over time. In the future, we hope to be able to prolong life and vital functions in patients with this terrible disease. In the more distant future, we can think about injecting AstroRx® in other neurological diseases in which neurons are affected."

For more details, see Gotkine et al., J Trans Med 2023.

Solution for type 1 diabetics
Another disease that cell therapy is expected to solve is insulin dependent diabetes, in which pancreatic cells, which produce the hormone insulin and other hormones that regulate blood sugar, die. "Our plan is to return to patients the cells damaged by the disease," declares Prof. Revel, and explains how: "The pancreas produces mainly juices for digestion, but there are clusters of cells inside it called islets, which contain the cells that produce hormones. Back in 2010, at Kadimastem, we developed a method to produce such islets in the laboratory. This is a highly complex differentiation process that takes about a month, but it yields active cells, which demonstrated that it can cure diabetic animals . The animals continued to live after the transplant and their blood sugar levels became normal and controlled."

There are different types of diabetes. Is the development relevant to everyone?
"The solution is aimed at insulin dependent diabetics who need to inject insulin. Type 1 diabetes is the more severe form of the disease. It also affects children and requires injections several times a day, which is difficult for patients and their parents. They have to calculate the exact amount of insulin each time, that exactly matches the child's diet and physical activity. This is a challenge and causes injection accidents that lower blood sugar below normal levels or don't lower it enough. This can cause serious long-term health problems, fainting, and even sudden death. Our goal is to completely free patients from the need for insulin injection, or at least greatly reduce it. From what we have seen in the trials, we believe that it is possible to reach a situation that makes insulin injection unnecessary."

"Type 2 diabetes is the most common and pervasive; 70% of patients can get by with drugs that remove sugar through the urine or transfer it from the blood to the muscles. The remaining 30% need insulin. We are also focusing on this group by our development of pancreatic islets made from stem cells. We know that this is feasible based on several studies worldwide, including one by an American company called iTolerance, which develops a product that causes immune tolerance where the cells are transplanted. iTolerance has developed a method that allows cells to be transplanted without the immune system attacking them. They found a way to make the immune system think that these are cells that should not be attacked, even though they are not the patient's but those of another person. They successfully tried their method on diabetic mice and monkeys, and recently integrated our cells with impressive success. Our cells were able to cure diabetes in mice over time."

Is iTolerance expected to be a partner or competitor?
"The cooperation between the companies received a prestigious grant from the BIRD Foundation (Israel-U.S. Binational Industrial R&D Foundation), which supports promising collaborations between American and Israeli companies. Following the joint success with our cells, IsleRx, and iTolerance's gel called ITOL100, we are in advanced talks to examine the continuation and even expansion of cooperation between the companies, with the aim of developing a joint product and conducting a clinical trial for testing it in humans. The insulin-dependent diabetes market has tens of millions of patients worldwide, so the demand is great and we are not concerned with competition."

Regenerative medicine is the future
Prof. Michel Revel received the Israel Prize for inventing the drug Rebif for the treatment of multiple sclerosis. The drug was sold to pharma giant Merck Serono, and it generates huge revenues of over $1.5 billion a year. 86% of MS patients who receive the drug do not have to use walking aids, although the disease causes loss of motor ability. The developments Kadimastem is currently working on are a continuation of Prof. Revel's contribution to the treatment of neurological diseases and the ongoing effort to improve the lives of those suffering from serious diseases.

"Multiple sclerosis is a neurological disease similar to ALS, but milder. The treatment I discovered for it has been working successfully for almost 20 years. The aspiration is to reach such a state with both ALS and diabetes," says Prof. Revel.

To strengthen the company team on this revolutionary medical journey, Kadimastem summoned Prof. Revel's son, Ariel, who is a specialist in gynecology, obstetrics, and fertility, focusing on fertility preservation. Already 25 years ago, Prof. Ariel Revel broke new ground in the research of ovarian transplantation, which he began at the University of Toronto and continued at Hadassah Hospital with many patients who underwent ovarian transplantation after chemotherapy. The discovery that ovaries could be frozen, then thawed and used helped cancer patients receive chemical treatments, known as fertility killers, and then conceive and give birth. Today this is a well-known and accepted medical practice. Prof. Ariel Revel intended to continue working in his field of expertise, when about four years ago the CEO of Kadimastem approached him and offered him to join the company founded by his father as medical director.

"I debated whether it was right for me to work alongside my father," he admits, "but I realized that the company was at a critical crossroads where I could make an important contribution. I felt it was right to take part in a project that could save millions of lives, even though it would take many years, and therefore it was important to manage it meticulously from all sides and in all respects. Cell therapy based on stem cells has tremendous potential, and I anticipate exciting developments in the field."

"The future cannot be stopped, and I predict that in the coming century, the use of stem cells will enable broad cell healing," adds Prof. Revel. "It will be possible to achieve radical cures for many diseases by introducing functioning cells as a replacement for damaged tissue. In contrast to the current situation, where at best a chronic treatment is provided, in the future, it will be possible to transplant an artificial organ, from a stem cell source, into the patient's body, where it will work 'like new.' It's a real paradigm shift, and I'm doing my best to be a part of leading it. Much of the medicine of the future will be regenerative, which will allow human cells to be printed and resume activities. Embryonic stem cells will make it possible to regenerate every cell in the human body and thus improve and sustain people in good health, with clear brains, good sensory organs, and well-functioning heart, lungs, and kidneys, far beyond the normal physiology we know in humans today."

Sounds like a real futuristic revolution.
"And we at Kadimastem strive to promote it. I have already appeared several times on television with children with juvenile diabetes and promised them on record that in another decade they will no longer need to inject insulin but will be treated with cellular medicine. We are determined to reach this goal, but to do so, the state needs to do more to help the scientific community. Israel has a significant advantage of scientific and academic leadership, and if it is cultivated, we will benefit a great deal, both in terms of Tikkun Olam and economically."

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