New hope for ALS patients

Amyotrophic lateral sclerosis, or Lou Gehrig’s disease, will forever be associated with the legendary baseball player whose diagnosis in 1939 brought this neurodegenerative condition to the public consciousness.

ALS continues to affect two out of every 100,000 people each year, driving a devastating trajectory that begins with the death of motor neurons in the brain and spinal cord, and ends with losing the ability to walk, talk, swallow, and breathe. During this process, the mind otherwise remains completely intact, silent witness to a progressive decline that typically culminates in fatal respiratory failure within five years.

With only one FDA-approved drug in existence - a compound that extends ALS patients’ lifespan by no more than three months - there is a critical need for new medical strategies. One strategy currently in development is based on the work of an emeritus Weizmann Institute faculty member, drug discovery pioneer, and Israel Prize winner, Prof. Michel Revel, of the Department of Molecular Genetics.

Prof. Revel is Chief Scientist of Kadimastem, a company based on stem cell technology he developed while at the Institute. Kadimastem’s focus is regenerative medicine—a clinical approach that seeks to harness the potential of stem cells to repair or replace damaged tissues in order to combat disease.

“Traditionally, drugs have been created by chemists, who use the tools of bioengineering to design molecules that can perform specific tasks in the body,” says Prof. Revel who, following his retirement from the Institute, co-founded Kadimastem together with company CEO Yossi Ben-Yossef in 2009. “But today, cells—not molecules—can be the medication. We are using human embryonic stem cells to produce precursor cells that—when transplanted into the spinal cord—differentiate into non-neural brain cells that slow the progression of ALS in a rat model. We believe this can work in human ALS patients as well.”

Kadimastem’s human trials on ALS patients are scheduled to begin at Jerusalem’s Hadassah Hospital in September 2017.

The path to the new, stem cell-based approach to ALS therapy began when Kadimastem licensed Prof. Revel’s stem cell patents from Yeda, the Weizmann Institute’s commercialization arm. But as Yeda CEO Gil Granot-Mayer explains, the most valuable intellectual property is human expertise. “In his long career at the Weizmann Institute, Prof. Revel was extremely successful in the bioengineering of molecules to create new drugs to fight disease. Our hope is that Prof. Ravel and his team’s unique expertise in stem-cell-based drug design will address this unmet need,” he says.

A regenerative approach

Prof. Revel is the creator of Rebif®, a multiple sclerosis drug now marketed by Merck, with sales on the order of $2.5 billion per year. At a time when most researchers were engineering medically useful protein molecules within yeast and bacteria, Prof. Revel took a more “exotic” route of using cells taken from the Chinese Hamster in order to obtain the protein interferon-beta in a form identical to the natural protein found in the human body. Rebif® was recently shown to prevent the more serious symptoms of advanced MS in 80 percent of earlystage patients who had been using the drug for 15 years.

In addition to Copaxone®, another MS drug developed at the Institute, Rebif® contributes to quality of life by slowing down disease progression. However, it was Prof. Revel’s desire to achieve a complete cure for MS that led him to the stem cell approach he is now using in the fight against ALS.

In 2000, he began to explore the use of stem cells to regenerate the neuron-insulating material lost as a result of MS. “But since MS is a diffuse process that occurs throughout the brain, it was not a practical target for stem cell therapy,” he says. “That’s when I turned my attention to generating a class of cells called astrocytes, which can mitigate the loss of motor neurons characteristic of ALS.”

Astrocytes are non-neural cells critical for maintaining chemical balance in the environment surrounding motor neurons. “The significance of these cells for promoting motor neuron survival “Kadimastem’s achievement is producing precursor cells that, once transplanted into the spinal cord, differentiate into the mature astrocytes that motor neurons need to survive. This is what we believe may be a real breakthrough for human ALS patients.”

Kadimastem is pursuing additional avenues, including a stem-cell derived approach to insulin production for diabetics (see box), and a technology for optimizing insulin generation by selecting the right stem cells, developed by Weizmann Institute professors Yoav Soen and Michal Walker, and recently licensed to the company by Yeda. Carried out by the Kadimastem’s 35 employees—including 12 research scientists—these projects are a continuation of the applicative approach that Prof. Revel developed over a 40-year career.

“In industry, the goal is to create a working technology that’s safe, and that meets all the regulatory requirements,” says Prof. Revel. “It’s a challenge, but if we can prolong and improve the lives of people suffering from disease, it’s all worth it.”

A device for diabetes?

With a global population of 150 million diabetics relying on injected insulin, the creation of a device for generating insulin in the body would be a revolutionary event. Kadimastem is collaborating on a system that uses human embryonic stem cells as a platform for creating the beta cells that produce insulin. The company’s goal is to create an encapsulated system that could be implanted in patients, constantly sensing blood glucose levels and secreting insulin accordingly, while avoiding rejection by the body’s immune system. Kadimastem is configuring the device and is aspiring for clinical trials in humans.