Stem cell and gene therapy combined show promising results in ALS patients

Cedars-Sinai researchers have developed an investigational therapy using supportive cells and a protective protein that can be delivered across the blood-brain barrier. This stem cell and gene therapy together can protect diseased motor neurons in the spinal cord of patients with amyotrophic lateral sclerosis, a potentially fatal neurological disorder known as ALS or Lou Gehrig’s disease.

In a first-of-its-kind trial, the Cedars-Sinai team has shown that delivering this combination treatment is safe for humans.

The results were reported today in the peer-reviewed journal nature medicine.

“Using stem cells is a powerful way to deliver important proteins to the brain or spinal cord that cannot otherwise cross the blood-brain barrier,” said senior author and reporter Cliff Svendsen, PhD, professor of biomedical sciences and medicine and executive director. Director of the Board of Directors of the Institute of Regenerative Medicine at the Cedar Sinai Board of Directors. “We were able to demonstrate that the engineered stem cell product can be safely implanted into human spinal cord. After a one-time treatment, these cells can survive and produce an important protein for more than three years that is known to protect motor neurons that die in ALS.”

Aimed to preserve leg function in ALS patients, the engineered cells are likely to be a powerful treatment option for this disease that causes progressive muscle paralysis, depriving people of their ability to move, speak and breathe.

None of the 18 patients were treated with treatment-; Developed by the Cedars-Sinai scholars; It had serious side effects after the transplant, according to the data.

The study used stem cells originally designed in Svendsen’s lab to produce a protein called glial cell line-derived neurotrophic factor (GDNF). This protein can promote the survival of motor neurons, the cells that pass signals from the brain or spinal cord to muscles to enable movement.

In ALS patients, diseased glial cells can become less supportive of motor neurons, and these motor neurons gradually degenerate, causing paralysis.

By transplanting protein-producing stem cells into the central nervous system, where compromised motor neurons are located, these stem cells can transform into new supportive glia and release the protective protein GDNF, which together helps motor neurons survive.

Pablo Avalos, MD, co-lead author of the paper and associate director of translational medicine on the board of directors of the Sinai Cedars Institute for Regenerative Medicine. “Because they are designed to release GDNF, we have a ‘double-hit’ approach whereby the new cells and protein can help dying motor neurons survive better in this disease.”

Along with Avalos, Robert Balloh, MD, PhD, former Professor of Neuroscience at Cedars-Sinai and now Global Head of Neuroscience at Novartis, and J. Patrick Johnson, MD, co-medical director of the Spine Center at Cedars-Sinai, They are co-authors of this post.

Safety trial

The primary objective of the experiment was to ensure that delivery of GDNF-releasing cells to the spinal cord had no safety issues or negative effects on leg function.

Because ALS patients typically lose strength in both legs at a similar rate, the researchers implanted the stem cell gene product into only one side of the spinal cord so that the therapeutic effect on the treated leg could be compared directly to the untreated leg.

The team developed a new injection device to safely deliver a stem cell gene product, called CNS10-NPC-GDNF, into patients’ spinal cords.

After the transplant, the patients were followed for a year until the team could measure strength in the treated and untreated legs. The aim of the experiment was to test safety, which was confirmed, as there was no negative effect of cell culture on muscle strength in the treated leg compared to the untreated leg.

“We’re excited that we’ve demonstrated the safety of this approach, but we need more patients to truly assess the efficacy, which is part of the next phase of the study,” said Johnson, who is also vice president of neurosurgery at Cedars-Sinai. . “Proving that we have cells that can survive for a long time and are safe in the patient is an essential part of moving forward with this experimental treatment.”

Although there were no serious side effects, the team found that in some patients the cells rose dramatically in the spinal cord, ending up in sensory areas, which can lead to cases of pain. They also saw benign growths associated with cell transplants in some cases. Svendsen noted that this will be addressed in future studies with a deeper targeting and a different surgical approach.

The investigators expect to start a new study with more patients soon. They will target the lower part of the spinal cord and enroll patients early in the disease to increase the chances of seeing the cells’ effects on the development of ALS.

“We are very grateful to all of the study participants,” Svendsen said. Amyotrophic lateral sclerosis is a difficult disease to treat, and this research gives us hope that we are getting closer to finding ways to slow this disease down.

The Cedars-Sinai team is also using GDNF-secreting stem cells in another clinical trial for ALS, transplanting the cells into a specific area of ​​the brain, called the motor cortex that controls movement initiation in the hand. They recently treated the first 16 patients in the new study that aims primarily to show safety but also to assess whether there are any effects on hand use over time.