Stem Cell-based Therapy to Produce GDNF Found Safe in Human Trial

Data show engineered stem cells survive, produce GDNF for over 3 years

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Stem cells engineered to mature into nerve-supporting cells that produce GDNF — a key factor for motor neuron survival — were safely delivered into the spinal cord of people with amyotrophic lateral sclerosis (ALS), according to data from a Phase 1/2a clinical trial.

These cells, dubbed CNS10-NPC-GDNF, were found to survive and produce GDNF for at least 42 months, or about 3.5 years.

“GDNF on its own can’t get through the blood-brain barrier, so transplanting stem cells releasing GDNF is a new method to help get the protein to where it needs to go to help protect the motor neurons,” Pablo Avalos, MD, the study’s co-first author, from the Cedars-Sinai Medical Center in Los Angeles, where the trial took place, said in a center press release.

The blood-brain barrier is a highly selective membrane that tightly regulates what substances from the bloodstream can enter the brain and spinal cord. It works to prevent bacteria and toxins from reaching the brain, but also can stop therapies from reaching their treatment targets.

“Because [these stem cells] are engineered to release GDNF, we get a ‘double whammy’ approach where both the new cells and the [GDNF] protein could help dying motor neurons survive better in this disease,” added Avalos, the associate director of translational medicine at the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

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J. Patrick Johnson, MD, another of the study’s co-first authors and co-medical director of the Spine Center at Cedars-Sinai, said the team is looking forward to further testing the stem cell-based therapy.

“We’re excited that we proved safety of this approach, but we need more patients to really evaluate efficacy, which is part of the next phase of the study,” Johnson said.

The study, “Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial,” was published in Nature Medicine.

Testing CNS10-NPC-GDNF in humans

In people with ALS, motor neurons — the nerve cells in the brain and spinal cord that control muscle movement — stop working or die, and can no longer send signals to the muscles in the body. As a result, the muscles waste away and become increasingly weaker over time.

This progressive loss of motor neurons may also be associated with defective astrocytes, star-shaped cells that protect and nurture nerve cells, including motor neurons. These cells’ protective effect against damage is associated, at least in part, with the release of a protein called GDNF.

While this protein is key for motor neurons to thrive, it cannot cross the blood-brain barrier. This means that potential GDNF-based approaches would have to administer the protein or promote its cell-derived production in the brain and/or spinal cord to result in benefits.

In a previous study, the Cedars-Sinai team transplanted human nerve cell-progenitor cells, which were genetically engineered to produce GDNF, into the brain of a mouse model of ALS. These cells were found to delay disease progression and extended the animals’ survival.

The team also found that this approach was associated with the stem cells’ maturation into astrocytes.

To assess whether this approach would be safe in people with ALS, the researchers launched a Phase 1/2a clinical trial (NCT02943850). The trial tested two doses of the engineered stem cells — those known as CNS10-NPC-GDNF — in 18 patients with leg weakness. The participants comprised 10 women and eight men.

The patients’ mean age was 57.5 years and they experienced the first symptoms of ALS a mean 18.8 months prior to the study’s start. Electromyography, a test that measures the electrical activity of muscle tissue, revealed that their leg muscles were cut off from their motor neuron supply.

Half of the participants were assigned to receive a total of 2 million engineered stem cells, while the other nine patients received 5 million stem cells in total.

Treatment was administered through 10 injections into one side of the spinal cord, and all patients completed several assessments over one year. This also allowed a comparison of the effects on the treated side, or leg, versus the untreated leg.

Each participant was given immunosuppressive treatment for up to one year to lower the immune system’s ability to fight off the transplanted stem cells.

Results showed that CNS10-NPC-GDNF was generally safe and well-tolerated, meeting the trial’s main goal. Immediately after treatment, 88.9% of patients in the low-dose group and 66.7% in the high-dose group experienced an abnormal sensation, or episodes of pain or discomfort, around the injection sites.

Foot pain on the treated side lasted more than six months in nine participants, five of whom required pain medication.

Common adverse events included falls, pain in the hands and feet, nausea, back pain, and muscle weakness — all of which are “typically associated with ALS, immunosuppression and surgery,” the team wrote.

No serious adverse events occurring during the trial were deemed related to treatment.

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Regarding secondary goals, the team found that the patients’ disease progression rate was typical of this patient population. On average, treated legs lost strength at a slower rate than untreated legs, but this difference failed to reach statistical significance, according to the trial data.

No negative effects found

Importantly, the therapy did not result in any negative effect on the progression of symptoms in the treated versus untreated legs.

Moreover, analyses of brain and spinal cord tissue taken after the deaths of treated patients showed that the transplanted cells not only remained alive, but also continued making GDNF following treatment. These analyses were conducted on 13 of the 14 patients who died of disease progression between 14 and 42 months after treatment.

The researchers noted that these results occurred despite the patients receiving immunosuppressive treatment for only one year. Further, in all but one case, no signs of rejection or an inflammatory reaction were detected.

Notably, while clinical MRI scans showed no spinal cord abnormalities, benign growths were frequently observed at several injection sites in deceased patients.

“We were able to show that the engineered stem cell product can be safely transplanted in the human spinal cord,” said Clive Svendsen, PhD, the study’s senior author.

“After a one-time treatment, these cells can survive and produce an important protein for over three years that is known to protect motor neurons that die in ALS,” added Svendsen, a professor of medical sciences and medicine, and the executive director at Cedars-Sinai.

The researchers said this trial was the first of its kind — and they’re already building on its positive results.

“Given encouraging outcomes from this initial trial, a combined cell and gene therapy approach holds great promise as a therapeutic option for ALS and other neurodegenerative diseases,” the scientists concluded.

An ongoing Phase 1/2a trial (NCT05306457), which enrolled 16 other ALS patients, is now testing how safe CNS10-NPC-GDNF is when transplanted directly into the motor cortex, a brain region involved in the control of voluntary movements.