The new ALS treatment is safe
Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons, leading to paralysis and death, usually within 3-5 years after diagnosis. The development of the disease probably contributes to the dysfunction of astrocytes – neuroglial cells responsible for the life support and repair of neurons.
A research team from Cedars-Sinai Medical Center has previously found that stem cells can be used to deliver important proteins to the brain or spinal cord that otherwise cannot penetrate the blood-brain barrier. The experimental therapy developed by the group with precursor cells of neurons carrying the neuroprotective protein gene was tested on animals. Stem cells, once in the spinal cord, differentiated into astrocytes and protected motor neurons from degeneration. Therapy has shown safety in animal models of ALS.
A new clinical trial of the safety of experimental therapy phase 1/2a involved 18 patients with ALS. Neurogenic progenitor cells were transplanted to all of them, previously modified by transduction to produce glial cell line-derived neurotrophic factor (GDNF). This protein can contribute to the survival of motor neurons – cells that transmit signals from the brain or spinal cord to skeletal muscles to provide movement.
Double whammy
The transduced progenitor cells, transduced by GDNF (CNS10-NPC-GDNF), entering the spinal cord, differentiated into astrocytes, which are involved in the repair of neurons. In addition, they released the neuroprotective protein GDNF, which protects motor neurons from degeneration characteristic of ALS.
The GDNF protein itself is not able to penetrate the blood–brain barrier, so the transplantation of stem cells carrying the GDNF gene is a new effective method of delivery to the central nervous system. Thus, a double-whammy effect is obtained, when both new cells and GDNF protect the suffering neurons.
Safety test
The main goal of the clinical study was to make sure that the delivery of GDNF-releasing cells to the spinal cord is safe and does not have negative consequences for leg function.
Since patients with ALS usually lose strength in both legs at the same rate, the researchers transplanted stem cells only to one side of the spinal cord so that the therapeutic effect on the leg of the same name could be directly compared with an untreated leg.
After the transplant, the patients were monitored for a year to assess the strength in both legs. The aim of the study was to check the safety, which was confirmed, since there was no negative effect of therapy on the muscle strength of the treated leg compared to the intact one.
Despite the absence of side effects, in some patients, the cells migrated up the spinal cord too actively, getting into sensitive areas, which may have led to pain.
Tissue analysis of 13 participants who died from disease progression showed graft survival and active GDNF production. In addition, benign neuromas near the sites of stem cell injection were frequent accidental findings during autopsy.
It is planned to avoid pain and the growth of neuromas in future studies by using more precise targeting and changing the surgical method of implantation.
The researchers expect that a new study involving more patients will begin in the near future. The target will be the lower parts of the spinal cord, and patients with an earlier stage of the disease will participate in order to more reliably assess the effect of GDNF-producing progenitor cells on the progression of ALS.
The group also uses stem cells carrying the GDNF gene in another ALS clinical study: these cells are planted in the motor cortex of the brain, which controls the initiation of movement in the arm. Recently, the first of 16 patients received treatment. The study is aimed primarily at demonstrating safety, as well as assessing the effects of treatment on hands over time.
Article by R.Baloh et al. Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial is published in the journal Nature Medicine.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru Based on Cedars-Sinai Medical Center: Stem cell-gene therapy shows promise in ALS safety trial.