Because a genetic defect causes progressive destruction of spinal motor neurons, most children with spinal muscular atrophy (SMA) will never be able to skip rope, hide and seek, or even walk. By correcting this mutation in the patient's stem cells, Italian scientists successfully controlled the disease's progression in a mouse model. The results of the study were published in the journal Science Translational Medicine, indicating that SMA patients may one day be able to provide neuronal grafts as donors to treat their own diseases.
"This is a wonderful study that analyzes the potential of using induced pluripotent stem cells (iPSCs) to treat genetic diseases," said Lisa Ellerby (not involved in the study) at the Buck Aging Institute. Ellerby is currently conducting research to use this technology to treat Huntington's disease (HD).
Over the past 2 years, stem cell therapy has achieved good results in early clinical trials of sporadic neurological diseases such as amyotrophic lateral sclerosis (ALS) and macular degeneration. Such treatments are also expected to be used to treat spinal cord injuries. Just this week, the US Food and Drug Administration (FDA) approved the biopharmaceutical company NeuralStem to begin phase I clinical trials of embryonic stem cells. This is the second approved spinal cord stem cell therapy trial in the United States. The first trial was first carried out by Geron, which suddenly stopped in 2011.
Combined with genetic correction, the scope of application of this program will be expanded to treat a wide range of genetic diseases, Ellerby said: "As the field proves that the patient's cells can be genetically corrected, we are using this new technology to establish diseases The model, or the development of new therapies for human patients, is another step closer. "
SMA is the main genetic cause of infant mortality, and one in every 6000 newborns worldwide dies from this disease. When the individual's SMN1 (survival motor neuron 1) gene is partially deleted, it will cause disease. SMN1 regulates multiple cellular processes of RNA metabolism. There is currently no cure for this disease.
Somewhere along the evolutionary path of humans, the SMN1 gene replicates, leading to SMN2 production, which can partially compensate for SMN1 deficiency in SMA patients. Every SMA patient has an SMN2 gene. Those patients with multiple copies of SMN2 are not so severe and can survive into adulthood. However, SMN1 and SMN2 are not the same: because a single nucleotide difference impairs the pre-mRNA splicing of SMN2, the rate of functional protein production is only one-tenth of that of SMN1 protein.
Giacomo Comi, a neurologist at the University of Milan, believes that if a single differential nucleotide of SMN2 is changed to mimic SMN1 in spinal neurons, perhaps the cells can survive. Instead of correcting the SMN2 gene in endogenous SMA neurons, because when the disease is diagnosed, the internal SMA neurons may have died or are dying, Comi proposed to replace these neurons with iPSCs that carry copies of corrected SMN2.
"The ideal treatment method for SMA will be a combination therapy strategy that uses molecular therapy to solve genetic defects, and cell transplantation can complement the disease pathology," said the first author of the article, Stefania Corti of the University of Milan.
To achieve this goal, Comi and colleagues reprogrammed skin cells from SMA patients into iPSCs. The researchers then transfected iPSCs with sequence-specific oligonucleotides to repair single-base mutant genes. In these two steps, the researchers did not use viral vectors, thus avoiding the risk of tumor formation or harmful immune reactions after transplantation. Finally, the researchers differentiated genetically modified iPSC cells into motor neurons and transplanted them into mice that showed symptoms of SMA.
SMA pups received “corrected†spinal cord transplantation of iPSC-derived neurons from SMA patients one day after birth, and showed significant reduction in spinal neuron loss and muscle atrophy. Open field experiments and grip strength tests show that they are more physically active and stronger. In addition, nerve transplantation has also extended their lifespan by 50%.
The results show that the transplanted neurons integrated into the spinal cord can alleviate motor dysfunction. In fact, fluorescence histology revealed that the transplanted neurons formed a neuromuscular junction with the muscle tissue near the spinal cord. Transplanting neurons also promotes the survival of endogenous neurons carrying SMA mutations, indicating that this treatment also provides neuroprotective benefits for surrounding tissues. When cultured in culture, corrected iPSC-derived neurons secrete more growth factors than uncorrected neurons, which may explain this transfer of vitality.
Of course, this research is still at a very early stage, and it will take several years to translate this achievement into the clinic, but "the significance is undoubtedly significant, not only for SMA disease, but also for similar neuropromotability such as ALS. Diseases and other neuromuscular diseases. These data indicate the feasibility of generating patient-specific disease-free cells, "Corti said.
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