ALS Treatment: Clinical success
Using a short synthetic chain of chemically modified nucleotides constructed at the Institute of RNA Therapy at the University of Massachusetts Medical School (UMass Chan Medical School), Robert Brown Jr., Jonathan Watts and their colleagues demonstrated the ability to suppress mutant forms of the C9ORF72 gene in a pilot study involving a single patient.
The C9ORF72 gene is the most common cause of familial amyotrophic lateral sclerosis (ALS) and familial frontotemporal dementia. The results obtained can serve as a basis for research in the treatment of ALS and other neurodegenerative diseases.
Therapy using antisense oligonucleotide (antisense RNA, asRNA) injected into the spinal canal resulted in a significant decrease in the level of ALS-related neurotoxins, known as proteins with dipeptide repeats, in the cerebrospinal fluid. During the study, the functional assessment of the ALS of the volunteer and other indicators of exposure were mostly stable or slightly improved. The patient who experienced weakness in the legs and feet prior to treatment did not have any neurological or other side effects.
The study showed that asRNA-based treatment, which had previously demonstrated efficacy in vitro, safely and effectively suppresses the C9ORF72 gene in a patient with ALS and reduces the level of the mutant C9ORF72 protein. Currently, clinical trials involving several people are being planned to find out whether this treatment can slow down the progression of the disease.
asRNAs are short synthetic single-stranded oligonucleotides that can connect to complementary regions of RNA or DNA and alter gene expression. The type of asRNA used in this study stops gene expression by binding to matrix RNA (mRNA). Once this binding occurs, the resulting hybrid sequence is naturally decomposed by enzymes in the cell.
The attractiveness of the development of antisense oligonucleotides for the treatment of ALS and other neurodegenerative diseases lies in its simplicity. They interfere with protein synthesis on the mRNA matrix, and the mutant protein will never be created. It remains only to determine how to deliver asRNA to a specific cell type. Theoretically, the method can be used to treat other neurodegenerative diseases only by changing the sequence of nucleotides. And by eliminating the pathogenic protein from the cell, it is potentially possible to stop or reverse the progression of the disease. To date, four asRNA–based treatments have been approved by the U.S. Food and Drug Administration: three of them are intended for the treatment of Duchenne muscular dystrophy, one for spinal muscular atrophy.
ALS is a progressive neurodegenerative disorder that is accompanied by the loss of motor neurons that control skeletal muscles. Approximately 10% of ALS are hereditary and are caused by a mutation in the patient's DNA. The remaining 90% of cases are classified as sporadic and occur in cases where there is no family history of diseases. Every year in the USA, 6,000 people are diagnosed with ALS. It is not known why motor neurons die in this disease, but it is believed that this neurodegeneration is associated with a complex complex of cellular and molecular processes.
Mutations in the C9ORF72 gene, which is the object of this study, account for 40% of familial ALS cases, as well as about 10% of non-hereditary cases. These mutations are also the cause of about 25% of cases of familial frontotemporal dementia. This is a large number, and it is hoped that the new therapeutic strategy will potentially help treat both diseases.
ALS patients with the C9ORF72 mutation have an abnormally long repeating pattern of a six-letter nucleotide sequence (YYYYCC). A person without a mutation usually has less than 20-30 such repeats, but in the presence of a mutation, these fragments can occur hundreds of times. The repeating sequence disrupts the expression of mutant C9ORF72, and additionally produces neurotoxins known as proteins with dipeptide repeats.
Even when it was understood that destroying mutations of a single gene that lead to neurodegenerative diseases could have a therapeutic effect, it turned out to be difficult to safely and efficiently deliver oligonucleotide agents to neurons. Another problem was the need to eliminate mutant proteins while maintaining a sufficient number of functional proteins for cell life. In other words, you can't just remove the entire C9ORF72 protein from neurons, because it can harm cells. Any potential treatment should be more selective.
In this study, Watts, Brown and colleagues targeted two specific isoforms of the C9ORF72 gene that generate toxic proteins with dipeptide repeats, and identified several asRNAs that reduce their levels. Once the ASO was identified, Watts modified them to adapt for insertion into the cerebrospinal fluid, increasing safety, distribution and stability in the brain and spinal cord. He identified combinations of various phosphate and carbohydrate components that allow cells to assimilate asRNA.
This study confirms that asRNA therapy in humans can effectively and safely suppress the expression of the C9ORF72 protein. The intervention is aimed not only at the mutant allele, but also at incorrect transcripts and proteins with dipeptide repeats generated by this allele. Suppression of the expression of mutant C9ORF72 should be studied further.
Article H.Tran et al. Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide is published in the journal Nature Medicine.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of UMass Chan Medical School: UMass Chan clinical trial shows antisense oligonucleotide safely suppresses mutant ALS gene in pilot human study.