How do Ionis pipeline drugs fight dementia and amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis (ALS) and pretation dementia (FTD) are two deadly neurodegenerative diseases with different clinical symptoms.
alS is the sexual degradation of motor neurons that control people's muscles, language and breathing ability.
FTD is the most common form of Alzheimer's disease under the age of 60 and can cause damage to the frontal temporal and/or frontal lobes of the brain.
with the development of the disease, patients' normal work and even self-care become more and more difficult.
these two diseases are thought to be caused by a common underlying mechanism: mutations in the C9orf72 gene cause the toxic build-up of TAR DNA binding protein 43 (TDP-43).
now, researchers at Mayo Medical Center and the University of Pennsylvania have provided more insight into this mechanism by revealing the role of another protein called poly (GR) in TDP-43 aggregation.
September 2nd, in a new study published in Science Translational Medicine, scientists found that an antisant oligonucleotide drug developed by Ionis Pharmaceuticals targeted polyly (GR) proteins to fight the accumulation of TDP-43 proteins as a promising treatment for neurodegenerative diseases.
the drug can reduce neurodegenerative lesions in mice with C9orf72 mutations.
photo source: Science Translational Medicine Many ALS and FTD cases are associated with abnormal amplification of the G4C2 repeat sequence in C9orf72, which causes transcription of different proteins, including poly (GR).
antonymic oligonucleotides (single-stranded RNA designed to inhibit target mRNA transcription as a harmful protein) is considered an effective way to address this problem.
Phase I trial for adult patients with ALS associated with C9orf72, developed in collaboration with Biogen and Ionis, is under way and data are expected to be released next year.
Image source: Professor James Shorter, co-author of the paper on the official website of Ionis Pharmaceuticals, said: "The abnormal amplification of the G4C2 repeat sequence in the C9orf72 gene has somehow led to the aggregation of TDP-43, but it is not clear how the two are linked.
found that if these toxic poly (GR) proteins were around, TDP-43 would gather faster, indicating a direct link between mutation, poly (GR) and TDP-43.
study, scientists first demonstrated the role of poly (GR) in TDP-43 aggregation at protein levels, and tested the results in human cell and mouse experiments.
specifically, Poly (GR) promotes TDP-43 aggregation primarily by disrupting the way neurons transport proteins between the cytonal and nucleic cells.
proved that poly (GR) directly led to TDP-43 aggregation, scientists continued to test whether the antisumptive oligonucleotide drug c9ASO, which targets repeated sequences of G4C2 (developed by Ionis Pharmaceuticals and currently being studied in clinical trials), could reduce the aggregation of TDP-43.
they injected c9ASO into the brains of 3-month-old G4C2 mutant mice, a treatment that significantly reduced the levels of poly (GR) and TDP-43, and also verified that a decrease in poly (GR) and other G4C2-related pathology was associated with a reduction in TDP-43 pathology.
c9ASO has previously been shown to turn off the repeated amplification of the C9orf72 gene and reduce poly (GR), but this is the first time it has been shown to reduce the aggregation of TDP-43.
A) RNA expression with G4C2 repeat sequences decreased after 3 months of treatment; B) poly (GR) treated with c9ASO and other DRP protein poly (GA) and poly (GP) decreased; C-E) TDP-43/a More importantly, scientists have found that the drug prevents the loss of neurons in these model mice and protects neurons from damage, using plasma nerve wire light chains, a known biomarker of neurodegenerative changes.
, the study is the first to reveal how the toxic poly (GR) protein produced by the mutated C9orf72 gene stimulates TDP-43 aggregation found in PATIENTs with ALS and FTD.
Hana Odeh, who was involved in the study, said: "This finding provides an exciting potential therapeutic target for these neurodegenerative diseases, poly (GR).
" References: 1 s investigational drug stops toxic proteins tied to neurodegenerative diseases (Source: medical press) 2 s Casey N. Cook etal. C9orf72 poly (GR) aggregation induces TDP-43 proteinopathy. Sci. Transl. Med. (2020). DOI: 10.1126/scitranslmed.abb3774 3' How Ionis' antisense drugs help combat ALS and dementia (Source: Fierce Biotech) 4. F. Gendron etron al. Poly (GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci. Transl. Med. (2017) Original title: Science Sub-Journal Revealed: Anthrotic Oligonucleotide Tap iomis Pipeline Drug, How to Fight Dementia and Amyotrophic Lateral Sclerosis?