In studies of both mouse and human motor neurons, a DNA designer drug restored levels of a protein necessary to keep motor neurons functioning, resulting in impaired activity in ALS. The results could lead to clinical trials. – Teach daily

In nearly all people with amyotrophic lateral sclerosis (ALS) and in up to half of all cases of Alzheimer’s disease (AD) and frontotemporal dementia, a protein called TDP-43 is lost from its normal location in the cell nucleus. In turn, this leads to the loss of Stathmin-2, a protein important for regeneration of nerve cells and maintaining their connections with muscle fibers, which is essential for contraction and movement.

Writing in the March 16, 2023 issue of Sciencesa team of scientists led by senior study author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences, and Cellular and Molecular Medicine at UC San Diego School of Medicine, with colleagues and elsewhere, has demonstrated that stathmin-2 loss can be rescued using DNA-designed drugs. which restores the normal processing of protein-coding RNA.

“With mouse models that we designed to misprocess their stathmin-2 RNA, as is the case in these human diseases, we show that administering one of these engineered DNA drugs into the amniotic fluid restores normal stathmin-2 levels throughout the body. Cleveland said.

Cleveland is widely credited with developing the concept of designer DNA drugs, which either turn on or off genes associated with several degenerative diseases of the aging human nervous system, including ALS, AD, Huntington’s disease and cancer.

Several designer DNA drugs are currently in clinical trials for multiple diseases. One of these drugs is approved to treat a childhood neurodegenerative disease called spinal muscular atrophy.

The new study builds on ongoing research by Cleveland and others regarding the role and loss of TDP-43, a protein associated with ALS, Alzheimer’s disease and other neurodegenerative disorders. In ALS, loss of TDP-43 affects the motor neurons that innervate and trigger skeletal muscle contraction, causing their deterioration, eventually leading to paralysis.

“In almost all cases of ALS, there is an aggregation of TDP-43, a protein that functions in the maturation of an RNA intermediate that encodes several proteins. Decreased activity of TDP-43 leads to misaggregation of the RNA-encoding protein stathmin-2. It is required to maintain nerve cell communication. kinetics with muscles,” Cleveland said.

“Without stathmin-2, motor neurons disconnect from muscles, leading to the paralysis that characterizes ALS. What we have now found is that we can mimic the function of TDP-43 using a tailored DNA drug, thereby restoring the correct Stathmin-2 RNA and protein level in Mammalian nervous system”.

Specifically, the researchers edited genes in mice to contain the sequence of the human STMN2 gene and then injected anti-interacting oligonucleotides — small fragments of DNA or RNA that can bind to certain RNA molecules, blocking their ability to make a protein or changing how the final RNAs are assembled. – in the cerebrospinal fluid. The injection corrected misprocessing of STMN2 pre-mRNA and restored stathmin-2 protein expression completely independent of TDP-43 function.

“Our findings lay the foundation for a clinical trial to delay immobilization in ALS by maintaining stathmin-2 protein levels in patients with our designed DNA drug,” Cleveland said.

Co-authors are Michael W. Bogen, John Lopez-Erauskin, Melinda S. Beccari, Roy Mimon, Sonia Vazquez-Sanchez, Jonathan W. Artats, and Eitan Ax, all at Ludwig Institute for Cancer Research – UCSD and UCSD. Ze’ev Melamed, Ludwig Institute for Cancer Research – UC San Diego, UC San Diego, and The Hebrew University of Jerusalem; Karen Ling, Payman Jafarnejad, Frank Rigo, and S. Frank Bennett, all at Ionis Pharmaceuticals; Amer Zuberi, Maximiliano Brisa, Elena Gonzalo Gil, and Kathleen Lutz, all in the Jackson Lab; Som Chaturvedi, Mariana Bravo-Hernandez, Vanessa Tobin, and Stephen Moore, all at UC San Diego; L. Sandra Ndayambaje and Ana R. Agra de Almeida Quadros, Harvard Medical School; Clotilde Laguerre Turenne, Harvard University and the Broad Institute of Harvard University and the Massachusetts Institute of Technology.

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