In virtually all persons with amyotrophic lateral sclerosis (ALS), a protein called TDP-43 is lost from its normal location in the nucleus of the cell. This triggers the loss of stathmin-2, a protein crucial to regeneration of neurons and the maintenance of their connections to muscle fibers, essential to contraction and movement.
In the study it can be demonstrated that stathmin-2 loss can be rescued using designer DNA drugs that restore normal processing of protein-encoding RNA.
“With mouse models we engineered to misprocess their stathmin-2 encoding RNAs, like in these human diseases, we show that administration of one of these designer DNA drugs into the fluid that surrounds the brain and spinal cord restores normal stathmin-2 levels throughout the nervous system,” study author Don Cleveland says.
Cleveland is broadly credited with developing the concept of designer DNA drugs, which act to either turn on or turn off genes associated with many degenerative diseases of the aging human nervous system, including ALS, AD, Huntington’s disease and cancer.
In ALS, TDP-43 loss impacts the motor neurons that innervate and trigger contraction of skeletal muscles, causing them to degenerate, eventually resulting in paralysis.
“In almost all instances of ALS, there is aggregation of TDP-43, a protein that functions in maturation of the RNA intermediates that encode many proteins. Reduced TDP-43 activity causes misassembly of the RNA-encoding stathmin-2, a protein required for maintenance of the connection of motor neurons to muscle,” said Cleveland.
“Without stathmin-2, motor neurons disconnect from muscle, driving paralysis that is characteristic of ALS. What we have now found is that we can mimic TDP-43 function with a designer DNA drug, thereby restoring correct stathmin-2 RNA and protein level in the mammalian nervous system.”
Specifically, the researchers edited genes in mice to contain human STMN2 gene sequences and then injected antisense oligonucleotides (small bits of DNA or RNA that can bind to specific RNA molecules blocking their ability to make a protein or changing how their final RNAs are assembled) into cerebrospinal fluid. The injections corrected STMN2 pre-mRNA misprocessing and restored stathmin-2 protein expression fully independent of TDP-43 function.
Michael W. Baughn, Ze’ev Melamed, Jone López-Erauskin, Melinda S. Beccari, Karen Ling, Aamir Zuberi, Maximilliano Presa, Elena Gonzalo-Gil, Roy Maimon, Sonia Vazquez-Sanchez, Som Chaturvedi, Mariana Bravo-Hernández, Vanessa Taupin, Stephen Moore, Jonathan W. Artates, Eitan Acks, I. Sandra Ndayambaje, Ana R. Agra de Almeida Quadros, Paayman Jafar-nejad, Frank Rigo, C. Frank Bennett, Cathleen Lutz, Clotilde Lagier-Tourenne, Don W. Cleveland. Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. Science, 2023; 379 (6637): 1140 DOI: 10.1126/science.abq5622
University of California – San Diego. “DNA treatment could delay paralysis that strikes nearly all patients with ALS: In both mouse and human motor neuron studies, a DNA designer drug restored levels of a protein necessary to keep motor neurons functioning, returning activity impaired in amyotrophic lateral sclerosis; findings could lead to clinical trials..” ScienceDaily. ScienceDaily, 16 March 2023. <www.sciencedaily.com/releases/2023/03/230316154104.htm>.
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