In both mouse and human motor neuron studies, a DNA designer drug restored levels of a protein necessary to maintain motor neuron function and restore activity impaired in amyotrophic lateral sclerosis; Findings could lead to clinical trials. – Zoo House News

In virtually 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 loses its normal position in the nucleus. This, in turn, triggers the loss of stathmin-2, a protein critical to regenerating neurons and maintaining their connections to muscle fibers, which are essential for contraction and movement.

In the March 16, 2023 issue of Science, a team of scientists led by senior study author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences and Cellular and Molecular Medicine at the University of California San Diego School of Medicine, wrote with colleagues and show elsewhere that stathmin-2 loss can be salvaged using designer DNA drugs that restore normal processing of protein-coding RNA.

“Using mouse models that we constructed to misprocess their stathmin-2-encoding RNAs, as in these human diseases, we show that administering one of these designer DNA drugs to the fluid lining the brain and spinal cord surrounds, restores normal stathmin-2 levels throughout the nervous system,” Cleveland said.

Cleveland is widely credited with developing the concept of designer DNA drugs that either turn on or off genes associated with many 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 such drug has been approved for the treatment of a childhood neurodegenerative disease called spinal muscular atrophy.

The new study builds on ongoing research by Cleveland and others on the role and loss of TDP-43, a protein implicated in ALS, AD and other neurodegenerative diseases. In ALS, TDP-43 loss affects the motor neurons that innervate skeletal muscles and cause them to contract, causing them to degenerate and eventually lead to paralysis.

“In almost all cases of ALS, there is aggregation of TDP-43, a protein that functions in the maturation of the RNA intermediates that encode many proteins. Reduced TDP-43 activity leads to misassembly of the RNA-encoding stathmin-2, a protein required for maintaining motor neuron-muscle connectivity,” Cleveland said.

“Without Stathmin-2, motor neurons separate from muscles, resulting in the paralysis characteristic of ALS. What we have now found is that we can mimic TDP-43 function with a designer DNA drug, thereby restoring correct levels of stathmin-2 RNA and protein in the mammalian nervous system.”

Specifically, the researchers engineered genes in mice to contain human STMN2 gene sequences and then injected antisense oligonucleotides — small pieces of DNA or RNA that bind to specific RNA molecules and block their ability to make a protein or change the composition of theirs final RNAs — into the cerebrospinal fluid. The injections corrected the misprocessing of STMN2 pre-mRNA and restored stathmin-2 protein expression completely independent of TDP-43 function.

“Our findings lay the groundwork for a clinical trial to delay paralysis in ALS by maintaining stathmin-2 protein levels in patients using our designer DNA drug,” Cleveland said.

Co-authors include: Michael W. Baughn, Jone López-Erauskin, Melinda S. Beccari, Roy Maimon, Sonia Vazquez-Sanchez, Jonathan W. Artates, and Eitan Acks, all at the Ludwig Institute for Cancer Research-UC San Diego and UC San Diego; Ze’ev Melamed, Ludwig Institute for Cancer Research-UC San Diego, UC San Diego and The Hebrew University of Jerusalem; Karen Ling, Paayman Jafarnejad, Frank Rigo and C. Frank Bennett, all at Ionis Pharmaceuticals; Aamir Zuberi, Maximilliano Presa, Elena Gonzalo-Gil and Cathleen Lutz, all at the Jackson Laboratory; Som Chaturvedi, Mariana Bravo-Hernández, Vanessa Taupin and Stephen Moore, all at UC San Diego; L Sandra Ndayambaje and Ana R Agra de Almeida Quadros, Harvard Medical School; Clotilde Lagier-Tourenne, Harvard University and Harvard University Broad Institute and Massachusetts Institute of Technology.