MSGID: 1:317/3 6413ecea   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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.    
      
     Date:   
         March 16, 2023   
     Source:   
         University of California - San Diego   
     Summary:   
         Researchers use a DNA designer drug to restore key protein levels   
         in motor neurons, delaying paralysis in a mouse model of ALS.   
      
      
         Facebook Twitter Pinterest LinkedIN Email   
   FULL STORY   
   ==========================================================================   
   In virtually all persons 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 nucleus of the cell. In turn, 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.   
      
      
   ==========================================================================   
   Writing 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 University   
   of California San Diego School of Medicine, with colleagues and elsewhere,   
   demonstrate 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," Cleveland said.   
      
   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.   
      
   Several designer DNA drugs are currently in clinical trials for   
   multiple diseases. One such drug has been approved to treat a childhood   
   neurodegenerative disease called spinal muscular atrophy.   
      
   The new study builds upon ongoing research by Cleveland and others   
   regarding the role and loss of TDP-43, a protein associated with ALS,   
   AD and other neurodegenerative disorders. 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 of 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 cerebral spinal fluid. The injections corrected STMN2   
   pre-mRNA misprocessing and restored stathmin-2 protein expression fully   
   independent of TDP-43 function.   
      
   "Our findings lay the foundation 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 Lo'pez-Erauskin, Melinda S.   
      
   Beccari, Roy Maimon, Sonia Vazquez-Sanchez, Jonathan W. Artates and   
   Eitan Acks, all at 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 Jafar-nejad, 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-Herna'ndez, 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 Broad Institute   
   of Harvard University and Massachusetts Institute of Technology.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Human_Biology # Genes # Amyotrophic_Lateral_Sclerosis   
                   # Nervous_System   
             o Mind_&_Brain   
                   # Huntington's_Disease # Neuroscience #   
                   Disorders_and_Syndromes # Alzheimer's   
       * RELATED_TERMS   
             o Excitotoxicity_and_cell_damage o Sensory_neuron o Mouse   
             o House_mouse o DNA_microarray o Motor_neuron o DNA o   
             Local_anesthetic   
      
   ==========================================================================   
   Story Source: Materials provided by   
   University_of_California_-_San_Diego. Original written by Scott   
   LaFee. Note: Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Michael W. Baughn, Ze'ev Melamed, Jone Lo'pez-Erauskin, Melinda S.   
      
         Beccari, Karen Ling, Aamir Zuberi, Maximilliano Presa, Elena   
         Gonzalo-Gil, Roy Maimon, Sonia Vazquez-Sanchez, Som Chaturvedi,   
         Mariana Bravo- Herna'ndez, 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   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/03/230316154104.htm   
      
   --- up 1 year, 2 weeks, 3 days, 10 hours, 50 minutes   
    * Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)   
   SEEN-BY: 15/0 106/201 114/705 123/120 153/7715 226/30 227/114 229/110   
   SEEN-BY: 229/111 112 113 307 317 400 426 428 470 664 700 292/854 298/25   
   SEEN-BY: 305/3 317/3 320/219 396/45   
   PATH: 317/3 229/426