A DNA drug designed to delay paralysis could be used in ALS

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 we engineered for an error in processing the RNA encoding stathmin-2, as is the case in these human diseases, we show that administration of a designed DNA drug into the amniotic fluid restores normal stathmin-2 levels throughout the tract. nervous. System.”

Don Cleveland, MD, Distinguished Professor of Medicine, Neurosciences, and Cellular and Molecular Medicine at the University of California San Diego School of Medicine

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 drug engineered from DNA, thereby restoring the correct Stathmin-2 RNA protein level and Protein in the mammalian nervous system”.

Specifically, the researchers edited genes in mice to contain the human STMN2 gene sequence and then injected antisense oligonucleotides-; small fragments of DNA or RNA that can bind to certain RNA molecules, hindering their ability to make a protein or altering the way the final RNA is assembled; in cerebral 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.


Journal reference:

bogen, mw, et al. (2023) Mechanism of STMN2 encoded polyadenylation binding and its correction of TDP-43 proteinopathy. Sciences. doi.org/10.1126/science.abq5622.

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