New Research Finds That Designer DNA Drugs May Help Delay Paralysis Among ALS Patients
A protein known as TDP-43 is lost from its usual cell nucleus location in nearly every case of amyotrophic lateral sclerosis (ALS) and up to half of Alzheimer’s disease (AD) and frontotemporal dementia cases.
This then triggers the loss of a key protein, stathmin-2, which is crucial for the regeneration of neurons and maintaining their connections with muscle fibers. This maintenance is critical for contraction and movement.
In a recent study published in Science, though, a team of researchers found that designer DNA drugs could rescue stathmin-2 loss and restore normal protein-encoding RNA processing.
“With mouse models that 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,” explained Don Cleveland, the study’s senior author.
Cleveland himself is widely credited with conceptualizing designer DNA drugs. They essentially work to turn on or turn off specific genes that are associated with various degenerative diseases, such as AD, ALS, cancer, and Huntington’s disease.
There are numerous designer DNA drugs currently undergoing clinical trials for several diseases. One drug has even been approved to treat spinal muscular atrophy– a childhood neurodegenerative disease.
This new study has built on Cleveland’s research regarding the role of TDP-43 and what happens when this protein is lost.
In cases of ALS, the loss of TDP-43 affects motor neurons that trigger skeletal muscle contractions– causing degeneration and eventually paralysis.
“In almost all instances of ALS, there is an aggregation of TDP-43, a protein that functions in the maturation of the RNA intermediates that encode many proteins,” Cleveland detailed.
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And when there is reduced TDP-43 activity, there is a misassembly of stathmin-2– or a protein necessary for the maintenance of connections between motor neurons and muscle.
If there is no stathmin-2, motor neurons ultimately disconnect from the muscle and lead to paralysis– which is characteristic of ALS. What Cleveland and his team found, though, was that they could use a designer DNA drug to mimic the TDP-43 function. This then restores correct stathmin-2 RNA and protein levels in the nervous system.
To do this, the researchers edited mice genes to contain STMN2 gene sequences. Then, they injected oligonucleotides into the cerebral spinal fluid. Oligonucleotides are small pieces of DNA or RNA that are able to bind to distinct RNA molecules. This blocks the RNA molecules’ ability to make a protein or to change how final RNAs are assembled.
The injections were able to correct STMN2 pre-mRNA misprocessing while restoring stathmin-2 protein expression. And remarkably, this was accomplished completely independently of the TDP-43 function.
Now, Cleveland believes his team’s findings could have significant implications for delaying paralysis among ALS patients.
“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,” he concluded.
To read the study’s complete findings, which have since been published in Science, visit the link here.
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