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Antisense Drugs Mimic TDP-43 Function, Might Treat ALS and Some Dementias

Key findings

  • In nearly all patients with amyotrophic lateral sclerosis (ALS), a protein called TDP-43 relocates from neuronal nuclei and accumulates in cytoplasm, causing a loss of stathmin-2, a protein required for connections between motor neurons and muscle
  • This study showed that the presence of TDP-43 in the nucleus blocks specific sites in stathmin-2 RNA to protect them from being misspliced, and this protection is absent when TDP-43 mislocates to the cytoplasm
  • The team developed antisense oligonucleotides (ASOs) that, when injected into cerebrospinal fluid of a mouse model, restored stathmin-2 synthesis independently of TDP-43 function
  • Restoring stathmin-2 levels via an ASO is a potential therapeutic approach for ALS and certain cases of frontotemporal dementia and Alzheimer's disease

An exciting advance in neuroscience is the recognition that several neurodegenerative diseases are TDP-43 proteinopathies, in which the RNA-binding protein TDP-43 is mislocalized from the nucleus of neurons and accumulates in the cytoplasm. TDP-43 disruption is found in 97% of patients with amyotrophic lateral sclerosis (ALS), about 50% of those with frontotemporal dementia, and 30% to 50% of those with Alzheimer's disease.

The RNA most affected by reduced TDP-43, STMN2, encodes stathmin-2, a protein necessary for axonal regeneration after injury and maintenance of connections between motor neurons and muscle.

In previous work, published in Nature Neuroscience, Massachusetts General Hospital and the University of California, San Diego researchers demonstrated in vitro that restoring stathmin-2 expression restored axonal regenerative capacity in motor neurons depleted of TDP-43.

Clotilde Lagier-Tourenne, MD, PhD, an investigator in the Sean M. Healey & AMG Center for ALS at Mass General, and colleagues recently expanded on those findings in Science. They determined the mechanism by which TDP-43 enables the correct processing of STMN2 mRNAs and developed a therapy that restored stathmin-2 protein levels in the central nervous system of mice.


The research team found that when TDP-43 is present in the nucleus, it blocks certain sites in stathmin-2 RNA to protect them from being misspliced. This protection is critical for production of normal stathmin-2 protein and is absent when TDP-43 is located in the cytoplasm.

The observation suggested that rather than restoring appropriate TDP-43 function, it may be possible to treat TDP-43 proteinopathies by finding ways to force the correct expression of stathmin-2.

Sidestepping the Dysfunction

The researchers partnered with a biotechnology company to develop antisense oligonucleotides (ASOs)—short, synthetic, single strands of DNA—that they injected into the cerebrospinal fluid (CSF) of mice bred to have chronically misspliced Stmn2 pre-mRNAs. Administration into CSF would also be possible in patients.

The injections corrected the missplicing and restored stathmin-2 protein expression independently of TDP-43 dysfunction. Stathmin-2 accumulation was elevated enough to restore axonal regrowth and transport in affected human motor neurons.

RNA Therapeutics in Managing Genetic Disorders

Nusinersen, which corrects missplicing of the pre-mRNA of the SMN2 (survival of motor neuron 2) gene, is already FDA-approved for the treatment of infantile-onset spinal muscular atrophy. Importantly, nusinersen improves disease symptoms and slowing the disease's progression.

Merit E. Cudkowicz, MD, MSc, chief of the Department of Neurology and director of the Sean M. Healey & AMG Center for ALS, and colleagues recently reported that the use of the ASO, tofersen, inhibits the production of a mutant protein in a familial form of ALS.

These findings suggest that, similarly, it may be possible to develop an antisense drug that improves ALS symptoms and delays the onset of paralysis in both familial and sporadic ALS.

Learn more about research in the Department of Neurology

Learn more about the Sean M. Healey & AMG Center for ALS


Clinical trials of amyotrophic lateral sclerosis (ALS) therapeutic strategies coordinated through Massachusetts General Hospital are prolonging patient life.


Loss of TDP-43 nuclear function is a major event in ALS pathogenesis and leads to widespread RNA processing alterations including reduced stathmin-2 levels. Stathmin-2 is shown to be crucial for axonal regeneration and to represent a novel therapeutic target in ALS.