NeuroVoices: Cathleen Lutz, PhD, on the Potential of Stathmin-2 as an ALS-Specific Biomarker

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The vice president of the Rare Disease Translational Center at the Jackson Laboratory provided context on a recently published study suggesting restoration of stathmin-2 as a therapeutic approach for ALS.

Cathleen M. Lutz, PhD

Cathleen M. Lutz, PhD

Amyotrophic lateral sclerosis (ALS), a neuromuscular disease characterized by selective degeneration of upper and lower motor neurons, is currently lacking validating disease-specific biomarkers. The field has seen significant progress in expanding the therapeutic options available to patients, highlighted by the recent approvals of AMX0035 (Relyvrio; Amylyx) and tofersen (Qalsody; Biogen), the first marketed therapy for SOD1-mutated forms of the disease. in addition, the discovery of cytoplasmic mislocalization of the RNA-binding protein TAR DNA-binding protein 43 (TDP-43) in affected neurons in more than 95% of ALS and at least 50% of frontotemporal dementia (FTD) has changed the direction of research in ALS and FTD.

Previous research identified that the stathmin-2 mRNA (encoded by the STMN2 gene) is the transcript most affected by reduction in TDP-43 function. Led by Cathleen M. Lutz, PhD, and others, a recently published study showed that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons. These results were produced using a combination of approaches, including transient antisense oligonucleotide (ASO)-mediated suppression, sustained shRNA-inducted depletion in aging mice, and germline deletion.

Published in Nature Medicine, the study not only demonstrated that stathmin-2 accumulates at the axon terminals of mature motor and sensory neurons in the adult nervous system, but that there is a continuing requirement for stathmin-2 in the maintenance of motor and sensory neuron synapses. Notably, the reduction of stathmin-2 did not compromise motor neuron survival in mice at least in the 8-month time frame analyzed, which may have been due to additional mRNA alterations occurring in TDP-43 proteinopathies, including the loss of UNC13A, that may compound the pathology driven by loss of stathmin-2 alone.

Lutz, vice president of the Rare Disease Translational Center at the Jackson Laboratory, sat down with NeurologyLive® as part of a new iteration of NeuroVoices to highlight the therapeutic potential of stathmin-2. In the discussion, she talked about whether it may be considered a disease-modifying protein, how the findings translate, and the next steps in exploring restoration types of approaches.

NeurologyLive®: Coming into the study, what were you looking to achieve?

Cathleen Lutz, PhD: That's a great question. I think we've known a lot about it; we have learned a lot about stathmin-2 in terms of some of its functions. We understand that there is missplicing in the absence of TDP-43, a common mechanism in ALS. We also knew that stathmin-2 was required for axonal regeneration. When you cut the axons in the absence of stathmin-2, you don't get regeneration, published data shows. Stathmin-2 is concentrated in the growth cones of axons, but its role in ALS aging and overall axon maintenance was unclear. So, while required for regeneration and involved in ALS missplicing, its broader role in aging needed clarification.

Among the top findings from the study, what should the clinical community key in on?

Yeah, it was a little challenging to address the question in mouse models of stathmin-2 depletion and missplicing. Stathmin-2 doesn't appear in the same context in mice. We've engineered mouse models humanizing stathmin-2, and we're eager to study them in the context of TDP-43 depletion. For this study, we focused on multiple approaches to stathmin-2 depletion in mouse models.

There were a number of different ways we did this. We used transient ASO (antisense oligonucleotide) expression, shRNA in a subpial injection into the spinal cord (similar to an intrathecal injection but more specific to the gray matter and motor neurons), and made stathmin-2 knockout animals. The question was, what do we see over time? With transient or complete loss of stathmin-2 in the mouse models, we observed signs of axonal problems. There wasn't clear impact on the motor neuron itself, but the axons were affected, showing collapsing and reduced diameter, with demyelination and altered neuromuscular junctions.

We’re seeing signs that transient depletion of stathmin-2 will provide over time, not immediately, signs of progressive sensory neuropathy and motor neuropathy. It doesn't appear instantaneously, mirroring ALS as a disease of aging, a cumulative effect of insults over time. In the face of TDP-43 mislocalization, stathmin-2 missplicing is a major molecular event. Understanding how stathmin-2 affects neuronal and axonal health in the context of ALS was the aim of these experiments.

We did a knockout model as well. It was interesting because it was a constitutive knockout of stathmin-2. In animals on a black six background, we observed lethality, indicating stathmin-2's necessity for survival in that context. Most animals died at birth, but some survived, showing deficits in rotarod and motor and neuromuscular deficits.

What are the next steps after this research? How do we translate these findings further?

I think what we are thinking of in terms of the holy grail of these mouse models is a model for ALS with TDP-43 mislocalization. Most current models don't show this, like c9orf72 or SOD1-GA93A mouse models. Our ongoing experiments involve conditional TDP-43 mouse models where TDP-43 depletion causes nuclear loss. In this context, in the face of humanized stathmin-2, we observe missplicing, providing a model to consider restoring stathmin-2. But these conditional models are proof-of-principle. We're also working on different mouse models for loss of nuclear TDP-43, more in line with the disease context.

How notable is it that stathmin-2 impacts neurofilament-dependent axoplasmic organization?

I think it's really important. Neurofilament light chain is a fantastic biomarker we follow in patients, like EMTs in electrophysiology. To have a fluid-based biomarker is crucial. Many neurological diseases show consistent and robust neurofilament light chain patterns. In this respect, we're thinking this aligns with what we've seen and is important to know.

Based on these findings, do we believe that stathmin-2 could be a disease-modifying biomarker?

It's an interesting question, and I'll say I don't know the answer. Certainly, in the face of TDP-43 nuclear loss, we see many changes in RNA splicing and the transcriptome. The ongoing question is whether stathmin-2 restoration, such as with antisense oligonucleotide therapy, will be enough to influence the disease. Will other cellular components need modification? It's an ongoing question, but we're moving in the right direction. Antisense oligonucleotides have been revolutionary, specific and impactful for a particular form of ALS. They're robust in their mechanism of action and follow-up.

Do you ever envision stathmin-2 becoming a part of clinical trials assessing potential agents?

Fluid-based biomarkers are easier to handle, and neurofilament is plasma-based, making it easier to follow. The effects of stathmin-2 as a therapeutic are interesting. As a biomarker, I'm not sure; experts like Bob Bowser may have a stronger opinion. The biology, mechanism of action, and its impact on ALS are all incredibly interesting and things for the ALS community and researchers to tackle.

Transcript was edited for clarity. For more iterations of NeuroVoices, click here.

REFERENCE
1. Lopez-Erauskin J, Bravo-Hernandez M, Presa M, et al. Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation. Nature. Published online November 23, 2023. doi:10.1038/s41593-023-01496-0
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