Bringing the Fight to Motor Neuron Disease: Selectively Treating Diseased Cells

Motor neuron disease (MND) is a life-limiting condition with debilitating progressive symptoms that currently lacks any effective therapeutic options. However, recent strides in research involving a protein known as TDP-43 bring new optimism to treating MND through selective cell targeting. Are “invisibility cloaks” the solution?

Motor Neuron Disease: The Degenerative Disease

The biological basis of MND, an umbrella term for several severe neurodegenerative diseases, continues to stump scientists. Amyotrophic lateral sclerosis (ALS) is perhaps the most recognized form of MND, typified by extensive degeneration of motor neuron cell bodies in the pathways that provide voluntary control of muscular movement, leading to muscular atrophy, paralysis, and death. Although ALS is rare, with an incidence of 1 in 300 (Martin et al. 2017), new evidence suggests an increased disease prevalence (Longinetti and Fang 2019). With an average post-diagnosis life expectancy for ALS of 2–5 years, there is an urgent need for effective therapies.

Current MND Therapies

Despite our ability to diagnose ALS through physiological tests, imaging, and fluid biomarkers, there is a distinct lack of clinically approved curative therapies. Standard treatments include physical therapy regimes and lifestyle modifications to manage symptoms and potentially extend life expectancy. Additionally, medications such as riluzole (a suppressant of glutamatergic activity) can be used to partially relieve symptoms and, in some cases, extend lifespan by delaying the onset of ventilator dependence. However, riluzole and similar therapeutics are not cures and cannot reverse prior damage caused by neurodegeneration.

One of the overwhelming reasons behind the lack of treatment options is the pathological complexities of diseases like ALS. Multiple processes, such as protein aggregation, oxidative stress, axonopathy, and impaired axonal transport, contribute to ALS manifestation (Mead et al. 2023), meaning that, since riluzole’s first trial in 1994 (Bensimon et al. 1994), tangible improvements in therapeutics have been sparse. However, recent developments in the study of TAR DNA binding protein 43 (TDP-43) provide hope for future treatments of proteinopathies — diseases defined by abnormal protein structures and accumulation, like ALS.

TDP-43: A Problematic Protein

TDP-43 is a protein involved in the regulation of RNA transcription. In a diseased state, post-translational modifications to TDP-43 result in its aggregation, mislocalization, and loss of function. One of these functional shortcomings allows for the introduction of cryptic exons — abnormally inserted sequences that can result in the production of defective proteins.

Aggregation of TDP-43 is documented in 97% of ALS cases (Scotter et al. 2015) and also reported in transgenic mutant invertebrate and cellular models (Johnson B et al. 2009). Additionally, there is growing evidence for TDP-43's ability to propagate through prion-like mechanisms. In post-mortem samples taken from human ALS patients, these abnormal aggregates of TDP-43 have been frequently identified, and over 50 mutations of the TDP-43 TARDBP gene have been linked to ALS (Suk and Rousseaux 2020). Moreover, this protein is a key player in ALS and a favorable target for disease-modifying therapeutics.

Studies that block these cryptic exon inclusions have demonstrated an ability to disrupt TDP-43 aggregation, confirming the involvement of cryptic exons in ALS progression and providing evidence that therapeutic intervention is possible (Lu S et al. 2022, Baughn M et al. 2023). However, such approaches lack cellular specificity and modify healthy cells as well as those demonstrating pathology, potentially exacerbating symptoms. There are also concerns about the unregulated disruption of protein clearance causing undesirable knock-on effects due to the interwoven nature of these pathways, potentially doing more harm than good (Babazadeh A et al. 2023). So, how can we make sure we only target the “sick” cells?

A Targeted Approach for Treating Neurodegenerative Diseases

In a collaborative effort, scientists at the Francis Crick Institute and University College London’s Institute of Neurology have developed a method to selectively target diseased cells in ALS using an “invisibility cloak” (Wilkins et al. 2024). The newly developed DNA molecules carry instructions that can only be correctly interpreted in diseased cells. Cryptic exons, prominently associated with TDP-43 loss of function and pathology in post-mortem ALS and frontotemporal dementia (FTD) samples, were used as a basis for manufacturing this tool and were further developed through AI and in silico algorithms. The resulting DNA molecules contain a sequence that recognizes cryptic exons, limiting transgene expression to situations where cryptic exons are present. The resulting tool therefore remains “invisible” when inside healthy cells but reveals itself when inside diseased cells.

Can “Invisibility Cloaks” Fight Back Against MND?

The applications of these hidden instructions in precision therapeutics are vast. The study by Wilkins and colleagues revealed the ability of their DNA molecules to detect TDP-43 aggregation, a realistic marker of human ALS, and loss of function. As such, the “invisibility cloak” could be used as a biomarker-like tool to detect disease for early ALS diagnosis and pharmaceutical research. Equally, the cloaks could be paired with gene editing tools to proactively repair diseased cells, which have been trialed with initial success by the team at UCL and the Crick. These advances provide a promising tool to selectively target and edit/repair cells that are diseased, while avoiding healthy cells. With these tools, a new age of precision medicine is quickly advancing, with the potential to treat a wide range of diseases such as cancer and heart disease.

These advances mark a significant step toward finally providing effective therapeutic avenues for neurodegenerative diseases, as well as providing a method of confirming therapeutic efficacy ahead of clinical trials. So, are invisibility cloaks the solution?

If paired with effective gene editing tools and therapeutics, precision medicine techniques such as the “invisibility cloak” certainly hold the capacity to become a key step in treating neurodegenerative diseases like ALS, offering cures for diseases that have eluded clinicians for decades.