Bait Oligonucleotides to Prevent TDP-43 Associated Neurodegeneration

This invention is a novel class of short RNA oligonucleotides, known as RNA chaperones, designed to specifically engage and stabilize aggregation-prone RNA-binding proteins implicated in neurological disorders. By preventing and, remarkably, reversing the pathological protein aggregation in patient-derived neurons and in vivo mouse models, these highly deliverable oligonucleotides offer a transformative therapeutic strategy for fatal proteinopathies like ALS and FTD.

Description

The core of this technology is a method using specific short RNA oligonucleotides (24-48 nucleotides) to correct the pathology of RNA-binding proteins (RBPs) like TDP-43 and FUS. In diseases like ALS and FTD, these RBPs transition from a functional liquid state to toxic, solid-like amyloid-like aggregates, which become trapped in the cytoplasm. The short RNA chaperones engage the RBP’s RNA-recognition motifs in a sequence-specific manner. This interaction acts as an allosteric regulator, stabilizing the RBP into a conformation that is resistant to aggregation, often by destabilizing the protein's aggregation-prone prion-like domain. This innovation’s key feature is its dual activity: the oligonucleotides can not only prevent the initial formation of these pathological aggregates but, uniquely, can also dissolve pre-existing aggregates in the cytoplasm of affected neurons. This dissolution restores the functional protein to the nucleus, simultaneously eliminating the toxic gain-of-function from the cytoplasmic aggregates and correcting the nuclear loss-of-function.

Applications

- Amyotrophic Lateral Sclerosis (ALS), targeting TDP-43 (most common pathology) and FUS-related forms of the disease.
- Frontotemporal Dementia (FTD), where RBP aggregation is a major pathological feature.
- Limbic-predominant Age-related TDP-43 Encephalopathy (LATE)
- Therapeutics for AD/CTE to address co-existing TDP-43 pathology in a significant percentage of cases.
- Platform for Oligonucleotide Drug Development targeting other RNA-binding proteins with prion-like domains implicated in proteinopathies.

Advantages

- Novel Disaggregase Activity that not only prevents but also dissolves pre-formed, toxic protein aggregates in neurons.
- Restores Functional Protein to the nucleus, simultaneously eliminating the toxic gain-of-function and correcting the loss-of-function pathology.
- Broad Spectrum Efficacy against both wild-type protein and diverse disease-linked variants, including those with pathological mutations or post-translational modifications.
- Highly Deliverable Therapeutic Format utilizing short RNA oligonucleotides (24-48 nts), which can be effectively delivered to the central nervous system.
- Mitigates Neurodegeneration In Vivo as demonstrated by correcting aberrant phenotypes in patient-derived neurons and showing therapeutic effect in a mouse model of the disease.

Invention Readiness

The technology is at an advanced preclinical stage, having moved past initial proof-of-concept to demonstrate efficacy in highly relevant biological models. Key data includes the identification of enhanced short RNA chaperone sequences and the elucidation of their allosteric mechanism of action, which promotes aggregation-resistant protein conformers. Furthermore, the invention has been shown to mitigate neurodegeneration and correct aberrant protein phenotypes in vivo in a mouse model of proteinopathy. The next phase of development will focus on lead optimization and the necessary preclinical studies to advance the lead compound toward clinical application.

IP Status

Research Tool

Related Publication(s)

Copley, K. E., Mauna, J. C., Danielson, H., Ngo, M., Xie, L., Smirnov, A., Davis, M., Mayne, L., Linsenmeier, M., Rubien, J. D., Portz, B., Lee, B. L., Odeh, H. M., Hallegger, M., Ule, J., Pasinelli, P., Poon, Y., Fawzi, N. L., Black, B. E., … Shorter, J. (2024). Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2024.12.14.628507

Guo, L., Mann, J. R., Mauna, J. C., Copley, K. E., Wang, H., Rubien, J. D., Odeh, H. M., Lin, J., Lee, B. L., Ganser, L., Robinson, E., Kim, K. M., Murthy, A. C., Paul, T., Portz, B., Gleixner, A. M., Diaz, Z., Carey, J. L., Smirnov, A., … Shorter, J. (2023). Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2023.09.04.555754