We are thrilled to announce the recipients of the Target ALS In Vivo Target Validation grants, focusing on proof-of-concept studies for promising therapeutics in a TDP-43 mouse model. This initiative, in collaboration with Biospective, is designed to accelerate the evaluation of potential therapeutics, bridging the gap from preclinical research to clinical trials. Biospective has implemented a modified, slower progressing version of the TDP-43 NLS8 (or ΔNLS) mouse model that was originally developed at the University of Pennsylvania (Walker et al., 2015). This model mimics disease symptoms and pathology that people living with ALS experience, including cytoplasmic TDP-43 mislocalization, neurodegeneration, and motor deficits. Using this standardized model, the team at Biospective will conduct robust behavioral and molecular assessments of candidate therapeutics for these preclinical efficacy studies. Successful results in this mouse model will enable groups to move their therapeutic candidate toward the clinic.
Key Objectives of the In Vivo Target Validation Program
The In Vivo Target Validation Program aims to:
- Generate high-quality data in animal models of ALS in an unbiased way based on standardized study designs and research tools.
- Break down barriers to ALS research by providing access to an in-kind funding for a resource-intensive step of drug discovery
- Validate candidate drug targets in ALS mouse models to accelerate their progress from preclinical testing towards clinical trials.
About Our Review Process
At Target ALS, we hold fairness and transparency paramount in our review process. The Target ALS Independent Review Committee (IRC) makes all research funding decisions without involvement from the organization’s staff or leadership, ensuring every application receives a fair evaluation. The IRC is comprised of experts across scientific disciplines from both industry and academia, reflecting the evolving nature of ALS research. To avoid any possible conflicts of interest, no member of the IRC can apply for or receive Target ALS funding for their own work. Members on the IRC abide by a comprehensive conflict of interest policy and are all under confidentiality agreements.
For more detailed information about our grants and the application process, please visit our In Vivo Target Validation Page.
2024 In Vivo Target Validation Grantees:
Nick J Brandon at Neumora Therapeutics
Title: Evaluation of a novel CK1d inhibitor in the TDP-43 ΔNLS mouse model for ALS
Summary: Neumora has identified a novel inhibitor of the kinase CK1d. CK1d is a key proximal kinase phosphorylating TDP-43, a protein implicated in the pathology of both sporadic and familial ALS and certain types of frontotemporal dementia (FTD). Protein aggregates containing phosphorylated TDP-43 are present in degenerating motor neurons of ALS patients. It is hypothesized that reduction of TDP-43 phosphorylation with a CK1d inhibitor will reduce TDP-43 driven pathology and slow disease progression. Neumora’s CK1d inhibitor “NMRA-CK1d” is in preclinical development. The goal of this project at Biospective is to evaluate the effects of NMRA-CK1d on key pathological endpoints, motor function, and translational biomarkers. These results will allow for better understanding of NMRA-CK1d’s potential impact on ALS pathology and will support the development of a biomarker strategy as it moves towards clinical development.
Jesse Lai at Dewpoint Therapeutics
Title: A brain-penetrant small molecule modulator of TDP-43 condensates reduces cytoplasmic TDP-43 pathology in vitro and in vivo
Summary: In 97% of ALS cases, toxic aggregation of the protein TDP-43 occurs within cells. These harmful aggregates are preceded by dynamic structures called TDP-43 condensates. The team at Dewpoint Therapeutics has developed a brain-penetrant small molecule that can interact with, prevent, and dissolve these TDP-43 condensates. By preventing the formation of toxic TDP-43 condensates, the Dewpoint small molecule has been shown to restore normal TDP-43 function in cells. Additionally, this molecule has demonstrated the ability to reduce TDP-43 pathology and neurodegeneration in mouse models. The objective of this proposal is to further evaluate the efficacy of this small molecule in rescuing TDP-43 pathology, preventing neurodegeneration, and improving motor function in Biospective’s TDP-43 mouse model. By assessing the impact of this innovative treatment in a preclinical setting, Dewpoint Therapeutics aims to gather critical data that could pave the way for future clinical applications.
Nikole Zuniga Quiroz at Mabylon AG
Title: Human-derived TDP-43 intrabodies to restore TDP-43 function in ALS
Summary: ALS is a devastating neurodegenerative disease with no cure available. A key feature of ALS is TDP-43 aggregation in neurons, leading to toxicity and neuronal loss. Mabylon AG has identified rare antibodies from human subjects that exclusively bind pathological TDP-43. Leveraging these antibodies, the team has developed a gene therapy approach that introduces these antibodies inside neurons (referred to as “intrabodies”). Mabylon’s lead candidate, MY014, is a stable intrabody that shows remarkable therapeutic potential by specifically targeting dysfunctional TDP-43 located in the cytoplasm, while enabling it to exert its vital function, which is crucial for disease recovery. This innovative intrabody approach offers a unique opportunity for a novel ALS treatment with the aim of delaying or halting disease progression. The results from this study will support rapid translation into clinical development, presenting a life-changing treatment option for ALS patients.
Ovadia Lazari at NRG Therapeutics Ltd
Title: Investigation of a mitochondrial pore inhibitor in the low-dox deltaNLS mouse model
Summary: Mitochondria, the batteries of cells, are crucial for energy production, especially in brain cells which have high energy demands. In diseases like ALS, mitochondria become defective, leading to brain cell death and disease progression. Recent findings have shown that dysfunctional TDP-43 protein – found in nearly all ALS patients – disrupts mitochondrial function and undesirably activates the immune system. NRG Therapeutics has discovered a new class of small molecule mitochondrial permeability transition pore inhibitors that can block this mitochondrial dysfunction. These inhibitors are designed to penetrate the brain effectively when taken orally. Preliminary experiments using a mouse model of ALS which contains the human gene for TDP-43 showed that NRG’s candidate therapeutic reduced brain cell death. However, due to the rapid disease progression in that mouse model, a full assessment of the therapeutic potential was not possible. This project aims to evaluate NRG’s small molecule inhibitor, in a modified ALS mouse model that progresses more slowly. This will allow for a comprehensive assessment of the inhibitor’s ability to protect mitochondria, reduce brain cell death, and decrease immune system activation. Additionally, the study will measure improvements in muscle function and strength. If successful, this project will provide crucial support for advancing NRG’s small molecule pore inhibitor into clinical trials for ALS.
Baris Bingol at Genentech
Title: Boosting Lysosomal Function for Benefit in ALS
Summary: Lysosomes, the cellular organelles responsible for breaking down and recycling cellular waste, play a crucial role in maintaining cellular health. Research indicates that impaired lysosomal function, including reduced clearance of cellular debris and accumulation of toxic protein aggregates, contribute to the degeneration of motor neurons in ALS. Genetic mutations in lysosomal function-related genes, such as C9orf72 and TBK1, have been linked to ALS. Moreover, abnormalities in critical processes for cellular maintenance that are regulated by lysosomes have been observed in ALS models and patient tissues.
This project aims to restore lysosomal function in ALS by targeting ion channels that regulate lysosomal physiology. These ion channels have genetic links to ALS and present promising targets for developing therapies aimed at slowing or halting disease progression. By enhancing lysosomal function, this research hopes to mitigate the effects of ALS, ultimately providing new therapeutic strategies for patients.
Our Vision and Commitment
At Target ALS, our mission is to break down barriers to ALS research to find effective treatments, to realize a world where Everyone Lives. Driven by our values of impatient optimism, deliberate disruption, and radical collaboration, we are dedicated to funding cutting edge research and building partnerships that accelerate progress towards effective treatments for all forms of ALS.
Together, we strive for a future where everyone diagnosed with ALS can live long, quality lives.
Thank you to all the applicants for their dedication and hard work. For more detailed information about our grants and the application process, please visit our In Vivo Target Validation Page.
