At least 70 different drugs have been tested in clinical trials completed or on-going. Many of these treatments aim to dampen disease factors that arise after motor neuron degeneration has been triggered. Target ALS-funded projects are taking bold, mechanistically driven approaches to tackle TDP-43 pathology at its roots. These efforts focus on novel strategies—ranging from disrupting toxic post-translational modifications and pathogenic protein–protein interactions, to using machine learning and computational modeling to design therapeutics highly specific to toxic forms of TDP-43. Together, these projects represent a new wave of TDP-43–directed therapies that aim to intervene at molecular choke points early in the ALS disease cascade and may even be used to prevent onset of clinical symptoms. Below are examples of Target ALS-funded projects and partnerships working to advance TDP-43-targeted therapeutics through diverse modalities.
RNA-Targeting Strategies: Antisense Oligonucleotides (ASOs)
With the success of RNA-based therapeutics for genetic forms of ALS – like the commercialized antisense oligonucleotide (ASO) Tofersen for SOD-1 ALS, ongoing efforts aim to apply RNA-based therapeutic strategies to TDP-43 and other downstream targets. Target ALS supports several groups using ASOs to directly target TARDBP or to target dysregulated RNAs downstream of TDP-43 dysfunction.
- n-Lorem Foundation: Target ALS provided funding to the n-Lorem foundation, a non-profit that discovers and develops ASOs for patients with nano-rare mutations, to cover a portion of the costs needed to develop two patient-specific ASOs for individuals with ultra-rare mutations in the TARDBP gene that encodes TDP-43. These ASOs are designed to be 10-100X selective for the mutant TDP-43 transcript with the aim of reducing toxic cytoplasmic accumulation while retaining normal function of wild-type TDP43 in the nucleus. The ASOs discovered and developed by n-Lorem may also be applicable to additional patients identified with the same mutations for which the ASOs were designed.
- Northwestern and NuCyRNA – Dual-Modality Strategy: A new collaborative project spearheaded by Northwestern University, UMass Chan Medical School and NuCyRNA Therapeutics will develop a dual-targeting oligonucleotide technology that can knock down modifier genes to mitigate TDP-43 pathology and correct specific TDP-43 loss-of-function phenotypes. This dual approach represents a novel therapeutic modality aiming to address both ends of the TDP-43 dysfunction spectrum in ALS. The NuCyRNA Therapeutics team has developed this dual-targeting oligonucleotide technology, surmounting the therapeutic obstacle of tackling two functions with a single candidate drug. This breakthrough will ease the path of this candidate therapeutic to clinic, allowing for typical preclinical safety, efficacy, and dosing tests.
Targeting Cytoplasmic Aggregation and Stress Granules
Stress granules are membraneless organelles that form in cells in response to cellular stressors, like heat shock or DNA damage. The Integrated Stress Response (ISR) is a pathway that can also be activated in response to these stressors. In ALS, stress granules and ISR activation occur in motor neurons and other cell types of affected individuals. Stress granules are even implicated in pathology and interplay with TDP-43 cytoplasmic aggregation. Target ALS supports and has supported several groups looking to impact ALS progression by developing therapeutics that target stress granule formation or ISR activation in disease.
Dewpoint Therapeutics:
Dewpoint is developing a molecule that selectively disrupts TDP-43 from associating with stress granules—membraneless organelles implicated in ALS pathology—without disturbing the granules themselves. This approach focuses on preventing an early stage in TDP-43 aggregation and restoring TDP43 to the nucleus.
Denali Therapeutics / UC San Diego Collaboration:
A long-standing partnership funded by Target ALS is investigating OTUD4, an RNA-binding protein and stress granule component. Knockdown of OTUD4 may prevent stress granule formation and the subsequent recruitment and aggregation of TDP-43.
eIF2B Activators – Denali:
Target ALS has also supported preclinical work that led to clinical trials with eIF2B activators, which aim to suppress the Integrated Stress Response—a pathway often dysregulated in ALS. This results in reduced stress granules/TDP-43 aggregation while improving protein synthesis and motor neuron survival. Several eIF2B activator trials recently failed to meet their primary endpoints in Phase II studies in individuals living with ALS. These trials clearly illustrate the difficulty in treating a complex disease like ALS, when modulation of an implicated cellular pathway in the disease is not able to successfully provide benefit to patients. Additional biomarker data is pending that may shed light on negative findings.
Protein-targeting Strategies
Many groups designing therapeutics for ALS seek to target dysfunctional TDP-43 protein directly. Whether they are altering how TDP-43 binds with protein partners or its modification by kinases, the following candidate therapeutics supported by Target ALS all aim to disrupt toxic TDP-43 aggregates at the protein level.
Acelot:
Using in silico simulations and proprietary experimental assays, Acelot developed small molecules that directly target aggregated TDP-43 and restore downstream function. Acelot’s use of the Target ALS Postmortem Tissue Core resource has proven critical in enabling the organization in their advancement of drug candidates towards the clinical phase of evaluation.
Neumora Therapeutics:
Neumora is developing a CK1δ inhibitor to block pathological phosphorylation of TDP-43 at key sites such as Ser409/410. These modifications are linked to TDP-43 aggregation and ALS progression. Through multiple In Vivo Target Validation studies, Target ALS is supporting the in vivo testing of this candidate therapeutic to determine whether inhibiting CK1δ can reduce TDP-43 toxicity. Results from these studies will be informative for the broader ALS therapeutic development community, as TDP-43 phosphorylation has long been implicated in ALS.
Leeanne McGurk Lab:
Dr. McGurk is developing an inhibitor that disrupts the interaction between TDP-43 and Tankyrase—a PAR polymerase that regulates TDP-43 under conditions of stress. Overactivation of Tankyrase can promote TDP-43 aggregation. Early results from fly and cell models show promise in reducing aggregation while preserving the other physiological functions of both proteins.
Latouche- Buratti-Cintrat-Sperandio Consortium:
As part of the Target ALS 2024 Basic Biology Consortia, Dr. Morwena Latouche’s current project, SISMIC-TDP-43, takes an innovative approach to tackling ALS pathology. This computational biology team is leveraging structural modeling of TDP-43 to identify small molecules capable of detecting or inhibiting its aggregation. The project exemplifies a rational, structure-guided approach to therapeutic development.
Mabylon – AAV-Delivered Intrabodies:
Mabylon is developing a gene therapy strategy using adeno-associated virus (AAV) vectors to deliver intrabodies—engineered antibodies designed to function inside cells. Unlike traditional antibodies that act extracellularly, these intrabodies are directly expressed in neurons and bind aggregated, post-translationally modified TDP-43, promoting its clearance from the cytoplasm. This intracellular targeting mechanism offers a novel and potentially transformative way to reduce toxic protein buildup at the source.
Strategies to restore RNA processing downstream from TDP43 dysfunction
While many therapeutic efforts target the toxic gain-of-function (GOF) effects of cytoplasmic TDP-43, a growing number of innovative strategies are focused on correcting the loss of its essential nuclear functions. TDP-43 plays a critical role in regulating RNA splicing and transcript stability; its nuclear depletion leads to widespread dysregulation of downstream targets. Target ALS is supporting several projects that aim to correct the downstream consequences of TDP-43 nuclear loss.
Trace – UNC13A Splice-Switching ASO:
Trace is developing a splice-switching antisense oligonucleotide (ASO) to rescue proper splicing of UNC13A, a key gene whose misregulation is directly linked to TDP-43 loss. This approach seeks to restore normal neuronal function by correcting one of the best-characterized downstream phenotypes of TDP-43 nuclear depletion. Unc13A protein is critical for neuronal function, as it acts at the synapse to drive synaptic vesicle release. Although numerous genes are misspliced in the absence of TDP-43, correction of UNC13A alone has potential to significantly rescue motor neuron function.
QurAlis – Cryptic Exon Splicing Rescue Programs:
QurAlis is pursuing multiple therapeutic strategies to restore TDP-43-dependent splicing events. QurAlis is advancing ASOs targeting STMN2, a critical axonal stability gene whose mis-splicing is a hallmark of TDP-43 loss of function. Target ALS has also supported QurAlis’ broader therapeutic pipeline—including clinical-stage assets—through previous funding rounds and biomarker core resources such as biofluid access.
