Target ALS and AFTD have announced $5 million in funding awards for work by six research teams to aid in the discovery of biomarkers and viable treatments for ALS and FTD, which overlap in genetic causes and biological mechanisms.

By joining forces, Target ALS and AFTD are leveraging the combined expertise of researchers in two fields, fueling collaboration in support of the most promising ideas. These newly funded projects will inform, and potentially result in, both viable treatments and the biomarkers critically needed to enable accurate diagnosis and measure disease progression. A brief overview of each funded award is provided below.

For more information on the research partnership, read this press release.

Detail on 2020 Target ALS and AFTD Funding Awards

 
Mechanistic validation of HDAC6 inhibitors as a disease-modifying therapeutic for ALS and FTD
(Eikonizo Therapeutics, VIB-KU Leuven, Mayo Clinic, UZ/KU Leuven)

Defects in axonal transport – the process of moving proteins, vesicles and organelles including mitochondria from the cell body to the synapse and back – are central to ALS and FTD pathobiology. Such defects cause or exacerbate further downstream problems like protein aggregation, stress and mitochondrial dysfunction. In ALS/FTD cell and animal models, inhibition of the enzyme histone deacetylase 6 (HDAC6) rescues axonal transport and improves hallmark pathologies and behaviors.

The goals of this consortium are to: 1) Advance brain-penetrant HDAC6 inhibitors as a disease-modifying therapeutic by evaluating motor neurons derived from individuals living with ALS/FTD and from a mouse model of ALS/FTD; and 2) Validate HDAC6 positron emission tomography (PET) in individuals with ALS/FTD, for use in therapeutic clinical trials.

Targeting G3BP1 and the stress granule response as a therapy for ALS and FTD
(Novation Pharmaceuticals, Inc., Université de Montréal/CRCHUM)

Gene expression can be regulated at the mRNA level through influencing mRNA stability or through translation. Recent findings by Dr. Christine Vande Velde suggest that TDP-43 binding to the G3BP1 transcript is essential for its stability and that the pathological changes in TDP-43 localization, as observed in ALS and FTD cases, result in a depletion of G3BP1 mRNA and thus depletion of G3BP1 protein. G3BP1 is a critical assembly factor for stress granules, intracellular structures that are key to cell survival following exposure to noxious conditions. G3BP1 depletion leads to compromised stress granule dynamics and subsequent cell death.

Novation has developed high throughput assays to identify small molecules that can influence mRNA stability and translatability through sequence elements, such as the TDP-43 regulated region identified in G3BP1. Thus, this proposal aims to combine Dr. Vande Velde’s recent findings with Novation’s drug discovery system in order to identify compounds that can counteract deficits in stress granule dynamics that may be core contributors to ALS/FTD pathogenesis.

Validating identified compounds with the existing functional cellular and C. elegans models, developed by Dr. Alex Parker, will be invaluable in demonstrating whether such compounds can restore G3BP1 levels, rescue stress granule function, and preserve neuronal viability. This work is envisioned as a stepping stone to move these compounds forward to more advanced preclinical models and eventual clinical translation of a novel ALS/FTD therapy based on this hypothesis.

Small Molecules Interacting with RNA (SMiRNA™) as a therapeutic strategy for C9ALS/FTD
(Expansion Therapeutics, Scripps Research Institute)

The most common genetic form of ALS and FTD is caused by a G4C2 repeat expansion in the C9orf72 gene. The goal of this project is to design small molecule precision-led medicines that target the RNA transcribed from the repeat expansion, or r(G4C2)^exp, which causes toxicity through a variety of mechanisms.

These compounds will be tested in various preclinical disease models to understand and optimize their therapeutic potential. Further, these small molecules that ameliorate C9ALS/FTD by inactivating r(G4C2)^exp could provide lead medicines that can be delivered to disease-affected tissues, without requiring direct delivery to the central nervous system. Thus, these studies could lower the burden for people living with ALS/FTD and for providers to deliver such medications.

Small molecule screen to identify selective inhibitors of aberrant TDP-43 biocondensates in a disease-relevant model
(Merck & Co., University of Pennsylvania, University of Pittsburgh)

Emerging data provide evidence that the propensity of TDP-43 to undergo liquid-liquid phase separation (LLPS) plays a major role in pathological TDP-43 aggregation, contributing to pathogenesis in ALS and FTD.

The Donnelly and Shorter labs recently demonstrated that RNA-deficient TDP-43 undergoes aberrant LLPS. They developed two model systems, including a cellular model employing an optogenetic TDP-43 construct, to induce TDP-43 cytoplasmic inclusions selectively under the spatiotemporal control of light.

They successfully showed that treatment with oligonucleotides composed of TDP-43 target sequences prevents inclusions and rescues neurotoxicity in these model systems.

This collaborative project will execute a focused small molecule screen using a combination of the protein-based and cellular-based assays. Identification of selective inhibitors of aberrant phase transition of TDP-43 in cytoplasm could represent a novel therapeutic strategy for both ALS and FTD.

Antisense oligonucleotides to restore expression of full length Stathmin 2 in sporadic ALS
(QurAlis, Harvard University, University of Massachusetts Medical School)

This collaboration is designed to provide tools, reagents, and possible therapeutics targeting the restoration of Stathmin 2 expression in the face of TDP-43 mis-localization.

It has long been known that approximately 95% of all individuals with ALS demonstrate mis-localization of TAR DNA binding protein (TDP-43). Prior work using models that induce greatly exaggerated expression of TDP-43 indicates that there may be a gain-of-function toxicity due to the mis-localization event. That is, high levels of TDP-43 in the cytoplasm of a cell can lead to cell death. More recently, it was demonstrated that mis-localization of TDP-43 also has a loss-of-function toxicity.

Loss of TDP-43 from the nucleus abrogates its normal function leading to mis-splicing of several proteins. The largest change is in the splicing and expression of Stathmin 2. Stathmin 2 is highly expressed in motor neurons and necessary for normal axonal maintenance and health. The presence of altered Stathmin-2 may be a proxy for the TDP-43 pathology that occurs in about half of all individuals with FTD and the majority of individuals with ALS. Truncated Stathmin-2 could potentially act as a surrogate biomarker, reflecting TDP-43 pathology and possibly as a measure of the effectiveness of treatments targeting the TDP-43.

This collaboration is designed to accomplish three goals: 1) to develop a humanized rodent model that can be used to aid in drug discovery; 2) provide tool compounds and possible drug candidates; and 3) provide a biomarker assay that can be used to determine that compounds are functioning as desired for people with ALS/FTD.

Poly(GR) and poly(GA) as biomarkers and therapeutic targets in C9ORF72-ALS/FTD
(Biogen, University of Massachusetts Medical School, University of Michigan Medical School)

C9ORF72 gene mutations, the most common genetic cause of ALS and FTD, result in the production of five different dipeptide repeat (DPR) proteins. DPRs appear to play a central role in ALS/FTD pathogenesis, and animal models expressing them exhibit many hallmarks of human disease.

Studies have indicated that reducing the levels of these proteins in experimental systems can alleviate disease-related phenotypes, suggesting that interventions targeting the selective reduction of DPRs may represent promising therapeutic strategies. But it remains to be determined whether DPRs can serve as biomarkers for diagnosis or target-engagement. To address these critical questions, this consortium will work together to: (1) Measure select DPRs in tissue samples from C9ORF72 mutation carriers, as well as C9ORF72 patient-derived experimental cellular models; and (2) Identify potential therapeutic leads that effectively reduce the level and/or protect against DPR toxicity in animal and cellular models of C9ALS/FTD.