Development of a PIKFYVE suppressing antisense oligonucleotide treatment for FTDFrontotemporal dementia (FTD) is a complex disease that results from many diverse genetic etiologies. Thereare no drugs that slow the progression of FTD. Although therapeutic strategies that target specific causalmutations (e.g. C9ORF72 ASOs) may prove effective against individual forms of FTD, these approaches cannotaddress the vast majority of cases that have unknown genetic etiology. Moreover, given the large number ofdifferent genes that likely contribute to FTD and the fact that each genetic form is relatively rare, this strategymay be difficult to implement for all cases. Thus, there is a pressing need for new therapeutic strategies thatrescue multiple forms of FTD, particularly those with unknown genetic etiologies. 45% of FTD patients display cytosolic aggregates of TDP-43 in cortical neurons, while another 45% harbortau aggregates. Studies suggest that these neuronal TDP-43 and tau aggregates drive neurodegeneration. Thus,to identify new therapeutic targets for FTD, we used cellular reprogramming to generate induced corticalneurons (iNs) from C9ORF72 FTD patients, who display TDP-43 aggregates, as well as MAPT FTD patients,who harbor tau aggregates. We then performed chemical screens to identify targets that rescue the degenerationof both C9ORF72 and MAPT FTD iNs. Inhibitors of PIKFYVE kinase were among the most potent compoundson both C9ORF72 and MAPT FTD iNs. Antisense oligonucleotide (ASO)-mediated suppression of PIKFYVEconfirmed that blocking PIKFYVE activity rescues FTD iN survival. In contrast to small molecules, antisense oligonucleotides (ASOs) provide a facile approach to targeting theCNS because they can be injected directly into the spinal cord, achieve sustained target engagement throughoutthe CNS, and are less likely to cause peripheral toxicity. Thus, we are pursuing ASO-mediated suppression ofPIKFYVE as a therapeutic approach for diverse forms of ALS. We have screened hundreds of humanPIKFYVE ASOs and identified ten lead ASOs with potent PIKFYVE knockdown in vitro . We havetested hundreds of human PIKFYVE ASOs and identified three promising leads for development. Theobjective of this Direct to Phase 2 proposal is to further characterize the efficacy of PIKFYVEsuppression, and the safety of the lead ASOs to select a bona fide development candidate foradvancement in GLP toxicity studies. Our discovery of secretory autophagy as a therapeutic approach inneurodegeneration is high impact for the field because activating the proteasome and autophagyhas had mixed results in neurodegeneration models.
Public Health Relevance Statement: Development of a PIKFYVE suppressing antisense oligonucleotide treatment for FTD
Project Narrative
Frontotemporal dementia (FTD) is a complex disease that results from many diverse causes. While there are
currently no drugs that slow the progression of FTD, most of the new promising therapeutic strategies are
focused narrowly on modifying the specific genetic mutations known to cause disease, however these
treatments won't work for the vast majority (>70%) of patients whose FTD has no obvious genetic cause.
Therefore, AcuraStem's focus has been to develop treatment that can work for all FTD patients, including those
for whom the genetic factors driving their disease have yet to be discovered - a large population with urgent
unmet need.
Project Terms: heavy metal lead ; Lipids ; Lysosomes ; Mus ; Mice ; Mice Mammals ; Murine ; Persons ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Patients ; Phosphotransferases ; Kinases ; Phosphotransferase Gene ; Transphosphorylases ; Production ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Safety ; Spinal Cord ; Medulla Spinalis ; Testing ; Work ; Antisense Oligonucleotides ; Anti-Sense Oligonucleotides ; Antisense Agent ; anti-sense agent ; anti-sense oligo ; antisense oligo ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; Ï Proteins ; Mediating ; analytical method ; method development ; Peripheral ; Phase ; multicatalytic endopeptidase complex ; 20S Catalytic Proteasome ; 20S Core Proteasome ; 20S Proteasome ; 20S Proteosome ; Macropain ; Macroxyproteinase ; Multicatalytic Proteinase ; Prosome ; Proteasome ; Proteasome Endopeptidase Complex ; Proteosome ; Chemicals ; Evaluation ; Individual ; nonhuman primate ; non-human primate ; TAR DNA-binding protein 43 ; TDP-43 ; TDP43 ; protein TDP43 ; protein TDP-43 ; Therapeutic ; Genetic ; Genetic Predisposition ; Genetic Susceptibility ; Inherited Predisposition ; Inherited Susceptibility ; genetic etiology ; genetic mechanism of disease ; genetic vulnerability ; genetically predisposed ; Genetic Predisposition to Disease ; Vesicle ; Frontal Temporal Dementia ; front temporal dementia ; frontal lobe dementia ; fronto-temporal dementia ; fronto-temporal lobar dementia ; frontotemporal lobar dementia ; frontotemporal lobe degeneration associated with dementia ; Frontotemporal Dementia ; Complex ; Autophagosome ; trafficking ; Toxicities ; Toxic effect ; Therapeutic Index ; Modeling ; BAC clone ; BACs ; Bacterial Artificial Chromosomes ; CNS Nervous System ; Central Nervous System ; Neuraxis ; preventing ; prevent ; small molecule ; chromosome 9 open reading frame 72 ; C9ORF72 ; Address ; Dose ; DNA Alteration ; DNA mutation ; Genetic mutation ; Sequence Alteration ; genomic alteration ; DNA Sequence Alteration ; Data ; in vivo ; Development ; developmental ; knock-down ; knockdown ; tau aggregation ; abnormally aggregated tau protein ; filamentous tau inclusion ; microtubule associated protein tau aggregation ; microtubule associated protein tau deposit ; paired helical filament of tau ; self-aggregate tau ; tau PHF ; tau accumulation ; tau aggregate ; tau fibrillization ; tau filament ; tau neurofibrillary tangle ; tau oligomer ; tau paired helical filament ; tau polymerization ; tau-tau interaction ; Ï aggregation ; Population ; mouse model ; murine model ; new therapeutic target ; new drug target ; new druggable target ; new pharmacotherapy target ; new therapy target ; novel drug target ; novel druggable target ; novel pharmacotherapy target ; novel therapeutic target ; novel therapy target ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; misfolded protein ; proteotoxic protein ; proteotoxin ; lead candidate ; causal variant ; causal allele ; causal gene ; causal mutation ; causative mutation ; causative variant ; TDP-43 aggregation ; TDP-43 aggregate ; TDP43 aggregate ; TDP43 aggregation ; inhibitor/antagonist ; inhibitor ; Automobile Driving ; driving ; Autophagocytosis ; autophagy ; Brain ; Brain Nervous System ; Encephalon ; Dipeptides ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Genes ; Government ; Human ; Modern Man ; In Vitro ; Lead ; Pb element ; heavy metal Pb ;
