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Defining short RNAs that antagonize deleterious phase transitions of TAF15 in ADRDs.

Award Number: R21AG091143
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2026
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Defining short RNAs that antagonize deleterious phase transitions of TAF15 in ADRDs. - PROJECT SUMMARY Effective therapeutics for several fatal neurodegenerative disorders, including frontotemporal dementia (FTD), an Alzheimer's Disease Related Dementia (ADRD) continue to remain elusive. Emerging evidence suggests that TAF15, an important RNA-binding protein (RBP) with a prion-like domain (PrLD), assembles into pathological fibrils in degenerating neurons of ~10% of all FTD cases (i.e., FTD-FET). These findings suggest that aberrant TAF15 phase transitions into pathological fibrils in the neuronal cytoplasm are problematic and difficult to resolve. Agents that prevent and reverse the aberrant phase transitions of TAF15 and restore functional TAF15 to the nucleus in the degenerating neurons of FTD-FET patients are likely to confer therapeutic effects. Indeed, such agents would simultaneously eliminate any toxic gain-of-function of aberrant TAF15 conformers in the cytoplasm, eliminate any prion-like TAF15 conformers that may spread pathology between neurons, and mitigate any toxic loss-of-function caused by depletion of TAF15 from the nucleus. However, TAF15 has been largely overlooked as a therapeutic target. Previously, we have established that short, specific RNAs (~25-34 nucleotides [nts]) provide a novel mechanism to antagonize neurotoxic phase transitions of two related RBPs with PrLDs that are also connected to neurodegenerative disease: TDP-43 and FUS. These short RNAs can engage TDP-43 or FUS, prevent aberrant TDP-43 or FUS phase separation, reverse the formation of existing TDP-43 or FUS aggregates, restore nuclear localization of TDP-43 or FUS, and protect human neurons against TDP-43 or FUS toxicity. Importantly, one short RNA penetrates into neurons, reverses TDP-43 proteinopathy, and mitigates neurodegeneration in mice. These short RNAs are similar in size to FDA-approved antisense oligonucleotides that can be delivered successfully to the CNS of patients to treat neurodegenerative disorders. Here, we propose to extend this approach to TAF15, which has emerged as a more important contributor to FTD-FET than previously appreciated. We hypothesize that short, specific, drug-like RNA oligonucleotides (25nts) can antagonize aberrant TAF15 fibrillization in a neuroprotective manner. Thus, we will pursue two aims: (1) Define RNA oligonucleotides that prevent and reverse aberrant TAF15 phase separation at the pure protein level; (2) Define RNA oligonucleotides that mitigate TAF15 toxicity in neuronal models of FTD-FET. Our studies hold the potential to yield the first therapeutic oligonucleotides that reverse TAF15 aggregation and mitigate toxicity in human neurons in culture. We envision a therapeutic strategy whereby specific short RNA oligonucleotides reverse TAF15 aggregation in FTD-FET and restore functional TAF15 to the nucleus.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $446,875 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	1	3/13/2026	NEW	$446,875
														Subtotal = $446,875

Grand Total All Awards = $446,875

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Defining short RNAs that antagonize deleterious phase transitions of TAF15 in ADRDs.

Award Number: R21AG091143

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/15/2026

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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