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A versatile transkingdom platform for therapeutic nucleic acid delivery to mucosal epithelial tissues

Award Number: R43AI140243
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2018
PERIOD OF PERFORMANCE END DATE: 05/10/2020

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A versatile transkingdom platform for therapeutic nucleic acid delivery to mucosal epithelial tissues - PROJECT SUMMARY The therapeutic applications of nucleic acids (NAs) have strong potential for a wide range of disease targets but major obstacles to clinical application include short-lived silencing effect and challenges in delivery to specific cells and tissues. Developing a delivery platform for targeted and stabilized intracellular delivery of RNAi mediating agents to specific tissues is essential to capitalizing on the therapeutic potential that NA-based technologies hold for translational human medicine. As many allergens and viral and bacterial pathogens invade the body via mucosal tissues, these sites represent an important target for delivery of NA-based therapeutics. Our transkingdom delivery platform is characterized by nonpathogenic bacteria that constitutively generate shRNAs for targeted intracellular delivery to mucosal epithelial cells and RNAi silencing without genomic integration. This platform theoretically overcomes challenges with delivery to specific cells and tissues. However, very few tissue types have been treated with this delivery vehicle and the short-lived RNAi effect is still problematic. To build upon our existing NA delivery platform technology and the success it has demonstrated to date, we propose here to improve the RNAi properties of the platform for a prolonged silencing effect and demonstrate this delivery platform's ability to target different tissues relevant to a wide range of clinical applications. Specifically, we will individually evaluate the shRNA-stabilizing effects of a constitutively expressed dsRNA binding protein and methyltransferase, and an RNase R mutant. Our specific aims are to 1) Improve the shRNA stability and the RNAi silencing effects of the parent delivery platform through three approaches to be evaluated in vitro, 2) Test the delivery feasibility, safety, biodistribution, immunogenicity, toxicity, and RNAi silencing effect of each variant in mucosal epithelial tissues in vivo, and 3) Evaluate the therapeutic application of the delivery vehicle variants in an established in vivo disease model. To accomplish this research, we have assembled a multidisciplinary team with specialized experience in RNAi- based antiviral development, development of molecular methods, RNA regulation and metabolism, pre-clinical and clinical drug development, and translational research. If the proposed aims are achieved, this work will provide proof of concept for a therapeutically viable NA delivery platform, and will highlight the feasibility of utilizing these transkingdom RNAi delivery vehicles to target clinically relevant mucosal epithelial tissues for a broad range of disease applications. Our unique approach provides a new perspective on NA delivery and addresses many of the shortcomings associated with current NA delivery approaches. Our delivery platform combines ingenuity with practicality and seeks to transform the field of NA therapeutics and RNAi into a clinical reality.


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: 2021 ( Subtotal = $0 )
2021	2018	SIVEC BIOTECHNOLOGIES LLC	1505 W MULBERRY ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	1	7/14/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	SIVEC BIOTECHNOLOGIES LLC	1900 E SEADRIFT DR UNIT A	WINDSOR	CO	80550	WELD	USA	Allergy and Infectious Diseases Research	000	1	5/4/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $293,142 )
2018	2018	SIVEC BIOTECHNOLOGIES LLC	1900 E SEADRIFT DR UNIT A	WINDSOR	CO	80550	WELD	USA	Allergy and Infectious Diseases Research	001	1	8/29/2018	NEW	$0
2018	2018	SIVEC BIOTECHNOLOGIES LLC	1900 E SEADRIFT DR UNIT A	WINDSOR	CO	80550	WELD	USA	Allergy and Infectious Diseases Research	000	1	8/20/2018	NEW	$293,142
														Subtotal = $293,142

Grand Total All Awards = $293,142

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A versatile transkingdom platform for therapeutic nucleic acid delivery to mucosal epithelial tissues

Award Number: R43AI140243

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/20/2018

PERIOD OF PERFORMANCE END DATE: 05/10/2020

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