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VLVs as platform for nucleic acid-based delivery:Combining therapeutic vaccine with shRNA-mediated PD-L1 blockade for the treatment of chronic hepatitis B virus

Award Number: R43AI149798
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: 09/14/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2021

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VLVs as platform for nucleic acid-based delivery:Combining therapeutic vaccine with shRNA-mediated PD-L1 blockade for the treatment of chronic hepatitis B virus - PROJECT SUMMARY/ABSTRACT Nucleic acids (NA) have a broad and expanding therapeutic potential, but a major limiting factor remains the difficulty to deliver these molecules. We have developed a highly scalable platform technology with the capacity for delivering NAs for use in multiple disease systems. Our goal is to adapt this technology to deliver small interfering RNA (siRNA) precursor form, short-hairpin (shRNA) as an NA–based therapeutic. In proof-of- concept studies, we have established that a VLV (RNA replicon-based vector) carrying RNA encoding all three HBV major antigens (MHBs, HBcAg and polymerase) in a single ORF (VLV-3xT2A) drives a broad multi- specific immune response that resulted in substantial clearance of HBV in the liver. In order to achieve long term viral suppression or complete elimination of the virus in the liver, we have targeted for disruption the checkpoint inhibitor, programmed cell death receptor ligand 1 (PD-L1) by shRNA technology. The hypothesis is that disruption of the PD-1/PD-L1 pathway will reinvigorate the otherwise exhausted T cell function. In preliminary studies, we have engineered CARG-101 to incorporate one or multiple copies of shRNA against PD-L1, and we have showed that these vectors specifically downregulate stably transfected PD-L1 in a BHK21 cell line. In this study, we will examine whether the in vivo blockade of the PD-1/PD-L1 pathway will enhance virus-specific T cell immunity that will lead to the complete resolution of chronic infection in mice. To this end, we will carry out the following specific aims: (1) Optimize VLV-shRNA vectors for inhibition of PD-L1; (2) Investigate the kinetics of PD-L1/PD-L2 and PD-1 expression in naïve and chronic HBV mice; and (3)Evaluate clearance using the AAV-HBV mouse model of HBV persistence. At the completion of Phase I, we will have: (a) established that VLV platform can deliver NAs to cells and tissues in vivo; (b) generated novel therapeutic that enhances the efficacy of therapeutic vaccine. A robust CD8+ T cell response via PD-1/PD-L1 pathway blockade will accrue, thereby driving a drastic or complete clearance of HBV in the liver. The demonstrated capacity to express NAs has broad utility for treating multiple diseases. Another compelling value proposition of this technology lies in its potential application to chronic and intractable diseases such as HIV, HPV, TB, malaria, and cancer which are refractory to current vaccine technologies but which may now be amenable to VLV technology.


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: 2022 ( Subtotal = $0 )
2022	2020	CAROGEN CORP	295 WASHINGTON AVE	HAMDEN	CT	06518	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	1	6/3/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $300,000 )
2020	2020	CAROGEN CORPORATION	295 WASHINGTON AVE	HAMDEN	CT	06518	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	1	9/14/2020	NEW	$300,000
														Subtotal = $300,000

Grand Total All Awards = $300,000

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VLVs as platform for nucleic acid-based delivery:Combining therapeutic vaccine with shRNA-mediated PD-L1 blockade for the treatment of chronic hepatitis B virus

Award Number: R43AI149798

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: 09/14/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2021

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