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Synthesis and Biological Activity Assessment of Different Diastereomers in siRNA Drug LEQVIO (Inclisiran) (U01) Clinical Trial Not Allowed
The purpose of this research is to systematically evaluate the diastereomeric composition of LEQVIO (Inclisiran), an FDA-approved, N-acetyl galactosamine (GalNAc)-conjugated siRNA drug, and to understand the biological/pharmacological activity of each diastereomer in LEQVIO through stereo chemically
controlled synthesis and biological activity assessment using in vitro and animal models.
The proposed studies will focus on 1) synthesis of each diastereomer of LEQVIO (Inclisiran) in stereo chemically pure form; 2) assessment of the biological activity of each stereo chemically pure diastereomer in inhibiting PCSK9 activity using in vitro assays and in a transgenic mouse model; 3) development of analytical methods to identify and characterize the stereochemical structure of each diastereomer in LEQVIO; and 4) assessment of the individual contribution of each diastereomer to the overall pharmacological activity of LEQVIO.
Tools developed in this research can also be applied to other similar GalNAc-conjugated siRNAs specifically, and other siRNAs in general.
Knowledge gained from this research will also contribute to the sameness evaluation of generic siRNAs, and to the quality control of oligonucleotide drugs.
The proposed studies will focus on 1) synthesis of each diastereomer of LEQVIO (Inclisiran) in stereo chemically pure form; 2) assessment of the biological activity of each stereo chemically pure diastereomer in inhibiting PCSK9 activity using in vitro assays and in a transgenic mouse model; 3) development of analytical methods to identify and characterize the stereochemical structure of each diastereomer in LEQVIO; and 4) assessment of the individual contribution of each diastereomer to the overall pharmacological activity of LEQVIO.
Tools developed in this research can also be applied to other similar GalNAc-conjugated siRNAs specifically, and other siRNAs in general.
Knowledge gained from this research will also contribute to the sameness evaluation of generic siRNAs, and to the quality control of oligonucleotide drugs.
Agency: Department of Health and Human Services
Office: Food and Drug Administration
Estimated Funding: $300,000
Office: Food and Drug Administration
Estimated Funding: $300,000
Who's Eligible
Obtain Full Opportunity Text:
http://Click on Application Tab above to download full announcement instructions and application package.
Additional Information of Eligibility:
All types of domestic applicants are eligible to apply, except nonprofit organizations described in section 501(c)(4) of the Internal Revenue Code of 1986 that engaged in lobbying activities after December 31, 1995.
Federally affiliated entities must adhere to the eligibility standards below: III.A.1.
DOE/NNSA National Laboratories DOE/NNSA National Laboratories are eligible to submit applications (either as a lead organization or as a team member in a multi-institutional team) under this FOA and may be proposed as subrecipients under another organization’s application.
If recommended for funding as a lead applicant or a team member, funding will be provided through the DOE Field-Work Proposal System and work will be conducted under the laboratory’s contract with DOE.
No administrative provisions of this FOA will apply to the laboratory or any laboratory subcontractor.
If recommended for funding as a proposed subrecipient, the value of the proposed subaward will be removed from the prime applicant’s award and will be provided to the laboratory through the DOE Field-Work Proposal System and work will be conducted under the laboratory’s contract with DOE.
Additional instructions for securing authorization from the cognizant Contracting Officer are found in Section VIII of this FOA.
III.A.2.
Non-DOE/NNSA FFRDCs Non-DOE/NNSA FFRDCs are eligible to submit applications (either as a lead organization or as a team member in a multi-institutional team) under this FOA and may be proposed as subrecipients under another organization’s application.
If recommended for funding as a lead applicant or a team member, funding will be provided through an interagency agreement Award to the FFRDC’s sponsoring Federal Agency.
If recommended for funding as a proposed subrecipient, the value of the proposed subaward may be removed from the prime applicant’s award and may be provided through an Inter-Agency Award to the FFRDC’s sponsoring Federal Agency.
Additional instructions for securing authorization from the cognizant Contracting Officer are found in Section VIII of this FOA.
III.A.3.
Other Federal Agencies Other Federal Agencies are eligible to submit applications (either as a lead organization or as a team member in a multi-institutional team) under this FOA and may be proposed as subrecipients under another organization’s application.
If recommended for funding as a lead applicant or a team member, funding will be provided through an interagency agreement.
If recommended for funding as a proposed subrecipient, the value of the proposed subaward may be removed from the prime applicant’s award and may be provided through an interagency agreement.
Additional instructions for providing statutory authorization are found in Section VIII of this FOA.
Full Opportunity Web Address:
http://Click on Application Tab above to download full announcement instructions and application package.
Contact:
Agency Email Description:
terrin.brown@fda.hhs.gov
Agency Email:
Date Posted:
2024-01-15
Application Due Date:
Archive Date:
2024-04-30
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