AJ12--Development/Production - Kidney GEC-Specific AAV Vector

The following is a Sources Sought/Request for Information notice. This posted notice is not a Pre- Solicitation or Solicitation document. The government is not currently soliciting bids, quotes or proposals at this time; however, reserves the right to do so at a later date. The Harry S Truman Memorial Veterans Hospital, Columbia, MO 65201 has a brand name only requirement for Development/Production- Kidney GEC- Specific AAV Vector.
Statement of Work (SOW)
For GEC Targeted Adeno Associated Virus Vector Development Contract Description: Development and production of a kidney glomerular endothelial cell specific AAV vector for VA preclinical research.
1.0 Scope of Work:
1.1 This requirement is a VA ORD Merit funded project (#1I21RD001234-01) to develop a kidney glomerular endothelial cell specific viral vector.
1.2 The goal of the project is to build a homing peptide enabled vector platform capable of targeting the glomerular endothelium to treat kidney injury and disease and to enhance traditional pharmacologic approaches.
1.3 The work will modify the capsid of an endothelial specific, non immunogenic viral vector by incorporating a peptide that specifically targets kidney glomerular endothelial cells (GEC), with the objective of increasing specificity, reducing off target transduction, and overcoming known limitations in vector targeting to the kidney.
2.0 Background:
2.1 This requirement in response to RD-01-PILT: ISRM Pilot Project Award I21 was selected for funding by ORD; Merit funded project (1I21RD001234-01).
2.2 Despite aggressive management of blood pressure and glycemic control, the prevalence of kidney disease continues to rise, highlighting the need for adjunctive, individualized approaches that advance precision medicine. The project aims to build a homing peptide enabled vector platform targeting the glomerular endothelium to treat kidney injury and disease and to augment current therapeutic strategies. 2.3 Effective vector targeting of the kidney is impeded by the filtering function of the glomerulus and the risk of off target transduction, which may cause adverse effects. These challenges are compounded by the complex architecture of the kidney. Phage enabled peptide homing provides a powerful tool to refine tissue and cell specificity. Developing a targeted vector for GECs cells central to kidney disease development has strong potential to increase selectivity and minimize off target effects. 2.4 To address this need, the requirement leverages two technologies:
(1) Biopanning with phage display to select peptides that specifically target kidney glomerular endothelial cells, and
(2) capsid modification of an endothelial specific, non immunogenic vector to improve specificity and reduce off target transduction. 2.5 The services required will:
2.5.1 Validate a GEC targeting peptide and incorporate it into an endothelial specific adeno associated virus (AAV) capsid to control transduction specificity.
2.5.1.1Aim 1 refines phage display selection between murine and human renal versus extra renal endothelial cells to confirm GEC selectivity, followed by incorporation into the AAV capsid
2.5.2 Test the feasibility of the GEC specific AAV vector in culture studies (binding and internalization) and in vivo (biodistribution and transduction efficacy). 2.5.1.2 Aim 2 evaluates the targeting peptide modified AAV vector in murine kidney slices and in vivo biodistribution studies, followed by ex vivo immunofluorescent validation. The vector will also be tested in a murine model of endothelial glomerular filtration barrier injury. 2.6 This requirement will overcome current limitations in kidney specific vector targeting caused by the organ s complex cellular architecture and will create a clinically translatable cell specific vector platform designed to reduce off target effects.
3.0 Technical Requirements/Tasks:
3.1 Within one year of the start date of the funding award. The contractor shall independently perform all technical tasks required to engineer, produce, and validate a kidney glomerular endothelial cell (GEC) specific viral vector. Task one will require a high level of demonstrated proficiency and efficiency to be able to complete within one year.
3.1.1 Task 1: Peptide Incorporation Into Viral Capsid
3.1.1.1 Identified targeting peptides shall be engineered by the contractor into the AAV VP1 capsid at amino acid position 588/589, a well tolerated insertion site.
3.1.1.2 Modified AAV viruses will be produced serially.
3.1.1.3 Verified GEC peptide+AAV capsid plasmids will be used to generate vectors containing an eGFP reporter for quantitative assessment of vector function.
3.1.1.4 Specificity and transduction efficiency will be evaluated across a panel of cell types using flow cytometry.
3.1.1.5 Peptide robustness will be evaluated through iterative comparisons of peptide alone versus peptide displayed on the AAV6 capsid.
3.1.1.6 Fluorescent peptide binding to a biomarker unique to GEC will be quantified (KD, IC50) to confirm specificity.
3.1.1.7 Task one will be considered complete when peptide sequencing is completed in accordance with the research protocol. Receipt of the data readout and a satisfactory progress report that outlines the data and any needed adaptations for the next tasks by end of funding period one will complete the task
3.1.2 Task 2: Will begin once there is satisfactory completion of task one. Testing of GEC Specific Peptide Vector Binding will be performed independently by the contractor beginning at the start of the second funding period and must be complete by the end of the second year of the award
3.1.2.1 Supernatant containing the GEC peptide+vector will be incubated with cultured murine kidney tissue slices to assess binding and internalization.
3.1.2.2 Round 1 panning will use laser capture microdissection to collect GEC bound phage.
3.1.2.3 Rounds 2 and 3 will refine targeting using mixed kidney derived cell populations and control tissues.
3.1.2.4 Uptake in non target cells (e.g., hepatocytes, AEC, RECs) will be collected for analysis of non specific binding.
3.1.2.5 Task two will be considered complete when the results of the testing of the GEC-Specific Peptide Vector Binding are submitted to the research team for review and analysis and deemed acceptable. If revision work is needed that will occur in conjunction with Task 3. Completion of this task will require satisfactory progress report that outlines the data and any needed adaptation for the next task.
3.1.3 Task 3: Specificity and Efficiency Testing of the Modified Vector
3.1.3.1 Bioluminescence imaging will be performed over a time course using luciferase reporter constructs to quantify transduction efficiency and determine optimal timepoints.
3.1.3.2 Renal artery infusion of the GEC peptide modified AAV (or control AAV) will be performed to assess target and off target accumulation.
3.1.3.3 Ex vivo whole organ imaging (IVIS Spectrum) and immunohistochemistry/immunofluorescence will confirm organ and cellular level distribution.
3.1.3.4 Vector genome presence will be assessed by AAV ITR specific PCR.
3.1.3.5 Tissue and plasma samples will be collected to evaluate kidney function and possible off target effects.
3.1.3.6 Task three will be considered complete when the research team and facility have determined the data report from the efficiency testing are acceptable and a final report outlining all data, interpretations of the data and conclusions and by the end of the second year of the award.
3.1.3.7 Reported data will be generated and sent to the Primary Investigator by the end of each funding period as outlined in the tasks above.
3.2 Other requirements
3.2.1 Quarterly reporting
3.2.1.1 From date of award onward the awardee shall provide quarterly reports verifying what tasks were completed, current stage and any recent or pending results in alignment with the three tasks 3.1.1, 3.1.2, and 3.1.3 from the VA ORD Merit funded project (#1I21RD001234-01).
3.2.2 Communication
3.2.2.1 The communication of the reports will occur through email or phone call communications delivered no later than 1700 Central Standard Time at the end of the quarter.
3.2.2.2 Weekly videoconference lab meetings held on Thursdays at a time coordinated post award.
3.2.2.3 Biannual face to face meetings that will take place through the VA Career Development Enhancement Award for the Principal Investigator (Government Employee) to go to Finland to meet with the contract awardee and review progress.
4.0 Contractor Qualifications 4.1 The vendor must maintain the following resources onsite for continuity of project implementation
4.1.1 Dedicated cell culture facilities
4.1.2 RNA and DNA laboratories
4.1.3 Histology Laboratories
4.1.4 Individual BSL-2 Laboratories
4.1.4.1 Specialized for Lentivirial work
4.1.4.2 Specialized for Adenoviral work
4.1.4.3 Adeno-Associated Viral work
4.1.5 Agilent Fragment Analyzer
4.1.6 Blue Pippin Instrumentation
4.1.7 Access to multiple qPCR and ddPCR platforms
4.1.7.1 StepOnePlus
4.1.7.2 Quant 3 Studio
4.1.7.3 QX200 Droplet Digital PCR
4.1.8 Protein analysis capability
4.1.8.1 Percellys 24 Tissue homogenizer
4.1.8.2 JESS simple western system
4.1.9 Incucyte S3
4.1.10 xCELLigence
4.1.11 Opera Phoenix Plus
4.1.12 Permeability assays
4.1.12.1 CellzScope TEER System
4.1.12.2 Clario STAR
4.1.13 Flow cytometry and cell sorting instruments
4.1.13.1 Cytoflex
4.1.13.2 Amnis Flowsight
4.2 Proven success in both animal and human cell vector delivery. Staff should have qualifications, experience in endothelial specific viral vector engineering, and prior work in related preclinical models
4.3 Scientists with established expertise in vector development using adeno-associated virus, endothelial biology, and has built preliminary kidney targeted applications.
4.4 Must be fully compliant with Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) and Federation of European Laboratory Animal Science Associations (FELASA) health standards
5.0 Data Rights:
5.1 All data generated under this contract that directly pertains to the development and characterization of the GEC targeting vector shall be provided to the Government with Government Purpose Rights and shall be retained per RCS10-1.
5.2 The contractor retains rights to pre existing proprietary methodologies, protocols, or technologies used in the performance of this work.
6.0 Records Management Language: When Federal agencies acquire goods or services, they need to determine what Federal records management requirements should be included in the contract. Federal contractors often create, send, or receive Federal records. Federal contracts should provide clear legal obligations describing how the contract employees must handle Federal records. Agency records officers, procurement counsel, and acquisitions officers must discuss how to integrate records management obligations into their existing procurement processes. NARA has developed the following language to be included as an agency-specific term and condition in Federal contracts for a variety of services and products. The majority of contracts should include language on records management obligations, but each contract should be evaluated individually. For example, the data-rights paragraph (Paragraph 10 below) may not be appropriate for all contracts. Instead, agencies may be better served by one of the established data-rights clauses in the Federal Acquisition Regulations. This language should not replace specific records management requirements included within Federal information system contracts. RECORDS MANAGEMENT OBLIGATIONS A. Applicability This clause applies to all Contractors whose employees create, work with, or otherwise handle Federal records, as defined in Section B, regardless of the medium in which the record exists. B. Definitions Federal record as defined in 44 U.S.C. § 3301, includes all recorded information, regardless of form or characteristics, made or received by a Federal agency under Federal law or in connection with the transaction of public business and preserved or appropriate for preservation by that agency or its legitimate successor as evidence of the organization, functions, policies, decisions, procedures, operations, or other activities of the United States Government or because of the informational value of data in them. The term Federal record: 1. includes VA Medical Center records. 2. does not include personal materials. 3. applies to records created, received, or maintained by Contractors pursuant to their VA Medical Center contract. 4. may include deliverables and documentation associated with deliverables. C. Requirements 1. Contractor shall comply with all applicable records management laws and regulations, as well as National Archives and Records Administration (NARA) records policies, including but not limited to the Federal Records Act (44 U.S.C. chs. 21, 29, 31, 33), NARA regulations at 36 CFR Chapter XII Subchapter B, and those policies associated with the safeguarding of records covered by the Privacy Act of 1974 (5 U.S.C. 552a). These policies include the preservation of all records, regardless of form or characteristics, mode of transmission, or state of completion. 2. In accordance with 36 CFR 1222.32, all data created for Government use and delivered to, or falling under the legal control of, the Government are Federal records subject to the provisions of 44 U.S.C. chapters 21, 29, 31, and 33, the Freedom of Information Act (FOIA) (5 U.S.C. 552), as amended, and the Privacy Act of 1974 (5 U.S.C. 552a), as amended and must be managed and scheduled for disposition only as permitted by statute or regulation. 3. In accordance with 36 CFR 1222.32, Contractor shall maintain all records created for Government use or created in the course of performing the contract and/or delivered to, or under the legal control of the Government and must be managed in accordance with Federal law. Electronic records and associated metadata must be accompanied by sufficient technical documentation to permit understanding and use of the records and data. 4. VA Medical Center and its contractors are responsible for preventing the alienation or unauthorized destruction of records, including all forms of mutilation. Records may not be removed from the legal custody of the VA Medical Center or destroyed except for in accordance with the provisions of the agency records schedules and with the written concurrence of the Head of the Contracting Activity. Willful and unlawful destruction, damage or alienation of Federal records is subject to the fines and penalties imposed by 18 U.S.C. 2701. In the event of any unlawful or accidental removal, defacing, alteration, or destruction of records, Contractor must report to the VA Medical Center. The agency must report promptly to NARA in accordance with 36 CFR 1230. 5. The Contractor shall immediately notify the appropriate Contracting Officer upon discovery of any inadvertent or unauthorized disclosures of information, data, documentary materials, records or equipment. Disclosure of non-public information is limited to authorized personnel with a need-to-know as described in the obligation. The Contractor shall ensure that the appropriate personnel, administrative, technical, and physical safeguards are established to ensure the security and confidentiality of this information, data, documentary material, records and/or equipment are properly protected. The Contractor shall not remove material from Government facilities or systems, or facilities or systems operated or maintained on the Government s behalf, without the express written permission of the Head of the Contracting Activity. When information, data, documentary material, records and/or equipment is no longer required, it shall be returned to VA Medical Center control, or the Contractor must hold it until otherwise directed. Items returned to the Government shall be hand carried, mailed, emailed, or securely electronically transmitted to the Contracting Officer or address prescribed in the obligation. Destruction of records is EXPRESSLY PROHIBITED unless in accordance with Paragraph (4). 6. The Contractor is required to obtain the Contracting Officer's approval prior to engaging in any contractual relationship (sub-contractor) in support of this contract requiring the disclosure of information, documentary material and/or records generated under, or relating to, contracts. The Contractor (and any sub-contractor) is required to abide by Government and VA Medical Center guidance for protecting sensitive, proprietary information, classified, and controlled unclassified information. 7. The Contractor shall only use Government IT equipment for purposes specifically tied to or authorized by the contract and in accordance with VA Medical Center policy. 8. The Contractor shall not create or maintain any records containing any non-public VA Medical Center information that are not specifically tied to or authorized by the contract. 9. The Contractor shall not retain, use, sell, or disseminate copies of any deliverable that contains information covered by the Privacy Act of 1974 or that which is generally protected from public disclosure by an exemption to the Freedom of Information Act. 10. The VA Medical Center owns the rights to all data and records produced as part of this contract. All deliverables under the contract are the property of the U.S. Government for which VA Medical Center shall have unlimited rights to use, dispose of, or disclose such data contained therein as it determines to be in the public interest. Any Contractor rights in the data or deliverables must be identified as required by FAR 52.227-11 through FAR 52.227-20. 11. Training. All Contractor employees assigned to this contract who create, work with, or otherwise handle records are required to take VA Medical Center -provided records management training. The Contractor is responsible for confirming training has been completed according to agency policies, including initial training and any annual or refresher training.














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