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This acquisition is being conducted under Federal Acquisition Regulations (FAR) Part 13 – Simplified Acquisition Procedures and the resultant contract award will include all applicable provisions and clauses in effect through Federal Acquisition Circular 2023-02 dated March 16, 2023.
This requirement is to undertake an evaluation of the potential efficacy of the novel experimental immunomodulatory drug 3-MonothioPomalidomide in a preclinical animal model of Parkinson’s disease to evaluate potential for developing the agent towards this disorder.
Project background: Parkinson's disease (PD) is the second most common neurodegenerative condition – with some 1.5% of the worldwide population over the age of 65 years suffering from this disorder. Current available therapies are focused on Dopamine (DA) replacement and, whereas such treatments can at the outset be effective in reducing motor symptoms associated with PD, as the disorder progresses complex clinically significant motor fluctuations and dyskinesias invariably develop that can dramatically reduce the quality of life and mobility of patients. Varying levels of success for ameliorating such motor complications have been achieved by recent therapies, including subcutaneous apomorphine infusions, continuous infusions of levodopa and deep brain stimulation, but these treatment strategies do not change disease progression. Furthermore, nondopaminergic systems within PD brain appear to become progressively dysfunctional with time, and link with development of depression, gait difficulties and dementia to detrimentally impact the quality of life of patients, and these are very often resistant to treatment. Consequently, a pressing current need exists to develop effective neuroprotective treatments with the potential to target pathways common across neurodegeneration to augment both dopaminergic and nondopaminergic systems within the brain, to lessen PD progression.
While PD is not considered an immune-mediated disease, mounting evidence suggests a major role of inflammation in the progression of PD. Markers of inflammation can be found around the regions of risk and adjacent to the appearance of Lewy bodies within the basal ganglia and the substantia nigra (SN) that are associated with PD pathology. In this regard, innate immune activation in PD is triggered by extracellular misfolded proteins released from dead or damaged neurons. These molecular aggregates induce microglial activation and the consequent release of pro-inflammatory immune factors such as tumor necrosis factor-a (TNF- a) that damage neighboring neurons and neuronal connections (Mosley et al., 2012; Jung et al., 2021). This, in turn, can upregulate the generation and secretion of a host of inflammatory factors by microglial and astrocytic cells to potentially result in a self-sustaining cycle of neuroinflammation that can drive disease progression. In this regard, neuroinflammation is a classical and invariant feature of PD that provides a hostile brain microenvironment for optimal neurological activity. Such neuroinflammation likely involves both peripheral and CNS sources and can potentially be mitigated.
Pomalidomide is a clinically approved drug widely used in the treatment of multiple myeloma – a form of cancer that impacts white blood cells. It is an immunomodulatory imide drug (IMiD) that reduces the generation of the proinflammatory cytokine TNF-a. A novel experimental drug - 3,6’-DithioPomalidomide – was generated by NIA on the backbone of pomalidomide and successfully previously evaluated in models of PD. It proved to be highly efficacious; however, its metabolic half-life is very short. A product of 3,6’-DithioPomalidomide breakdown is 3-MonothioPomalidomide.
In PD management, a current primary concern is the development of abnormal involuntary movements that inexorably arise following long-term L-DOPA therapy (the most widely used current symptomatic treatment for PD). This L-DOPA-induced dyskinesia (LID) has proven difficult to pharmacologically treat, and its mitigation continues to be an urgent unmet therapeutic need for which interest is growing on repurposing drugs for its amelioration.
The focus of the present requirement is to assess whether 3-MonothioPomalidomide may mitigate key elements of PD in a well-established preclinical model of this disorder.
SCOPE OF WORK
General Requirements: Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government as needed to perform the Statement of Work below:
Specific Requirements:
ESSENTIAL Requirements from Contractor: The focus of this study is to evaluate whether 3-MonothioPomalidomide is capable of mitigating LID in a well-established preclinical animal model of PD.
1. Pharmacological animal studies - All experimental procedures must either be conducted under (i) National Institutes of Health (NIH) Guidelines using the NIH handbook Animals in Research or (ii) meet the guidelines and protocols approved by the European Community (2010/63 UE L 276 20/10/2010). In accord with these, animal studies must be undertaken on approved protocols of the contractor’s institutional Animal Care and Use Committee.
A full nigrostriatal lesion will be performed in male Sprague Dawley rats (weighting approx. 275-300 g) under anesthesia (such as fentanyl: 3 mg/kg i.p.) and, by use of a stereotaxic apparatus, a unilateral injection of 6-OHDA will be made into the left medial forebrain bundle, as previously described [Fenu et al., Eur J Pharmacol. 2016; 788:183-191]. The cylinder test and TH (tyrosine-hydroxylase) immunohistochemistry in the Substantia Nigra pars compacta (SNpc) will be performed for the assessment of dopamine depletion. Only animals showing an asymmetry score (n. of affected limb wall touches/n. of unaffected limb touches) <0.25 and a nigrostriatal degeneration above 95 % will be included in the experimental evaluation.
2. Treatment - Three weeks after 6-OHDA lesioning, rats will be treated for ten days as follows: Drug vehicle (Veh) rats will receive saline plus 0.5% carboxymethylcellulose (n=10-15 depending on variance), Veh+L-DOPA rats will receive vehicle and 6 mg/kg each of L-DOPA+benserazide (n=10-15 depending on variance), 3-MonothioPOM+L-DOPA rats will receive 3-MonothioPOM (26.47 mg/kg (aka., equivalent to 25 mg/kg thalidomide)) and L-DOPA+benserazide (6 mg/kg)( (n=10-15 depending on variance), and assorted control groups will be 3-MonothioPOM+Veh (26.47 mg/kg) (n=4). 3-MonothioPOM will be administered daily 30 minutes before L-DOPA.
3. Behavioral studies - Limb and axial abnormal involuntary movements (AIMs) will recorded as a rodent model of LID daily during the 10 day treatment, together with contralateral turning behavior. Rats will individually monitored for 1 minute every 20 minutes within 2 hours after L-DOPA administration, as described [Mulas et al., Exp Neurol. 2016; 286:83-92]. The time (sec) spent in limb and axial AIMs and the number of contralateral turns will be recorded.
4. Immunohistochemistry - On the last day of pharmacological treatments, rats will be deeply anesthetized and transcardially perfused with 4% paraformaldehyde (PFA) 1 hour after L-DOPA administration. Brains will be collected, post-fixed and 40 µm thick coronal sections will be cut by vibratome [Mulas et al., Exp Neurol. 2016; 286:83-92].
Striatal or midbrain sections will be pre-incubated with a blocking solution with normal serum/BSA and then immunoreacted with primary antibodies for single or double immunolabelling: polyclonal rabbit anti-TH (1:1000, Millipore); monoclonal mouse anti-GluR1 (1:1000, Novus Biologicals); monoclonal mouse anti-OX-42 (1:400, Serotec-Oxford); polyclonal rabbit anti-TNF-α (1:500, Novus Biologicals) polyclonal rabbit anti-IL-10 (1:200, Abbiotec); polyclonal rabbit anti-GFAP (1:1000, Novus Biologicals); monoclonal mouse anti-vimentin (1:1000, Novus Biologicals). Control slices will be incubated without primary antibodies, and all slices will thereafter be incubated with the appropriate fluorochrome-conjugated secondary antibodies. A three-step detection will be used to increase the signal of cytokines, as previously described [Carta et al., Neuroscience. 2011; 194:250-61].
5. Confocal microscopy analysis - Qualitative and quantitative analysis for GLUR1 expression, all markers of neuroinflammation and angiogenesis immunoreactivity (IR) will be performed using a Leica 4D or alike confocal laser scanning microscope, equipped with an argon-krypton laser. Confocal images will be generated as previously described [ Carta et al., Neuroscience. 2011; 194:250-61; Pissanu et al., Neurobiol Dis. 2014; 71:280-91]. The volume occupied by GLUR1, cytokines/OX-42colocalization and vimentin will be determined by Imaris 7.3 or an alike technique (n=30-40). The unlesioned side of Veh-treated brains will be utilized as the inner control across studies.
6. Statistical analysis - All data will be statistically analyzed by Statistica 8 (Stat Soft Inc., Tulsa, OK, US) or an alike statistical program. Data from behavioral studies (AIMs and contralateral turning) will be analyzed by Two-way ANOVA with repeated measures or One-way ANOVA, followed by Newman-Keuls post-hoc tests. Linear regression will be calculated to assess sensitization of AIMs. Immunohistochemistry data will analyzed by One-way ANOVA followed by Tukey's HSD post-hoc test. Significance will be set at p<0.05.
7. A short report with appropriate statistical analysis and representative Figures will be generated.
8. The Contractor’s Institution can take up to, but no more than,10% of the contract as overhead charges.
LEVEL OF EFFORT: Experienced neuropharmacologist focused on neurodegeneration in Parkinson’s disease and drug development. Expected time required: 200 hours.
GOVERNMENT RESPONSIBILITIES
The Government will provide: Scientific input, as required, and 3 MonothioPomalidomide for services.
DELIVERY OR DELIVERABLES
Deliverables and Timeline (timeline = 4-6 months from award of contract): A short report focused on research results with data and representative Figures – maximum 5 page – as an electronic file).
REPORTING REQUIREMENTS
A report is required – see deliverables, above.
The Contractor will have a short (approx. 15 min) once every two-week phone meeting with the NIA/NIH Principal Investigator to highlight progress and define any problems that need input for resolution.
TRAVEL: No travel is required. However, contractor should interact with the key NIA scientist involved in the studies via phone and email, as necessary.
KEY PERSONNEL: The contractor must have a background in neuropharmacology – and a focus in Parkinson’s disease animal models – together with an approved animal protocol and necessary access to equipment to undertake the described SOW. The Contractor shall provide staff that can demonstrate expert knowledge and experience in the following areas:
- An extensive background in preclinical studies of neuroinflammation in Parkinson’s disease is an essential requirement (supported by publications in PubMed)
- Contractor MUST previously have evaluated drugs in a LID model of Parkinson’s disease (supported by publication in PubMed)
- Contractor MUST have previously worked with the Immunomodulatory (IMiD) drug class (specifically with either thalidomide or pomalidomide and/or close analogues (supported by publication in PubMed)
- Contractor MUST have Institutional ACUC approved animal protocols that are in line with either (a) National Institutes of Health (NIH) Guidelines using the NIH handbook Animals in Research or (b) meet the guidelines and protocols approved by the European Community (2010/63 UE L 276 20/10/2010).
DATA RIGHTS: The National Institute on Aging shall have unlimited rights to, and ownership of all deliverables provided under this contract including reports, recommendations, briefings, work plans and all other deliverables. This includes the deliverables provided under the basic contract and any optional task deliverables exercised by the contracting officer. In addition, it includes any additional deliverables required by contract change. The definition of “unlimited rights” is contained in Federal Acquisition Regulation (FAR) 27.401, “Definitions.” If appropriate, data generated will be made available to the public by publishing the data in a scientific journal.
CONFIDENTIALITY OF INFORMATION: N/A
SUMMARY STATEMENT:
The Unique Entity Identifier (UEI), the Taxpayer Identification Number (TIN), certification of country of ownership, and the certification of business size must be included in the response.
All offerors must have an active registration in the System for Award Management (SAM) www.sam.gov.
Quoter Terms and Conditions (To be completed by the Offeror):
- Period of Performance OR Delivery Date After Receipt of Order:
- Shipping Point (F.O.B. OR Destination):
- Payment Discount Terms:
- NIH Blanket Purchase Agreement (BPA) Number:
- SAM UEI No:
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ADDITIONAL TERMS AND CONDITIONS, PROVISIONS, AND REPRESENTATIONS
The FAR Clauses are incorporated by reference and are provided in full text at https://www.acquisition.gov/
- FAR Clause 52.213-4 (March 2023) is applicable to this solicitation.
- FAR Clause 52.232-1, Payments, in solicitations and contracts when a fixed-price supply contract, a fixed-price service contract, or a contract for nonregulated communication services is contemplated.
- FAR Clause 52.243-1 Changes – Fixed Price (Aug 1987) is applicable to this solicitation.
- FAR Clause 52.227-14, Rights in Data - General (May 2024).
In addition, the following FAR provisions and clauses are applicable to this solicitation and incorporated by reference:
- 52.204-7 System for Award Management (Oct 2018),
- 52.204-13 System for Award Management Maintenance (Oct 2018),
- 52.204-16 Commercial and Government Entity Code Reporting (Aug 2020),
- 52.204-18 Commercial and Government Entity Code Maintenance (Aug 2020)
- HHSAR 352.239-73, Electronic and Information Technology Accessibility Notice (December 18, 2015).
The following provisions and clauses apply to this acquisition and are incorporated as an attachment. Offerors MUST complete the provision at 52.204-24 and 52.204-26 and submit completed copies as separate documents with their quotation.
- FAR 52.204-24, Representation Regarding Certain Telecommunications and Video Surveillance Services or Equipment (Nov 2021)
- FAR 52.204-25, Prohibition on Contracting for Certain Telecommunications and Video Surveillance Services or Equipment (Nov 2021)
- FAR 52.204-26, Covered Telecommunications Equipment or Services-Representation (Oct 2020)
- NIH Invoice and Payment Provisions
All responses must be received by May 26, 2023 at 12:00 pm EST and must reference announcement/ solicitation number NIA-23-006142. Responses may be submitted electronically to Carla Blalock (carla.blalock@nih.gov). Fax responses will not be accepted.
Interested parties may identify in writing their interest and capability in response to this requirement. Responses to this notice shall contain sufficient information to establish the interested parties’ bona-fide capabilities for fulfilling the requirement and include: unit price, list price, shipping and handling costs, the delivery period after contract award, the prompt payment discount terms, the F.O.B. Point (Destination or Origin), the Dun & Bradstreet Number (DUNS), the Taxpayer Identification Number (TIN), and the certification of business size. All offerors must have an active registration in the System for Award Management (SAM) www.sam.gov.
All responses must be received by closing date and must reference the announcement. Responses may be submitted electronically to the attention of the contract specialist. Fax responses will not be accepted.
All responsible sources may submit a bid, proposal, or quotation which shall be considered by the agency.