Source: NANOSUR LLC submitted to NRP
DEVELOPMENT OF EFFICACIOUS RNAI-BASED BAITS FOR RIFA CONTROL
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
COMPLETE
Funding Source
Reporting Frequency
Annual
Accession No.
1027234
Grant No.
2021-33610-35759
Cumulative Award Amt.
$649,000.00
Proposal No.
2021-06451
Multistate No.
(N/A)
Project Start Date
Sep 1, 2021
Project End Date
May 31, 2024
Grant Year
2021
Program Code
[8.2]- Plant Production and Protection-Biology
Recipient Organization
NANOSUR LLC
1951 NW 7TH AVE
MIAMI,FL 331361104
Performing Department
(N/A)
Non Technical Summary
The following is a Non-Technical Summary of the project:The red imported fire ant (RIFA) is an invasive pest introduced in the United States from Argentina in the 1930s). Currently, imported fire ants infest over 140 million hectaresin 14 states. Like many exotic pest species, invasive fire ants were introduced without most of the natural enemies that occur in their native South American range. As a consequence, fire ant population densities in the USA are 5-10 times higher than those in South America. Fire ants are particularly pestiferous because they: 1) prefer disturbed habitats (human activities), 2) have large population densities (18-35 kg/ha) and a huge need for resources, 3) are aggressive and have a potent sting - the venom can cause hypersensitivity in humans, and 4) have a large reproductive potential (300,000 new potential queens/ha/yr).Damages related to fire ants include household, crop and livestock losses, higher equipment repair and replacement costs, damages to the lawn, yard, farmstead, medical and veterinary expenditures, and cost of materials and equipment to control them. In addition to the most noticeable problem they cause, i.e., stinging of humans and animals, RIFA is also responsible for damages to soybeans, citrus, potatoes, corn, okra, and eggplants. Additionally, some agricultural commodities in infested areas, e.g., nursery and sod, must be quarantined because regulations mandate treatment of materials to be shipped to non-infested areas.The estimated annual 3+ billion dollars spent on fire ant control is indicative of the impact this ant has exerted on human activities.Current pesticides used to control RIFA have active ingredientswith varied modes of action; however, none of them is selective to fire ants, therefore they also kill organisms that are beneficial to agriculture, e.g., predatory and pollinating insects. For example, hydramethylnon, fenoxycarb, and pyriproxyfen, are toxic to fish, methoprene is toxic to amphibians, and spinosad and fipronil are toxic to honeybees. Furthermore, large-scale use of chemical insecticides is gradually being more restricted due to their effects on non-target organisms.Biological control of fire ants has been pursued, with most success with phorid fly (Pseudoacteon spp.) parasites of fire ants. Five species of these flies, from South America, were successfully released into USA fire ant populations over the past 25 years. They are self-sustaining. While they do not control fire ant colonies, they do reduce population densities.Thus, there is a need for novel fire ant active ingredients and formulations that have greater fire ant specificity, fewer effects on non-target species, and therefore, are safer for the environment/ecosystem. A gene-targeted insecticidedeveloped by NanoSUR's in this projectpresentsunique advantages for RIFA management and control by selectively targeting only RIFA without broader environmental effects and consequences.NanoSUR's technology applied to RIFA control is one of several applications aiming at first complementing, and eventually replacing, most chemical pesticides. We believe that NanoSUR has the best - if not the only - viable solution to the worldwide threat posed by chemical pesticides to the health of consumers and the ecosystem.
Animal Health Component
80%
Research Effort Categories
Basic
10%
Applied
80%
Developmental
10%
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
72152201060100%
Goals / Objectives
This project has one major goal: the development of an efficaciousinsecticide to control the red imported fire ant (RIFA) which is safe for boththe people handling it and the environment and is commercially attractive to commercial partners.Four objectives will be undertaken to achieve this goal. First, we will investigate means to optimize a) the safety of a candidate double strand ribonucleic acid material (MdsRNA) with respect to non-target organisms, aiming at accessing the largest range of applications and thus a larger market and b) the efficacy of MdsRNAs to the point where the technology is economically attractive for formulating into baits targeting RIFA (MdsRIFA). Second, we will focus on the scale up and characterization of the MdsRIFA-based baits, aiming at setting specifications required for their large-scale manufacturing, essential to make our product commercially viable. Third, we will develop oil-based broadcast baits for the top MdsRIFA candidates and test the ability of these baits to control queenright RIFA colonies. Forth, we will determine the minimum concentration of MdsRIFA in the bait to consistently achieve RIFA control under field conditions.
Project Methods
The following Methods will be used for the conduction of theproject:Chemically modified double strand RNAs (MdsRNAs) will be prepared by the reaction of at least 5% of the2'OH of the riboses comprised in double strand RNAs (dsRNAs) targeting a vital RIFA gene and having greater than 30 base pairs with reagents imparting lipophylic character to the dsRNAs or making them less susceptible to RNAses, such as N-methylisatoic anhydride and benzoyl cyanide. Reactions will be carried out in a solvent comprising aprotic solvents such as dimethylsulfoxide, dimethylformamide, urea, or acetonitrileand water, at temperatures between 30ºC and 95ºC. The derivatization extent of the dsRNAwill be estimated after complete hydrolysis of an aliquoted of the aqueous purified MdsRNA with 5M NaOH aqueous solution. A Photo Diode Arraydetector monitoring UV absorbance at 254 nm coupled to a high pressure liquid chromatography instrument will beused to quantify the resulting N-methylanthranoic acid and RNA nucleotides and thus evaluate the degree of modification of the dsRNA reactant.The increased lipophylic character of the resulting MdsRNA compared to the dsRNA reactant will be evaluated by quantifying the fraction of MdsRNA or dsRNA extracted from its aqueous solution with a non-polar solvent like n-octanol or dichloromethane. The stability of MdsRNA upon storage at 37ºC and theimproved stability of MdsRNAas compared to dsRNAtowards digestion with RNAses will be evaluated by quantifying the fraction of MdsRNA or dsRNA degraded, by incubation without and with RNAse III, using gel electrophoresis.MdsRNAs functioning as RNAi triggers in RIFAwill be screened for lethality using a bioassay involving feeding for 4 days a group of 20 worker ants 50 µl of liquid per day containing the MdsRNA at a known concentration in 10% sucrose aqueous solution and measuring the mortality rate of worker ants. Each cohort will consist on 4 replicates of 20 ants each. RIFA mortality resulting from feeding on MdsRNA-laced edible oil-based baits will be evaluated in the laboratory using colony fragments composed of brood and workers and in queenright feeding experiments. It will be also evaluated in the field at locations near Gainsville, Florida.For laboratory colony tests, acceptability, consumption, and distribution through worker trophallaxis of the baits will be monitored through the addition of a dye to the prototype baits that will allow visualization of the bait in brood and nestmates. A total of 8 baits, 4 with each MdsRNA will be evaluated. Controls will be bait formulations with the bait carrier, soybean oil, and a dye. The mortality effects of the prototype baits will be monitored by physically collecting dead workers and either counting them directly or by weighing 10 dead ants and then weighing the total dead ants to give approximate measure of mortality. Prototype baits that show more than >80% mortality in this feeding assay will be advanced to queenright feeding experiments.The size of the laboratory reared queenright colonies will vary from 1,000 workers to 50,000 workers. Initially, the prototype baits will be presented to small colonies. The feeding regime will be guided by the results from the colony fragment experiments conducted earlier. Queen weight, brood production (worker, male, female sexual) and mortality will be quantitated in treatments and controls at various time periods after treatment as measures colony health and the effectiveness of the prototype baits.In order to detect significant differences between treatments and controls in the field, we will 1) identify of all colonies (via GPS) at the field site; 2) measure the population Index (PI, colony height and diameter plus an estimate of the number of workers in each colony); 3) Colonies with similar PIs will be paired (control and treatment), 4) The same individual will calculate the PIs throughout the experiment to decrease variability, 5) The control and treatment baits will applied after the dew has evaporated 11:00 to 12:00 noon, 6) Controls and treatments will be applied as simultaneously as possible (within 10 min of each other), 7) PI values will be determined once a week for up to 8 weeks or longer, depending on the results.

Progress 09/01/21 to 05/31/24

Outputs
Target Audience:Our RNAi-based formulations for the control of RIFA are selective and will not affect organisms that are beneficial to agriculture, e.g. predatory and pollinating insects. In addition, these biopesticides are safe for the environment, i.e. are not persistent, and are also safefor livestock, pets, and humans. The target audiences that werethe focus of our efforts during this projectare companies that manufacture, distribute, and sell pesticides for the control of the Red Imported Fire Ant (RIFA) as well as farmers, national park managers and consumers that need to control RIFA in their homes. Our business development activities uncovered the need for our product to control RIFA in the production of nuts such as almonds and pistachios, and also in the maintenance of golf courses in the South and Southwest areas of the country. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest?In November 2022, two scientists from NanoSUR attended the North America ESA meeting held in Vancouver and participated in the RNAi for Ag Symposia discussions. In November 2023 Dr. Juan Arhancet presented "Improving the delivery of RNA biopesticides " at the2023 Annual Meeting of the Entomological Society of America in Maryland. What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? Our first project objective calls foridentifying two RIFA dsRNA sequences using bioinformatics. These sequences do not have a sequence identity of more than 18 contiguous nucleotides with 5 relevant species of NTOs (non-target organisms). We used these sequences to prepare modified dsRNA trigger formulations and testedthem against worker ants in a feeding bioassay. Both candidates met the efficacy criteria. We developed a process called ionic solvation, which is non-aqueous, to prepare MdsRNA triggers. Weproduced up to 10g of MdsRNA, which is enough for field trials and the process can be scaled up for commercial use. We successfully modifiedthedsRNA with polymers like polyethylene glycol (PEG). These pegylatedMdsRNA materials are stable in the solid form and soluble in sucrose solutions. Combining these new polymer groups with the fatty acids identified in Phase I, we creatednew RNAi triggers that are more effective against worker ants and have increased lipophilicity. We demonstrated the solubility of MdsRNAs modified with fatty acids in vegetable oil, the traditional carrier used for ant broadcast baits. In a significant breakthrough, we found vegetable oil/adjuvant mixtures that produced stable solutions or fine dispersions of up to 10% active ingredients. Various vegetable oils and sugar-like or sugar-derived surfactants resulted in stable suspensions of the MdsRNA. We then focused on selecting the best formulation based on their attractivenessto workers ants determined by the Choice test performed at USDA ARS, Gainsville. The top 2 formulations will be optimized with corn grits to prepare broadcast baits. Encouraged by these results we studied oil-based formulations of pegylated dsRNAs. In addition to oil/adjuvant solutions, we found oil in water emulsions that passed the choice test. In conclusion, by selecting the modifying group, we preparedRNAi triggers that are soluble in vegetable oil/adjuvant mixtures that were stable and accepted by the ants and thus suitable to prepare traditional baits for agriculture applications. The efficacy of one MdsRNA active ingredient was tested in 2 queen right colony testsat our collaborators' laboratory. In this first evaluation, the laboratory-reared colonies (with brood, workers, and queen) had about 15K workers plus the queen and brood. The protocol called for feeding each treated colony for 14 days and observing any mortality in the workers or changes in the queen's weight. The ants consumed the daily amount of treatment solution within hours. Thus, they were not fedthe treatmentcontinuously and the totality of the treatment tubes wereconsumed in 10 days. The colonies were monitored for another 15 days. No significant mortality in the treatment colonies was observed for the duration of the study. For the second colony test, six queenright RIFAcolonies reared in the ARS laboratory were obtained from newly mated queens from the field and fed sucrose water and crickets. The colonies had grown to ca. 5,000 workers each before the start of the experiment.The six colonies were separated into 2 groups of 3 colonies each, such that the estimated number of workers was similar for the 2 groups. These two groups werein turn divided into 3 treatments and 3 controls. Thus, the treatment and the control each had 3 replicates. All treatment solutions were consumed by Day 23. After Day 23, control and treatment colonies were fed the same diet of crickets and 10% sucrose water.The treatments showed higher mortality and variation than the controls.However, since one treatment colony repetition was lost, the observed mortality was not statistically significant. Overall, this mortality bioassay should be considered a probing experiment where whole colonies were continuously provided Active Ingredientover a long period of time. Due to the number of repetitions being limited, additional bioassays assessing the efficacy of our top3 modified sequences andcombination sequences willbe conducted.

Publications


    Progress 09/01/22 to 08/31/23

    Outputs
    Target Audience: Our RNAi-based formulations for the control of RIFA are selective and will not affect organisms that are beneficial to agriculture, e.g. predatory and pollinating insects. In addition, these biopesticides are safe for the environment,livestock, pets, and humans. The target audiences that werethe focus of our efforts during this reporting periodwerecompanies that manufacture, distribute, and sell pesticides for the control of the Red Imported Fire Ants (RIFA) in the home and on golf courses in the South, Southeastand Southwest areas of the country as well as producers of nuts such as almonds and pistachios. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest?NanoSUR was invited to present at the Entomology Society of America (ESA) 2023 Meeting, within the Improving the Delivery of RNA symposium. Our presentation was very well attended. What do you plan to do during the next reporting period to accomplish the goals?To accomplish Goal 3 of this project we intendto optimize the SBO/adjuvant blends to createstable solutions or emulsions of MdsRIFA. These improvedformulationswillbe testedin queenright colony tests to determine their effectson both worker ants and the queen. The ultimate aim is to identify an effective RNA product candidate to control RiFA.

    Impacts
    What was accomplished under these goals? During the reporting period, our objective was to develop stable formulations of MdsRIFA containing soybean oil (SBO), which serves as the phagostimulant in broadcast baits. These formulations must attract worker ants effectively, allowing them to transfer the active ingredient to the rest of the colony. Naive (unmodified) dsRNA is incompatible with SBO or other non-polar solvents thus, it cannot be formulated in baits. Ourmodification of the dsRNAs yielded more hydrophobic constructs soluble in SBO, albeit at lower concentrations than those required for good efficacy against RIFA. We then investigated the formulation with one or more adjuvants, studying three different approaches: 1. Modification of dsRNA with both hydrophobic and hydrophilic groups. We successfully prepared MdsRNA with a range of % modifications for both the polar and non-polar modifiers. Although the resulting RNA constructs had much higher hydrophobicity than the starting dsRNA, low solubility dominated the overall property profile, and we were unable to prepare stable formulations at the desired concentration of AI. As a result, we abandoned this approach. 2. Electrostatic complexation of MdsRNA with cationic surfactants. These complexes were soluble in organic solvents compatible with SBO, such as DMSO. We prepared and tested several formulations of the MdsRNA complex with mixtures of SBO/DMSO and surfactants, all at different ratios. These formulations were testedin the Ant Choice assay, yielding mixed results. 3. Mixtures of SBO and adjuvants with intermediate polarity between SBO and the MdsRNAs. This approach has yielded the most promising results in providing formulations that are both stable at the desired concentrations of MdsRIFA and accepted by the ants at the same rate as 100% SBO. We have successfully scaled up our MdsRIFA candidate and initiated queenright colonytests to determine its efficacy.

    Publications


      Progress 09/01/21 to 08/31/22

      Outputs
      Target Audience:Our RNAi-based formulations for the control of RIFA are selective and will not affect organisms that are beneficial to agriculture, e.g. predatory and pollinating insects. In addition, these biopesticides are safe for the environment, i.e. are not persistent, and for livestock, pets, and humans. The target audience that was the focus of our efforts during this the 2022 end-of-year reporting period was companies that manufacture, distribute and sell pesticides for the control of the Red Imported Fire Ant (RIFA) as well as farmers, national park managers and consumers that need to control RIFAin their homes. Our business development activities uncovered the need for our product to control RIFA in the production of nuts such as almonds and pistachios, and also in the maintenance of golf courses in the South and Southwest areas of the country. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest?In November 2022, scientists from NanoSUR attended the North America ESA meeting held in Vancouver. Following their successful discussions during the RNAi for Ag Symposia, they were invited to present at the next ESA meeting scheduled to take place in Maryland in 2023. What do you plan to do during the next reporting period to accomplish the goals?Our first step will be to maintain close collaboration with our CRADA partners to pinpoint modified RNA formulas that the ants will accept. Once we have identified the most effective and well-accepted formulation, we will increase its production and proceed with full colony field testing.

      Impacts
      What was accomplished under these goals? In this reporting period, we were able to achieve our first project objective by identifying two RIFA dsRNA sequences using bioinformatics. These sequences do not have a sequence identity of more than 18 contiguous nucleotides with 5 relevant species of NTOs (non-target organisms). We used these sequences to prepare modified dsRNA trigger formulations to test their effectiveness against worker ants in the laboratory. Once we have determined the top candidate, we will proceed to conduct colony field tests. We have developed a process called ionic solvation, which is non-aqueous, to prepare MdsRNA triggers. This process can produce up to 10g of MdsRNA, which is enough for field trials and can be scaled up for commercial use. This process also makes it possible to modify dsRNA with a wider range of groups, including polymers like polyethylene glycol (PEG). These polymer groups make the MdsRNAs stable and soluble in water. We combined these new polymer groups with fatty acids identified in Phase I to create new RNAi triggers that are more effective against worker ants and have increased lipophilicity. Additionally, we have developed analytic methods to determine the specifications needed for the pilot scale. We have made a significant breakthrough by showing that dsRNAs when modified with a combination of fatty acid and PEG, can dissolve in vegetable oil and create stable suspensions. This makes it possible to create oil-based baits to effectively control RIFA in natural environments. Throughout this period, we engaged in various initiatives to bring our potential products to market. One such initiative involved our TABA consultant conducting a thorough market analysis, as well as developing comprehensive strategies for NanoSur. This included defining our mission, vision, and values, exploring different strategic alternatives, and creating a roadmap for achieving our goals. Additionally, a SWOT analysis was conducted to identify our strengths, weaknesses, opportunities, and threats.

      Publications