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A Universal Fungal Transposase System for Increasing Natural Product and Protein Titers

Award Number: R43AT012434
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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A Universal Fungal Transposase System for Increasing Natural Product and Protein Titers - PROJECT SUMMARY. Fungal natural products (NPs) and enzymes are valued for their unique and diverse bioactivities. Flagship NPs command hundreds of millions of dollars in agricultural and tens of billions in pharmaceutical markets per year globally, illustrating a broad appetite for fungal molecules across disparate industries. Global markets for all microbial NPs are projected to exceed $300 billion (USD) by 2030. Fungal enzymes represent over half the worldwide enzyme market, which is projected to exceed $10 billion by 2031. Despite recent progress in our computational understanding of the breadth of chemical and enzymatic diversity encoded in fungal genomes, limitations in existing synthetic biology expression tools have stymied rapid access to new and improved products. The current bottleneck in developing novel fungal products is specifically at the strain engineering step as it is routinely observed that heterologous strains do not produce enough product, even for something as fundamental as molecular detection or functional screening, let alone scaleup for industrial production. This research proposal seeks to simplify and shorten development timelines for generating stable, high titer heterologous production strains by integrating recent advances in fungal synthetic biology tools with proven eukaryotic transposase technologies. This approach would overcome limitations seen with existing methods that result in low titer performance. Leap-InTM and piggyBacTM transposase products have revolutionized mammalian cell culture industries by rapidly engineering high titer production-worthy strains by stably integrating multiple copies of an intact transposon payload, regardless of size or sequence content, by a cut-and-paste mechanism multiple times throughout the genome preferentially into active chromatin. With this technology, the production of stable antibody producing cell lines now only takes a few months rather than a year or more. Unlike anything on the market currently, the proposed Fungal Transposase engineering platform will leverage these benefits to directly address quantitative and qualitative limitations in heterologous strain performance by ensuring payloads remain intact, stable, and as transcriptionally active throughout the genome as possible. Supporting this objective are the following specific aims: (1) Build a Fungal Transposase toolkit for heterologous overexpression, and (2) Overexpress NP BGCs by Fungal Transposase-enabled multiple integrations. These aims will address the technical challenges inherent to adapting a mammalian cell engineering technology to the difficult filamentous fungi and assess its capacity for engineering improved high titer strains. This proposal can be completed using established molecular techniques and leveraging known reporter and NP controls: luciferase as a single enzyme product to evaluate copy number-based transcriptional overexpression, and NP BGCs encoding imizoquin and pestalamide which have been demonstrated to heterologously express in the model organism Aspergillus nidulans.


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: 2026 ( Subtotal = $0 )
2026	2023	VARIGEN BIOSCIENCES CORP	3220 DEMING WAY STE 160	MIDDLETON	WI	53562	DANE	USA	Research and Training in Complementary and Integrative Health	000	1	3/2/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $295,306 )
2023	2023	VARIGEN BIOSCIENCES CORPORATION	3220 DEMING WAY STE 160	MIDDLETON	WI	53562	DANE	USA	Research and Training in Complementary and Integrative Health	000	1	9/5/2023	NEW	$295,306
														Subtotal = $295,306

Grand Total All Awards = $295,306

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A Universal Fungal Transposase System for Increasing Natural Product and Protein Titers

Award Number: R43AT012434

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/05/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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