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WO2025217587A1 - Procédés et systèmes d'analyse de molécules sur la base de réactions de déplacement d'acide nucléique - Google Patents

Procédés et systèmes d'analyse de molécules sur la base de réactions de déplacement d'acide nucléique

Info

Publication number
WO2025217587A1
WO2025217587A1 PCT/US2025/024382 US2025024382W WO2025217587A1 WO 2025217587 A1 WO2025217587 A1 WO 2025217587A1 US 2025024382 W US2025024382 W US 2025024382W WO 2025217587 A1 WO2025217587 A1 WO 2025217587A1
Authority
WO
WIPO (PCT)
Prior art keywords
region
molecule
nucleic acid
acid molecule
complementary
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/024382
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English (en)
Inventor
Wei Chen
Ashwin Gopinath
David Yu Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biostate Ai Inc
Original Assignee
Biostate Ai Inc
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Filing date
Publication date
Application filed by Biostate Ai Inc filed Critical Biostate Ai Inc
Publication of WO2025217587A1 publication Critical patent/WO2025217587A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6804—Nucleic acid analysis using immunogens
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B30/00—Methods of screening libraries
    • C40B30/04—Methods of screening libraries by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding

Definitions

  • the present disclosure relates generally to methods and systems for analyzing target molecules, and more specifically to methods and systems of approximating amounts of the target molecules by measuring the amount of product from a nucleic acid displacement reaction.
  • nucleic acid molecules such as protein molecules
  • methods and systems for detecting non-nucleic acid molecules, such as protein molecules based on nucleic acid displacement reactions.
  • Existing methods for detecting and measuring non-nucleic acid molecules, e.g., protein molecules cannot be easily multiplexed and or analyzed on a large scale.
  • nucleic acid molecules are routinely analyzed via easily scalable and massively parallel sequencing technologies.
  • the methods and systems described herein incorporate nucleic acid sequencing techniques into a method for analyzing non-nucleic acid molecules, such as proteins.
  • the methods and systems described herein extend the benefits native to sequencing techniques, such as an ease of multiplexing and scalability, to a method for analyzing non-nucleic acid molecules, such as proteins.
  • the methods and systems described herein can approximate the amount of a target molecule.
  • a protein-to-DNA signal conversion assay method that uses a molecular construct based on a proximity-assisted strand displacement (PSD) reaction at a three-way DNA junction.
  • the initial molecular construct can consist of a first molecule and a second molecule: two matched, and single-stranded DNA-conjugated affinity ligands specific to orthogonal epitopes on a protein-of-interest.
  • Target detection in solution can bring the two DNA-conjugated affinity ligands in close proximity to each other and can allow for the formation of a three-way DNA junction.
  • a subsequent strand displacement reaction can result in a unique DNA barcode for each protein-of-interest which can be read out using quantitative polymerase chain reaction (qPCR), next generation sequencing (NGS), or other approaches following barcode amplification.
  • the molecular construct may be immobilized on a solid support prior to the assay reaction to mitigate the effects of reagent cross -reactivity and allow for highly- multiplexed assays.
  • the methods and systems based on PSD reactions described herein convert a signal from a non-nucleic acid molecule, e.g., a protein molecule, to a signal from a nucleic acid molecule.
  • the methods and systems described herein provide high sensitivity and high specificity for detecting, in parallel, at least one to thousands of proteins in the human proteome.
  • the molecular complex for the PSD reaction can be performed in solution as standalone hybrid constructs or on a support, e.g., solid surfaces that can be amorphous or structured DNA nanostructures, or inorganic nanoparticles, gel matrices, semiconductor or nonsemiconductor chips, etc..
  • the described supports can be functionalized to harvest distinct advantages suiting multiple applications.
  • Samples can be obtained from complex biological matrices ranging from single cells to organ systems.
  • the solid surfaces can be thermo- and enzyme-stable and/or monofunctional or have other properties suitable for a variety of human and non-human proteomic applications.
  • the readout can be a unique DNA barcode strand for every captured analyte that can be quantified using low-to-mid throughput qPCR or mid-to-high- throughput NGS systems with traditional enzyme-based or enzyme-free amplification.
  • a method for analyzing a target molecule from a sample comprising: a) contacting the target molecule with a first molecule and a second molecule, to form a complex, the first molecule comprising a first binder molecule and a first nucleic acid molecule comprising a first spacer region SRI, a priming region PR, and a toehold region TR, the second molecule comprising a second binder molecule and a second nucleic acid molecule comprising a second spacer region SR2, a complementary priming region C-PR, and a strand displacement region SDR, and the PR of the first molecule hybridizing to the C-PR of the second molecule; b) displacing an eluting nucleic acid molecule with the complex, thereby forming a reacted complex and releasing a product nucleic acid molecule from the eluting nucleic acid molecule, the eluting nucleic acid molecule comprising
  • a method for generating a complex comprising: a) contacting a target molecule with a first molecule and a second molecule, the first molecule comprising a first binder molecule and a first nucleic acid molecule comprising a first spacer region SRI, a priming region PR, and a toehold region TR, and the second molecule comprising a second binder molecule and a second nucleic acid molecule comprising a second spacer region SR2, a complementary priming region C-PR, and a strand displacement region SDR; and b) hybridizing the PR of the first molecule to the C-PR of the second molecule, to generate the complex.
  • the methods can further comprise: hybridizing the complex to a support, the first nucleic acid molecule comprising a first support-binding region SBR1, the support comprising a first complementary binding region C-SBR1, and the C-SBR1 hybridizing to the SBR1, thereby hybridizing the complex to the support.
  • a plurality of molecules comprising: a first molecule comprising a first binder molecule and a first nucleic acid molecule comprising a first spacer region SRI, a priming region PR, and a toehold region TR; a second molecule comprising a second binder molecule and a second nucleic acid molecule comprising a second spacer region SR2, a complementary priming region C-PR, and a strand displacement region SDR; and the PR of the first molecule hybridized to the C-PR of the second molecule.
  • an eluting nucleic acid molecule comprising: a tag, a third spacer region SR3, a complementary toehold region C-TR, a fourth spacer region SR4, a complementary strand displacement region C-SDR, a duplicate strand displacement region D- SDR, an anti-leak region ALR, a complementary anti-leak region C-ALR, and a barcode region BR.
  • an eluting nucleic acid molecule comprising: a tag, a third spacer region SR3, a complementary toehold region C-TR, a fourth spacer region SR4, a complementary strand displacement region C-SDR, a duplicate strand displacement region D- SDR, an anti-leak region ALR, a complementary anti-leak region C-ALR, and a barcode region BR.
  • FIG. 1 provides exemplary methods for analyzing a target molecule by using a nucleic acid displacement reaction to measure an amount of a product nucleic acid molecule.
  • FIG. 2 provides exemplary methods for analyzing a target molecule by using a nucleic acid displacement reaction immobilized on a support to measure an amount of a product nucleic acid molecule.
  • the target molecule can be contacted with a first molecule and a second molecule, to form a complex.
  • the first molecule can include a first binder molecule and a first nucleic acid molecule.
  • the first nucleic acid molecule can include a first spacer region SRI, a priming region PR, and a toehold region TR.
  • the second molecule can include a second binder molecule and a second nucleic acid molecule.
  • the second nucleic acid molecule can include a second spacer region SR2, a complementary priming region C-PR, and a strand displacement region SDR.
  • the described systems and methods are highly sensitive in detecting the target molecule, e.g., protein, while providing high signal-to-noise ratios for the measured signals that indicate the target molecule amounts.
  • the systems and methods described herein take advantage of the exponential amplification properties of enzyme-based or enzyme-free techniques to achieve a strong readout signal, which provides assay sensitivity on par or better than traditional enzyme- linked immunosorbent assays (ELIS As).
  • the systems and methods described herein use extremely small sample volumes to measure large numbers of proteins simultaneously, making them highly beneficial in cases where precious samples are in limited supply, such as in studies that use human samples from clinical cohorts or biobank material.
  • the systems and methods described herein are expected to use only 5-10 uL of sample for its assays, regardless of the scale required. Additionally, low sample volumes reduce the concentration of potentially interfering substances, and specifically tailored blocking reagents in the methods described herein can further minimize sample matrix interference.
  • PSD reaction-based methods and systems described herein are suitable for a broad range of applications, ranging from highly targeted, hypothesis-driven studies, to the largest screening projects.
  • next generation sequencing (NGS) readouts are suitable, for example, for conducting high-throughput studies with large numbers of human serum or plasma samples against the complete library of proteins.
  • NGS next generation sequencing
  • This technology can provide a highly specific and sensitive approach for detecting low-abundance proteins, which can allow researchers to search for actionable protein signatures within a low-abundant proteome.
  • qPCR readouts can be used for small- and medium-scale projects, e.g., highly targeted, hypothesis-driven studies.
  • the systems and methods described herein can provide a highly specific and scalable approach to detect and measure the expression levels of multiple non-nucleic acid molecules, e.g., proteins, simultaneously. Enzyme-free isothermal approaches such as hybridization chain reaction, rolling circle amplification, or other approaches, can also be used as a readout for the systems and methods described herein.
  • the PSD reaction-based systems and methods described herein can be used by clinicians for liquid biopsy investigations to improve disease detection, aid more personalized healthcare, and allow a better understanding of real-time human biology.
  • the systems and methods described herein comprise a combination of immunoassay and functional DNA nanotechnology, to provide a powerful technique for proteomics within research and clinical settings.
  • the systems and methods described herein merge an affinity binder-based immunoassay with highly efficient DNA strand displacement combined with the ubiquity of efficient amplification reactions.
  • the described systems and methods offer readout options using either quantitative real-time PCR (qPCR) or next generation sequencing (NGS).
  • qPCR quantitative real-time PCR
  • NGS next generation sequencing
  • the complex at the core of the PSD reaction-based methods comprises a first and second molecule that can assume the form of two matched, DNA-conjugated affinity binder pairs — e.g., NHS-amine, DBCO-azide, or other approaches for monofunctional affinity binder-DNA complexes — with partial complementarity over their DNA domains.
  • Two such affinity binders can be used to detect any given protein analyte of interest. While floating freely in solution, these reagents may interact with other affinity reagents. Still, the DNA domains are designed specifically to keep any one pair as orthogonal from the others as possible. In addition, the designed orthogonality can be tuned to not limit the workflow and operations of the methods and systems based on PSD reactions.
  • the freely diffusing matched pairs i.e., the first and second molecules
  • the freely diffusing matched pairs can find their binding domains on the target molecule and form a two-lever arm complex based on the proximity of the DNA domains.
  • the first and second molecules would not form a stable complex at room temperature.
  • the forming of the complex is followed by the introduction of a single population or multiple sets of “eluting strands” containing multiple domains.
  • the domains of the eluting strand and/or the complex can comprise the following components: a) Biotin or other tags: The tag, e.g., biotin, pulls down the strand-displaced three-way junction away from the released barcode. b) Spacer: The spacer region (e.g., SRI, SR2, SR3, or SR4) can be a Poly-T, PEG, or other such domain. c) Toehold: The toehold region (e.g., TR) induces the displacement and release of the barcode region by interacting and hybridizing with the immunocomplex formed after the introduction of the target analyte.
  • Biotin or other tags The tag, e.g., biotin, pulls down the strand-displaced three-way junction away from the released barcode.
  • Spacer The spacer region (e.g., SRI, SR2, SR3, or SR4) can be a Poly-T, PEG, or other such domain.
  • Toehold region
  • Strand displacement region The encroachment of the toehold onto the two-lever molecular construct begins the process of unraveling the strand displacement region (e.g., SDR) from its original position, with its complementary strand (associated with the toehold region) strand hopping to form a three-way junction on the previously two-junction immunocomplex construct and resulting in the release of the unique barcode associated with the target molecule.
  • strand displacement region e.g., SDR
  • Anti-leak region The anti-leak region allows for the displacement of the two-way junction at a later timepoint and is an indirect way of determining the concentration of unique elution strands consumed during the reaction, thereby quantifying the target analyte.
  • Barcode region (e.g., BR) is uniquely assigned to each target molecule. Therefore, amplifying and sequencing the barcode region allows for the determining of the target molecule’s identity. Given that the barcode sequence is a nucleic acid sequence, potentially unlimited permutations of the sequence space are available for scaling up the technology, so that multiplexed studies can be performed at arbitrarily large or small levels.
  • the barcode region is read using qPCR, NGS, or other enzyme-free methods to identify the sequence associated with every construct.
  • the barcode region allows for the transduction of a protein signal into a DNA signal.
  • the PSD reactions can be interpreted as comprising a highly efficient biosensor and transducer.
  • the components described above can then operate according to the following: A) complex formation, B) binder proximity and nucleic acid strand displacement, and C) barcode release and amplification.
  • the target molecule e.g., protein
  • the target molecule can be bound by the first molecule and the second molecule, in order to generate the complex.
  • the formed complex can be stable either independently in solution or on a support.
  • the complex can then be subject to strand displacement, such that a stable three-way junction is formed due to the proximity of the affinity binder pairs (e.g., the first binder molecule and the second binder molecule) and the partial complementarity in the DNA extensions.
  • the strand displacement reaction can result in barcode release, and the barcode can be isolated from the construct for amplification using enzyme-based or enzyme-free approaches via specifically designed primers, dNTPs, and polymerases via thermal cycling or under isothermal reaction conditions. Depending on a target molecule’s expected or known concentration, a dilution factor may be introduced, or amplification may not be necessary.
  • the DNA barcode can then be read out using qPCR or NGS approaches, depending on the number of unique barcodes generated through the assay. Definitions
  • ‘About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.
  • the terms “comprising” (and any form or variant of comprising, such as “comprise” and “comprises”), “having” (and any form or variant of having, such as “have” and “has”), “including” (and any form or variant of including, such as “includes” and “include”), or “containing” (and any form or variant of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, un-recited additives, components, integers, elements, or method steps.
  • ordinal terms such as “first”, “second”, “third”, etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.
  • use of a), b), etc., or i), ii), etc. does not by itself connote any priority, precedence, or order of steps in the claims.
  • the use of these terms in the specification does not by itself connote any required priority, precedence, or order.
  • the eluting nucleic acid molecule can comprise a tag, a third spacer region SR3, a complementary toehold region C-TR, a fourth spacer region SR4, a complementary strand displacement region C-SDR, a duplicate strand displacement region D- SDR, an anti-leak region ALR, a complementary anti-leak region C-ALR, and a barcode region BR, the product nucleic acid molecule comprising the D-SDR, the ALR, and the BR, and the reacted complex comprising the TR and the SDR of the complex hybridized to the C-TR and the C-SDR from a portion of the eluting nucleic acid molecule.
  • the two arms e.g., the first and second nucleic acid molecules of the complex
  • the immobilization on the solid phase surface may mitigate the cross -reactivity observed between free-floating affinity binders when the sample is introduced into the solution.
  • the immobilizing of the complex before or after strand displacement onto DNA or other solid phase supports may depend on the number of analytes to be detected and the orthogonality between the various binders involved.
  • the immobilizing surface may be monofunctional, thermostable, both, or have unique material or functional properties.
  • an intermediate step of transferring strand-displaced complexes to other solid phase surfaces may be introduced for the purposes of separation, purification, signal-to-noise improvement, or similar.
  • the solid surfaces could be composed of functional moieties arranged in a patterned or unpattemed fashion using lithographic or other techniques.
  • the functional moieties can be responsible for linkage to the complex’s lever arms (e.g., the first and second nucleic acid molecules) or other solid surfaces.
  • the functional moieties can be interspersed with passivating moieties of various shapes, sizes, charges, to boost the signal to noise ratio (and thereby sensitivity) and may include, but not be limited to, any one of the following in singular or in combination:
  • DNA spacers such as Poly T with or without other functional moieties
  • BSA Bovine Serum Albumin
  • This section provides an example protocol that can be used for analyzing a target molecule in accordance with the systems and methods described herein.
  • Two matched affinity binders e.g., antibodies, specific to orthogonal epitopes on the target molecule, e.g., protein.
  • o IL-6 Two matched affinity binders, e.g., antibodies, specific to orthogonal epitopes on the target molecule, e.g., protein.

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  • Engineering & Computer Science (AREA)
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  • Urology & Nephrology (AREA)
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  • Wood Science & Technology (AREA)
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  • Genetics & Genomics (AREA)
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  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention concerne des procédés et des systèmes d'analyse d'une molécule cible. Les procédés peuvent comprendre, par exemple, la mise en contact de la molécule cible avec une première molécule et une deuxième molécule, pour former un complexe ; le déplacement d'une molécule d'acide nucléique d'élution avec le complexe, formant ainsi un complexe ayant réagi et la libération d'une molécule d'acide nucléique de produit à partir de la molécule d'acide nucléique d'élution ; la purification de la molécule d'acide nucléique de produit ; et la mesure d'une quantité de la molécule d'acide nucléique de produit.
PCT/US2025/024382 2024-04-12 2025-04-11 Procédés et systèmes d'analyse de molécules sur la base de réactions de déplacement d'acide nucléique Pending WO2025217587A1 (fr)

Applications Claiming Priority (2)

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US202463633429P 2024-04-12 2024-04-12
US63/633,429 2024-04-12

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WO2025217587A1 true WO2025217587A1 (fr) 2025-10-16

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6150097A (en) * 1996-04-12 2000-11-21 The Public Health Research Institute Of The City Of New York, Inc. Nucleic acid detection probes having non-FRET fluorescence quenching and kits and assays including such probes
WO2020185681A2 (fr) * 2019-03-09 2020-09-17 The Regents Of The University Of California Compositions et procédés liés à l'hybridation d'acides nucléiques médiée par l'or
US20210095333A1 (en) * 2019-09-30 2021-04-01 X Development Llc Quantification of molecules using nucleic acid strand displacement detection
US20220064699A1 (en) * 2016-05-27 2022-03-03 President And Fellows Of Harvard College Conditional primer extension for single-molecule detection

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6150097A (en) * 1996-04-12 2000-11-21 The Public Health Research Institute Of The City Of New York, Inc. Nucleic acid detection probes having non-FRET fluorescence quenching and kits and assays including such probes
US20220064699A1 (en) * 2016-05-27 2022-03-03 President And Fellows Of Harvard College Conditional primer extension for single-molecule detection
WO2020185681A2 (fr) * 2019-03-09 2020-09-17 The Regents Of The University Of California Compositions et procédés liés à l'hybridation d'acides nucléiques médiée par l'or
US20210095333A1 (en) * 2019-09-30 2021-04-01 X Development Llc Quantification of molecules using nucleic acid strand displacement detection

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