Application of TTR variation site marker in prediction of curative effect of tetramer stabilizer on ATTRv-PN disease

Abstract

The invention discloses application of a TTR variation site marker in prediction of the curative effect of a tetramer stabilizer on ATTRv-PN disease, and belongs to the field of biological medicine. The invention provides application of a reagent for detecting a variation site marker in a sample in preparation of a product for predicting the curative effect of a tetramer stabilizer for treating ATTRv-PN diseases, a related product, a related method, a related system, related equipment and a computer readable storage medium. The method is used for evaluating the curative effects of patients suffering from ATTRv-PN diseases when the patients receive different treatment drugs, so that personalized treatment is provided.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine and relates to the application of TTR mutation site markers in predicting the efficacy of tetramer stabilizers in treating ATTRv-PN disease. Background Art

[0002] Hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) is a rare, fatal, but treatable autosomal dominant genetic disease caused by mutations in the TTR gene. TTR encodes a homotetramer, transthyretin. When TTR mutates, the tetramer becomes less stable and dissociates into monomers. The monomers misfold to form amyloid fibers that are deposited in various organs and cause disease. In the past, liver transplantation was considered the only effective treatment. With a deeper understanding of the pathogenesis, several TTR-targeted drugs have been developed, mainly divided into TTR silencers (gene therapy, including RNA silencing and gene editing therapy), TTR tetramer stabilizers, and TTR amyloid removers.

[0003] At present, the treatments for patients in China include tetramer stabilizers (clofentacil, diflunisal), gene editing therapy, and RNA silencing therapy. Some studies have confirmed that after tetramer stabilizer treatment, the concentration of TTR tetramers in patients increased, while the concentration of unstable TTR decreased (total TTR protein concentration - tetramer concentration). After gene therapy treatment, the concentration of TTR protein in patients decreased significantly. Summary of the invention

[0004] The total soluble TTR protein in the human body includes stable TTR tetramers and dissociated unstable monomer dimers. Most previous studies used immunoturbidimetry to measure the total TTR concentration. In recent years, with the development of biotechnology, some studies have begun to focus on the concentration of TTR tetramers. The determination method mainly involves taking serum samples, adding small molecule fluorescent probe A2, separating TTR tetramers by UPLC, and determining the serum TTR tetramer concentration with the help of A2 fluorescence intensity. At present, there is no biomarker that can timely evaluate the efficacy of different drugs in patients. Only a few studies have detected the concentration of TTR tetramers in patients taking clofazodone, and have not evaluated the concentration of tetramers in patients taking diflunisal.

[0005] In order to solve the technical problems existing in the prior art, the present invention provides the following technical solutions.

[0006] The present invention provides the use of a reagent for detecting a variant site marker in a sample in the preparation of a product for predicting the efficacy of a tetramer stabilizer in the treatment of ATTRv-PN disease, wherein the variant site marker includes one or more of the amino acid variants at positions 83, 42, 33, 61, 34, and 47 of the TTR protein.

[0007] Furthermore, the variant site marker includes one or more of the variant sites at positions 307, 185, 157, 241, 161, and 200 of the TTR gene.

[0008] Furthermore, the sample includes blood, serum, plasma, peripheral blood, tissue, blood cells, bone marrow, ascites, fine needle biopsy samples, body fluids containing cells, free floating nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, stool, lymph, skin swab, oral swab, nasal swab or lavage.

[0009] Furthermore, the sample is blood, serum, plasma, or peripheral blood.

[0010] In some embodiments, the sample is taken directly from the subject without further processing, for example, blood can be obtained from the subject's peripheral circulatory system (e.g., via a blood collection needle). The sample may include, for example, blood, urine, feces, saliva, cerebrospinal fluid, and sweat. Non-limiting examples of such samples include blood (or components of blood - e.g., white blood cells, red blood cells, platelets) obtained from any anatomical location of a subject (e.g., tissue, circulatory system, bone marrow), cells obtained from any anatomical location of a subject, skin, heart, lung, kidney, exhaled breath, bone marrow, stool, semen, vaginal fluid, tissue fluid from tumor tissue, breast, pancreas, cerebrospinal fluid, tissue, throat swab, biopsy, placental fluid, amniotic fluid, liver, muscle, smooth muscle, bladder, gallbladder, colon, intestine, brain, cavity fluid, sputum, pus, microbiota, meconium, breast milk, prostate, esophagus, thyroid, serum, saliva, urine, gastric and digestive fluids, tears, ocular fluids, sweat, mucus, earwax, oils, glandular secretions, cerebrospinal fluid, hair, nails, skin cells, plasma, nasal swab or nasopharyngeal wash, cerebrospinal fluid, umbilical cord blood, lymphatic fluid and / or other excreta or body tissues.

[0011] The term "sample" used in the present invention refers to a large amount of biological material, which in some embodiments is from a patient and contains cells and / or cell-free DNA; that is, the term can be used interchangeably with the term "specimen" or "tissue sample". The term "sample" is sometimes also used in the statistical sense of obtaining a subset or part of a larger group or amount of (for example) recombinant nucleic acids, respectively; in particular, the statistical use of the term "sample" can also be understood to mean a "representative sample", in which case such a sample is understood to reflect or approximate the relative frequency of different nucleic acids in (for example) a tissue. A person skilled in the art will be able to discern the correct use of the term from the context. In particular, the sample used in the present invention refers to a collection of similar cells obtained from a patient's tissue. The source of the tissue or cell sample can be solid tissue from a fresh, frozen and / or preserved organ or tissue sample, or a biopsy or aspirate. The tissue sample can be a primary or in vitro cultured cell or cell line. Optionally, the tissue or cell sample is obtained from a diseased tissue / organ. Tissue samples may contain compounds that do not naturally mix with the tissue, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like.

[0012] Furthermore, the tetramer stabilizer includes diflunisal and clofazodone.

[0013] Furthermore, when the 83rd amino acid of the TTR protein is Arg, the subjects have a better efficacy after taking clofazodone.

[0014] Furthermore, when the 42nd amino acid of the TTR protein is Gly, the efficacy of clofazodone after the subjects took it was poor.

[0015] Furthermore, when the 33rd amino acid of the TTR protein is Val, the subjects have a better efficacy after taking clofazodone.

[0016] Furthermore, when the 61st amino acid of the TTR protein is Lys, the subjects have a better efficacy after taking clofazodone.

[0017] Furthermore, when the 34th amino acid of the TTR protein is Thr, the subjects have a better efficacy after taking clofazodone.

[0018] Furthermore, when the 47th amino acid of the TTR protein is Glu, the subjects experience better efficacy after taking diflunisal.

[0019] Furthermore, when the genotype at position 307 of the TTR gene was a heterozygous GC, the subjects had a better efficacy after taking clofazodone.

[0020] Furthermore, when the genotype at position 185 of the TTR gene is heterozygous for AG, the efficacy of clofazodone after the subject takes the drug is poor.

[0021] Furthermore, when the genotype at position 157 of the TTR gene was heterozygous for TG, the subjects had a better efficacy after taking clofazodone.

[0022] Furthermore, when the genotype at position 241 of the TTR gene was heterozygous for AG, the subjects had a better efficacy after taking clofazodone.

[0023] Furthermore, when the genotype at position 161 of the TTR gene was a heterozygous GC, the subjects had a better efficacy after taking clofazodone.

[0024] Furthermore, when the genotype at position 200 of the TTR gene was heterozygous for GA, the subjects had a better efficacy after taking diflunisal.

[0025] In some embodiments, the reagents include reagents for detecting the genotypes of positions 07, 185, 157, 241, 161, and 200 of the TTR gene by direct sequencing, single base extension, allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, allele-specific nucleotide incorporation, 5' nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation polymorphism methods.

[0026] In the present invention, the TTR gene refers to the gene with the gene number Gene ID: 7276 in NCBI, and the specific sequence code is NC_000018.10; in the present invention, the TTR protein refers to the specific sequence number NP_000362.1.

[0027] The present invention provides a product for predicting the efficacy of tetramer stabilizers in treating ATTRv-PN disease, and the product includes a reagent for detecting a mutation site marker in a sample in the aforementioned application.

[0028] Furthermore, the product includes one or more of a kit, a chip, a test paper, a high-throughput sequencing system.

[0029] Furthermore, the reagent includes a nucleic acid affinity ligand for the variant site marker.

[0030] Furthermore, the nucleic acid affinity ligand includes a primer or a probe.

[0031] Furthermore, the probe includes DNA, RNA, DNA RNA chimera, PNA or other derivatives.

[0032] In some embodiments, the length of the probe is usually at least 14 base pairs, and generally no longer than 30 base pairs. The optimal length for complementarity with the target nucleotide sequence is 15-25 base pairs.

[0033] Furthermore, the kit may also include one or more substances selected from the following group: a container, instructions for use, a positive control substance, a negative control substance, a buffer, an adjuvant or a solvent.

[0034] Furthermore, the tetramer stabilizer includes diflunisal and clofazodone.

[0035] Furthermore, the reagents include reagents conventionally used in PCR reaction, RT-PCR derivatization reaction, 3SR amplification, LCR, SDA, NASBA, TMA, SYBR Green, TaqMan probe, molecular beacon, double hybridization probe, composite probe, ISH, microarray, Southern blot, Northern blot, multi-analyte spectrum test, enzyme-linked immunosorbent assay, radioimmunoassay, immunofluorescence assay, enzyme immunoassay, immunoprecipitation assay, chemiluminescence assay, immunohistochemistry assay, dot blot assay or slot blot assay; the reagents are used to detect the protein type or genotype of the variant site marker.

[0036] In the context of the present invention, the term "probe" as used refers to any molecule that is capable of selectively binding to a specific intended target biomolecule, and can be indirectly or directly, covalently or non-covalently bound to or associated with any molecule of any substrate and / or reaction product and / or protease disclosed herein, and its association or binding can be detected using the methods disclosed herein. Probes in the context of the present invention include fluorescent probes, antibodies, or absorbance-based probes. If it is an absorbance-based probe, the chromophore pNA (p-nitroaniline) can be used as a probe for detecting and / or quantifying the target nucleic acid sequence disclosed herein; it can also be a nucleic acid sequence containing a fluorescent molecule or substrate, which becomes fluorescent when exposed to an enzyme, and the nucleic acid sequence is complementary to a fragment of a nucleic acid sequence.

[0037] The present invention provides a computer-assisted evaluation method for predicting the efficacy of tetramer stabilizers in treating ATTRv-PN disease, the method comprising: Obtaining TTR protein or gene sequence data of the subject; The computer retrieves the amino acid information at position 83, position 42, position 33, position 61, position 34, and / or position 47 of the TTR protein from the acquired TTR protein data, or the computer retrieves the genotype information at position 307, position 185, position 157, position 241, position 161, and / or position 200 of the TTR gene from the acquired TTR gene data, and matches the retrieved amino acid information or genotype information with an existing database; When the amino acid information or genotype information matches successfully, the computer-assisted evaluation results are output.

[0038] Furthermore, the existing database includes: When the 83rd amino acid of the TTR protein was Arg, the subjects had better efficacy after taking clofazodone; When the 42nd amino acid of the TTR protein is Gly, the efficacy of clofazodone is poor in the subjects; When the 33rd amino acid of the TTR protein was Val, the subjects had better efficacy after taking clofazodone; When the 61st amino acid of the TTR protein is Lys, the subjects have better efficacy after taking clofazodone; When the 34th amino acid of the TTR protein is Thr, the subjects have better efficacy after taking clofazodone; When the 47th amino acid of the TTR protein is Glu, the subjects have better efficacy after taking diflunisal; When the genotype at position 307 of the TTR gene was heterozygous for GC, the subjects had a better efficacy after taking clofazodone; When the genotype at position 185 of the TTR gene was heterozygous for AG, the subjects had poor efficacy after taking clofazodone; When the genotype at position 157 of the TTR gene was heterozygous for TG, the subjects had a better efficacy after taking clofazodone; When the genotype at position 241 of the TTR gene was heterozygous for AG, the subjects had a better efficacy after taking clofazodone; When the genotype at position 161 of the TTR gene is a heterozygous GC, the subjects have a better efficacy after taking clofazodone; or When the genotype at position 200 of the TTR gene was heterozygous for GA, the subjects had better efficacy after taking diflunisal.

[0039] The present invention provides a computer-assisted evaluation system for predicting the efficacy of tetramer stabilizers in treating ATTRv-PN disease based on the above-mentioned method, and the computer-assisted evaluation system comprises: Data acquisition unit: obtaining TTR protein or gene sequence data of the subject; Data processing unit: the computer retrieves the amino acid information at position 83, position 42, position 33, position 61, position 34, and / or position 47 of the TTR protein from the acquired TTR protein data, or the computer retrieves the genotype information at position 307, position 185, position 157, position 241, position 161, and / or position 200 of the TTR gene from the acquired TTR gene data, and matches the retrieved amino acid information or genotype information with an existing database; Data output unit: When the amino acid information or genotype information matches successfully, the computer-assisted evaluation results are output.

[0040] The present invention provides a device or a computer-readable storage medium, wherein the device includes a processor and a memory, wherein the processor is used to call program instructions, and when the program instructions are called and executed, the computer-assisted evaluation method described above is implemented; and a computer program is stored on the computer-readable storage medium, and when the computer program is called and executed by the processor, the computer-assisted evaluation method described above is implemented.

[0041] The systems, devices or units described above may be implemented by computer chips or entities, or by products having certain functions. A typical implementation device is a computer. Specifically, the computer may be, for example, a personal computer, a laptop computer, a cellular phone, a camera phone, a smart phone, a personal digital assistant, a media player, a navigation device, an email device, a game console, a tablet computer, a wearable device, or a combination of any of these devices.

[0042] In some embodiments, the above-mentioned units or steps can achieve the effect through a computing device. In some embodiments, the units or steps can be concentrated on a single computing device. In some embodiments, the units or steps can be distributed on multiple computing devices, and multiple computing devices are linked by a network or other linking methods. In some embodiments, the computing device stores a program code for executing the above-mentioned units or steps, and the program code is stored in a storage device. In some embodiments, the units or steps can be prepared into integrated circuits respectively, or they can be combined into a single integrated circuit. In the specific embodiments of the present invention, no implementation method is limited, whether it is hardware or software.

[0043] The term "unit" used in the present invention refers to an application specific integrated circuit (ASIC), an electronic circuit, a processor (such as a shared processor, a dedicated processor or a group processor, etc.) and memory for executing one or more software or firmware programs, a combined logic circuit and / or other suitable components supporting the described functions.

[0044] The term "processor" used in the present invention refers to any type of processor, including more than one processor, such as a multi-core design or multiple processors with a multi-core design for each processor. The processor can be configured to execute a sequence of computer program instructions, such as a sequence of those instructions stored in a memory, to perform various operations, processes and methods according to the exemplary embodiments of the content of the present invention.

[0045] The term "memory" as used in this disclosure refers to any type of long-term, short-term, volatile, non-volatile or other memory, and should not be limited to any specific type of memory or any specific number of memories or types of media storing memory.

[0046] In the context of the present invention, the term "subject" used refers to any animal, including humans and non-human animals. Non-human animals include all vertebrates, for example, mammals, such as non-human primates (particularly higher primates), sheep, dogs, rodents (such as mice or rats), guinea pigs, goats, pigs, cats, rabbits, cattle, and any livestock or pets; and non-mammals, such as amphibians, reptiles, etc. In a preferred embodiment, the subject is a human.

[0047] As used herein, the terms "comprises" or "includes," and variations thereof, in connection with elements of a defined or described object, composition, apparatus, method, process, system, etc., are meant to be all-inclusive or open-ended, allowing for additional elements, thereby indicating that the defined or described object, composition, apparatus, method, process, system, etc. includes those specified elements—or, where appropriate, their equivalents—and that other elements may be included and still fall within the scope / definition of the defined object, composition, apparatus, method, process, system, etc.

[0048] The term "therapeutic effect" of a treatment according to the invention can be measured based on changes in the disease during its response to a use or method according to the invention.

[0049] Advantages and beneficial effects of the present invention: 1. Real-time evaluation of patients' treatment response to different therapies: By detecting different mutation sites, the treatment effect can be reflected promptly and accurately, especially when different tetramer stabilizers are used.

[0050] 2. Optimize personalized treatment plans: Based on the different markers of the mutation sites, guide clinicians to adjust drug dosages or change treatment plans according to the drug sensitivity type of the patient to avoid blind treatment. Enhance the flexibility and accuracy of individualized treatment plans for patients.

[0051] 3. Improved efficacy monitoring: Variant site markers more accurately reflect disease progression and efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 It is a statistical graph of the average TTR tetramer concentration results after treatment in different treatment groups. DETAILED DESCRIPTION

[0053] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with specific embodiments.

[0054] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0055] Example

[0056] 1. Experimental Materials Patient blood samples: Serum was collected from patients diagnosed with ATTRv-PN in this cohort, and TTR tetramer concentrations were measured in patients before and after treatment with tetraclofop, diflunisal, and gene-editing drugs according to the aforementioned method.

[0057] TTR tetramer detection: The concentration of TTR tetramer in patient serum was determined by ultra-performance liquid chromatography (UPLC). The Waters Acquity H-Class UPLC plus pro ultra-performance liquid chromatograph and Protein-pakTM Hi RCSQ (5μm, 4.6×100mm) chromatographic column were both from Waters.

[0058] 2. Experimental methods Step 1: Sample collection.

[0059] Serum was collected from patients before treatment and 6 months after treatment to measure TTR tetramer and total TTR protein concentrations.

[0060] Step 2: TTR tetramer detection.

[0061] Step 3: Detection of total TTR protein concentration.

[0062] The total TTR protein concentration in the same sample was measured using the conventional immunoturbidimetric method for comparison.

[0063] Step 4: Data analysis.

[0064] Compare the changes in TTR tetramer concentrations in patients before and after receiving different treatments.

[0065] 3. Experimental results Before treatment, the serum TTR tetramer concentration of ATTR patients was significantly lower than that of the healthy control group; after treatment with tetramer stabilizers, the average serum TTR tetramer concentration of ATTR patients increased, and there was no significant difference with the healthy control group; after diflunisal treatment: different patients carrying 3 different mutations; after clofaconazole treatment: 15 patients carrying 6 different mutations, including 11 patients carrying the A97S mutation; the tetramer concentration of patients after diflunisal treatment was not significantly different from that after clofaconazole treatment. Six months after gene editing treatment, the tetramer concentration of patients was extremely low. The results are as follows Figure 1 shown.

[0066] However, further studies have found that patients taking different drugs have different mutation sites and different effects. Figure 1 The statistics of the variant sites involved are shown in Table 1.

[0067] Table 1 Mutation sites in patients taking different drugs

[0068] When further observation was conducted after screening out some variant sites, it was found that patients in the clofazolin group and the diflunisal group treated with different variant sites had different drug sensitivities, as shown in Table 2. The results showed that when the 83rd amino acid of the TTR protein was Arg, the 33rd amino acid was Val, the 61st amino acid was Lys, and the 34th amino acid was Thr, the subjects had better efficacy after taking clofazolin; when the 42nd amino acid of the TTR protein was Gly, the subjects had poorer efficacy after taking clofazolin; when the 47th amino acid of the TTR protein was Glu, the subjects had better efficacy after taking diflunisal.

[0069] Table 2 TTR tetramer concentration detection results at different mutation sites

[0070] When the genotype at position 307 of the TTR gene is a heterozygous GC, the genotype at position 157 is a heterozygous TG, the genotype at position 241 is a heterozygous AG, and the genotype at position 161 is a heterozygous GC, the subjects have a better efficacy after taking clofaconazole; when the genotype at position 185 of the TTR gene is a heterozygous AG, the subjects have a poorer efficacy after taking clofaconazole; when the genotype at position 200 of the TTR gene is a heterozygous GA, the subjects have a better efficacy after taking diflunisal.

[0071] The above-mentioned embodiments are only used to understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principle of the present invention, and these improvements and modifications will also fall within the scope of protection of the claims of the present invention.

Claims

1. Use of a reagent for detecting a variant site marker in a sample in the preparation of a product for predicting the efficacy of a tetramer stabilizer in the treatment of ATTRv-PN disease, wherein the variant site marker includes one or more of the amino acid variants at positions 83, 42, 33, 61, 34, and 47 of the TTR protein.

2. The use according to claim 1, wherein the variant site marker comprises one or more of the variant sites at positions 307, 185, 157, 241, 161, and 200 of the TTR gene.

3. The use according to claim 1, wherein the sample comprises blood, serum, plasma, peripheral blood, tissue, blood cells, bone marrow, ascites, fine needle biopsy sample, body fluid containing cells, free floating nucleic acid, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, skin swab, oral swab, nasal swab or lavage; Preferably, the sample is blood, serum, plasma or peripheral blood.

4. The use according to claim 1, wherein the tetramer stabilizer comprises diflunisal and clofazodone; Preferably, when the 83rd amino acid of the TTR protein is Arg, the efficacy of clofazodone after the subject takes it is better; Preferably, when the amino acid at position 42 of the TTR protein is Gly, the efficacy of clofazodone after the subject takes the drug is poor; Preferably, when the amino acid at position 33 of the TTR protein is Val, the efficacy of clofazodone after the subject takes it is better; Preferably, when the amino acid at position 61 of the TTR protein is Lys, the drug efficacy of the subject after taking clofazodone is better; Preferably, when the 34th amino acid of the TTR protein is Thr, the subject has a better efficacy after taking clofazodone; Preferably, when the 47th amino acid of the TTR protein is Glu, the efficacy of diflunisal is better after the subject takes it.

5. The use according to claim 1, wherein when the genotype at position 307 of the TTR gene is a heterozygous GC, the subject has a better efficacy after taking clofazodone; Preferably, when the genotype at position 185 of the TTR gene is a heterozygous AG, the efficacy of clofazodone after the subject takes the drug is poor; Preferably, when the genotype at position 157 of the TTR gene is a heterozygous TG, the subject has a better efficacy after taking clofazodone; Preferably, when the genotype at position 241 of the TTR gene is heterozygous for AG, the subject has a better efficacy after taking clofazodone; Preferably, when the genotype at position 161 of the TTR gene is a heterozygous GC, the subject has a better efficacy after taking clofazodone; Preferably, when the genotype at position 200 of the TTR gene is a heterozygous GA, the subject has a better efficacy after taking diflunisal.

6. A product for predicting the efficacy of tetramer stabilizers in treating ATTRv-PN disease, the product comprising a reagent for detecting a variant site marker in a sample in the application described in any one of claims 1 to 5.

7. The product according to claim 6, wherein the product comprises one or more of a kit, a chip, a test strip, a high-throughput sequencing system; Preferably, the tetramer stabilizer includes diflunisal and clofazodone; Preferably, the reagents include reagents conventionally used in PCR reaction, RT-PCR derivatization reaction, 3SR amplification, LCR, SDA, NASBA, TMA, SYBR Green, TaqMan probe, molecular beacon, double hybridization probe, composite probe, ISH, microarray, Southern blot, Northern blot, multi-analyte spectrum test, enzyme-linked immunosorbent assay, radioimmunoassay, immunofluorescence assay, enzyme immunoassay, immunoprecipitation assay, chemiluminescence assay, immunohistochemistry assay, dot blot assay or slot blot assay; the reagents are used to detect the protein type or genotype of the variant site marker.

8. A computer-assisted evaluation method for predicting the efficacy of tetramer stabilizers in treating ATTRv-PN disease, the method comprising: Obtaining TTR protein or gene sequence data of the subject; The computer retrieves the amino acid information at position 83, position 42, position 33, position 61, position 34, and / or position 47 of the TTR protein from the acquired TTR protein data, or the computer retrieves the genotype information at position 307, position 185, position 157, position 241, position 161, and / or position 200 of the TTR gene from the acquired TTR gene data, and matches the retrieved amino acid information or genotype information with an existing database; When the amino acid information or genotype information matches successfully, the computer-assisted evaluation results are output; Preferably, the existing database includes: When the 83rd amino acid of the TTR protein was Arg, the subjects had better efficacy after taking clofazodone; When the 42nd amino acid of the TTR protein is Gly, the efficacy of clofazodone is poor in the subjects; When the 33rd amino acid of the TTR protein was Val, the subjects had better efficacy after taking clofazodone; When the 61st amino acid of the TTR protein is Lys, the subjects have better efficacy after taking clofazodone; When the 34th amino acid of the TTR protein is Thr, the subjects have better efficacy after taking clofazodone; When the 47th amino acid of the TTR protein is Glu, the subjects have better efficacy after taking diflunisal; When the genotype at position 307 of the TTR gene was heterozygous for GC, the subjects had a better efficacy after taking clofazodone; When the genotype at position 185 of the TTR gene was heterozygous for AG, the subjects had poor efficacy after taking clofazodone; When the genotype at position 157 of the TTR gene was heterozygous for TG, the subjects had a better efficacy after taking clofazodone; When the genotype at position 241 of the TTR gene was heterozygous for AG, the subjects had a better efficacy after taking clofazodone; When the genotype at position 161 of the TTR gene is a heterozygous GC, the subjects have a better efficacy after taking clofazodone; or When the genotype at position 200 of the TTR gene was heterozygous for GA, the subjects had better efficacy after taking diflunisal.

9. A computer-assisted evaluation system for predicting the efficacy of the tetramer stabilizer in treating ATTRv-PN disease according to claim 8, the computer-assisted evaluation system comprising: Data acquisition unit: obtaining TTR protein or gene sequence data of the subject; Data processing unit: the computer retrieves the amino acid information at position 83, position 42, position 33, position 61, position 34, and / or position 47 of the TTR protein from the acquired TTR protein data, or the computer retrieves the genotype information at position 307, position 185, position 157, position 241, position 161, and / or position 200 of the TTR gene from the acquired TTR gene data, and matches the retrieved amino acid information or genotype information with an existing database; Data output unit: When the amino acid information or genotype information matches successfully, the computer-assisted evaluation results are output.

10. A device or a computer-readable storage medium, the device comprising a processor and a memory, the processor being used to call program instructions, and when the program instructions are called and executed, the computer-assisted evaluation method of claim 8 is implemented; the computer-readable storage medium has a computer program stored thereon, and when the computer program is called and executed by the processor, the computer-assisted evaluation method of claim 8 is implemented.

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