WO2016067459A1 - Développement d'un agent thérapeutique pour l'hypertension artérielle pulmonaire - Google Patents

Développement d'un agent thérapeutique pour l'hypertension artérielle pulmonaire Download PDF

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WO2016067459A1
WO2016067459A1 PCT/JP2014/079098 JP2014079098W WO2016067459A1 WO 2016067459 A1 WO2016067459 A1 WO 2016067459A1 JP 2014079098 W JP2014079098 W JP 2014079098W WO 2016067459 A1 WO2016067459 A1 WO 2016067459A1
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gene
pde1a
study
discovery
snps
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PCT/JP2014/079098
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Japanese (ja)
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恵一 福田
元昭 佐野
鎌谷　直之
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学校法人 慶應義塾
株式会社 スタージェン
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • 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
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/44—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving esterase

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  • the present invention relates to a method for screening a substance effective in the treatment and / or prevention of pulmonary hypertension (PAH (hereinafter sometimes simply referred to as PAH)). More specifically, a method for screening a substance effective for the treatment and / or prevention of pulmonary hypertension, including a step of detecting the activity of an enzyme encoded by a PDE1A (phosphodiesterase 1A) gene, and a substance obtained by the method
  • PAH pulmonary hypertension
  • IPAH idiopathic pulmonary hypertension
  • Non-Patent Document 1 As shown in Non-Patent Document 1, in recent years, Germain et al. Published the results of a PAH genome-wide association study (genome-wide association study; GWAS (hereinafter sometimes simply referred to as GWAS)), and 18q22.3. Reported that the CBLN2 locus mapped to is a sensitive locus for PAH. However, in this analysis, patients with the BMPR2 gene were excluded from the analysis.
  • Non-Patent Document 1 GWAS of PAH was performed and it was reported that the CBLN2 locus mapped to 18q22.3 is a PAH sensitive locus. As described above, in this analysis, patients with the BMPR2 gene were reported. Excluded from analysis. However, because the penetration rate of mutations in the BMPR2 gene is as low as 20%, patients with or without the BMPR2 gene mutations may have other common genetic diversity that may affect the onset of the disease. Therefore, the present inventors conducted a GWAS study of IPAH including patients having the BMPR2 gene in the present invention, and as a result of attempting a more accurate analysis, only the PDE1A
  • this PDE1A gene belongs to PDE (phosphoesterase) superfamily, and PDE superfamily has 11 families. A plurality of genes often belong to each family. Furthermore, a protein encoded by one gene is often composed of a plurality of proteins due to differences in mRNA processing, and the number of proteins encoded by PDE superfamily is said to exceed 100 (non-patented). Reference 2). As shown in Non-Patent Document 3, this PDE1A gene belongs to the PDE1 family, and the enzyme encoded by the gene belonging to the PDE1 family is a Ca (2 +) / calmodulin-dependent PDE (Cyclic Nucleotide Phosphoesterase (hereinafter simply referred to as PDE). May be shown)).
  • PDE Cyclic Nucleotide Phosphoesterase
  • Non-Patent Document 4 reports that in experiments using vascular smooth muscle, the PDE1A gene is related to the contraction, proliferation and survival of vascular smooth muscle.
  • Non-Patent Document 5 describes that it is necessary for an SS-linked reductase necessary for degrading a protein folded in the rough endoplasmic reticulum.
  • the PDE1A gene found to be strongly related to IPAH is an enzyme (PDE) that hydrolyzes cyclic nucleotides such as cAMP and cGMP.
  • PDE enzyme
  • PDE1A belonging to the PDE1 family is a Ca (2 +) / calmodulin-dependent PDE and is known to be activated by calmodulin in the presence of Ca.
  • PDE is a collection of an extremely large number of proteins and is distributed in various organs, tissues, and cells. Since cAMP and cGMP play an important role in signal transduction, inhibitors of PDE which is an enzyme that degrades cAMP and cGMP are expected to be effective as therapeutic agents for various diseases. However, despite many years of research, few drugs are widely used worldwide as PDE inhibitors.
  • the PDE3 inhibitors milrinone (Non-patent document 6) and cilostazol (Non-patent document 7) are used for cardiovascular disorders
  • the PDE5 inhibitors sildenafil, vardenafil, and tadelafil are used as therapeutic agents for male erectile dysfunction (impotence).
  • Non-Patent Document 2 the PDE5 inhibitors are also used for the treatment of pulmonary hypertension.
  • PDE has a huge number of proteins and is expected to be associated with various diseases. The reason is that it is difficult to specify a target disease and protein combination (Non-patent Document 2).
  • Non-Patent Document 2 Although there is no doubt that the PDE5 inhibitor already used is effective for pulmonary hypertension, many side effects have been reported, and it has not been a sufficient therapeutic agent in terms of safety and the like. Therefore, it has been desired to obtain a safer and more effective substance in the treatment and prevention of PAH. To this end, it was necessary to determine which of the many genes belonging to PDE superfamily specifically related to pulmonary hypertension.
  • An object of the present invention is to provide a method for screening a substance effective for the treatment and / or prevention of PAH.
  • the present inventors have found a step of detecting the activity of the enzyme encoded by the PDE1A gene in screening for a substance effective for the treatment and / or prevention of PAH. It was found that inclusion was useful, and the present invention was completed.
  • the present invention relates to the screening method described in the following (1) or (2), and a therapeutic and / or prophylactic agent for pulmonary hypertension containing a substance screened by the method as an active ingredient.
  • a method for screening a substance effective for the treatment and / or prevention of pulmonary hypertension comprising a step of detecting the activity of an enzyme encoded by the PDE1A gene.
  • a therapeutic and / or prophylactic agent for pulmonary hypertension comprising as an active ingredient a substance screened by the method described in (1) above.
  • the screening method of the present invention it is possible to provide a therapeutic and / or prophylactic agent for PAH, which is a rare disease with severe and poor prognosis.
  • the screening method of the present invention is different from conventional PDE inhibitors obtained based on functional evidence obtained from molecular biological studies and animal experiments, or hypotheses from known data, and searches the entire genome. As a result, the PDE1A gene specified as the target molecule is targeted.
  • Such a screening method of the present invention for inhibiting the activity of the enzyme encoded by the PDE1A gene cannot be easily conceived by any scientific method so far. It is possible to provide a treatment method and the like.
  • the “method for screening a substance effective for the treatment and / or prevention of pulmonary hypertension” of the present invention is conventionally known as long as it includes a step of detecting the activity of an enzyme encoded by the PDE1A gene. Any other process may be included.
  • This “step of detecting the activity of the enzyme encoded by the PDE1A gene” means that the PDE1A gene is selectively detected by screening various substances such as compounds using the enzyme activity measurement system encoded by the PDE1A gene. This refers to the step of identifying a substance that suppresses the activity of the enzyme encoded by.
  • a substance that suppresses the activity of the enzyme encoded by the PDE1A gene does not inhibit the activity of a PDE other than the enzyme encoded by the PDE1A gene, that is, an enzyme encoded by PDE2-11 superfamily, etc., and PDE1 other than PDE1A
  • a substance that selectively inhibits the enzyme encoded by the PDE1A gene without inhibiting the enzyme encoded by the gene belonging to family is desirable. However, it is only necessary to inhibit the enzyme encoded by the PDE1A gene, and other conditions are not necessarily satisfied.
  • Several variants are known in the mRNA encoded by the PDE1A gene, and there are also some variants in the enzyme encoded by the PDE1A gene. Any enzyme may be inhibited.
  • the “therapeutic and / or prophylactic agent for pulmonary hypertension” of the present invention comprises, as an active ingredient, a substance that selectively inhibits the enzyme encoded by the PDE1A gene identified by the above screening, Any drug useful for the treatment and / or prevention of pulmonary hypertension may be used. Since the substance identified by the screening method of the present invention is a substance that selectively inhibits the enzyme encoded by the PDE1A gene, a conventionally known PDE inhibitor for the treatment and / or prevention of pulmonary hypertension It can be predicted that new effects and mechanisms of action may be exhibited.
  • ⁇ Method> 1 Study population The diagnosis of PAH in all patients of this example (both discovery and reproduction studies) was hemodynamically diagnosed by right heart catheterization. Patient specimens were collected at Keio University, Chiba University, and Kyorin University. For all patients, pulmonary hypertension (PAH) was defined as a pulmonary artery pressure of 25 mmHg or greater and a pulmonary capillary wedge pressure of 15 mmHg or less at baseline. In the diagnosis of idiopathic PAH (IPAH), all known causes were excluded based on clinical and biological examinations, and cases of pulmonary diseases and liver diseases other than pulmonary hypertension, whether mild or not, were also excluded.
  • PAH pulmonary hypertension
  • Genotyping in discovery research DNA was extracted from the blood of subjects, and DNA from PAH patients was genotyped using Illumina Human Omni2.5-8 Beadchip ver 1.1 SNP array (Illumina). The DNA derived from the control was subjected to genotyping by means of a SNP array (Illumina Corp.) of Illumina Human Omni2.5-8 Beadchip ver 1.0 (control). These arrays determine genotypes for approximately 2.5 million SNPs per person. Conditions for DNA preparation, array injection, and genotyping were in accordance with the supplier's manual.
  • Genotyping in reproducibility studies Patient genotyping for reproducibility studies was performed at Keio University by sequencing by the Sanger method. Control genotyping for reproducibility studies was extracted from data obtained with the Illumina Human Omni2.5-8 Beadchip ver 1.0 SNP array.
  • the eight loci are: CDC73
  • Table 1 shows the data of one SNP having the smallest P value for each locus, but the data of two SNPs (rs7142857, rs13023449) are shown for PDE1A
  • FIG. 2 shows a local plot near the two SNPs in the vicinity of the PDE1A gene region. As a result, as shown in these figures, related SNPs were accumulated on the 5 ′ side of the PDE1A gene.
  • the HapMap3 SNP was subjected to an imputation on the genotype near the PDE1A gene region. As a result, as shown in FIG. 4, the result of the calculation was almost the same as the result of the actual genotyping, but some neighboring SNPs were added as related SNPs.
  • Summary Table 1 summarizes the results of the above discovery and reproduction studies targeting IPAH.
  • Gene column of Table 1 in the Gene column of Table 1, in the GWAS study as a discovery study of IPAH, 8 loci with SNPs with P values less than 10-5 were shown.
  • the SNP indicating the lowest P value without any contradiction in the cluster for SNP typing is shown.
  • DNAJC10 loci are shown because they are important.
  • Table 1 summarizes the results of a meta-analysis of these nine SNPs and a meta-analysis based on data from discovery and reproducibility studies. The row of Stage in Table 1 shows the distinction between discovery research, discovery research, and meta-analysis.
  • CHR is the chromosome number
  • POS is the location of the chromosome
  • Minor Allele is the allele with a frequency of 0.5 or less in the control group
  • Major Allele is the other allele
  • MAF is Minor Allele.
  • the frequency HWE is the P value of Hardy-Weinberg equilibrium test
  • Odds Ratio is the odds ratio
  • P is the P value of the result of the test. The odds ratio and P value that could not be calculated were indicated as NA.
  • Table 2 shows specific examples in which a protein encoded by a related gene found by GWAS is a therapeutic drug target.
  • the “character” in Table 2 refers to the disease or symptom, “gene” refers to the relevant gene identified by GWAS, “target disease or symptom” to the target disease or symptom, and “therapeutic drug” effective treatment Examples of drugs are given.
  • CSF3 detected by GWAS of white blood cell count encodes GCSF (Granulocyte Colony Stimulating Factor), but as shown in Reference Material (5), this protein is leukocyte It is used as a therapeutic drug for reduction.
  • CTLA4, TNFAIP3, IL2RA, IL2RB, and TRAF1 have been detected in GWAS of rheumatoid arthritis, but these molecules and molecules closely related to these are targeted.
  • drugs for rheumatoid arthritis There are drugs for rheumatoid arthritis.
  • an antibody of a protein encoding RANKL detected by osteoporosis or bone density GWAS is effective as a therapeutic agent for osteoporosis.
  • a monoclonal antibody against a protein encoded by PCSK9 detected by GWAS targeting LDL-cholesterol levels is effective in treating hypercholesterolemia. It has been reported.
  • PDE has long been the focus of interest for pharmaceutical companies. This is because the substrates cAMP and cGMP are important molecules for signal transduction in many organs and tissues. Since inhibitors of PDE are expected to have various pharmacological actions, they are considered to have many clinical usefulness. However, few PDE inhibitors are currently used clinically. The reason is that, as described above, there are a large number of PDE enzymes, and therefore it is not known which PDE enzyme inhibitor should be used for which disease. Although there are ways to actually try many compounds in patients, they are enormously expensive and costly to the patient. As described above, GWAS is extremely effective for finding the optimal target enzyme and target disease.
  • PDE1A the only gene found in the pulmonary hypertension GWAS this time, has a deep relationship with a PDE5 inhibitor (Non-patent Document 8) that has already been used for the treatment of pulmonary hypertension. That is, the genes encoding PDE1A and PDE5 belong to the same PDE superfamily. Therefore, a compound that selectively inhibits the enzyme encoded by the PDE1A gene among many PDE molecules is considered to be effective as a therapeutic agent for pulmonary hypertension.
  • the relationship between the genetic variation found in this example and IPAH has a high odds ratio, and it can be said that the effect size is quite high.
  • intervention on the enzyme encoded by the PDE1A gene affects the expression of IPAH.
  • measurement of the enzyme encoded by the PDE1A gene is effective as a therapeutic drug search method for IPAH. Therefore, from this example, by screening various compounds and compositions using the enzyme activity measurement system encoded by the PDE1A gene, it becomes an IPAH therapeutic agent, preventive agent, or an active ingredient thereof. Substance screening becomes possible.

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Abstract

Cette invention concerne un procédé de criblage pour identifier une substance efficace pour traiter et/ou prévenir l'hypertension pulmonaire. Le procédé de criblage pour identifier une substance efficace pour traiter et/ou prévenir l'hypertension pulmonaire selon l'invention est caractérisé en ce qu'il comprend une étape de détection de l'activité d'une enzyme codée par le gène PDE1A.
PCT/JP2014/079098 2014-10-31 2014-10-31 Développement d'un agent thérapeutique pour l'hypertension artérielle pulmonaire WO2016067459A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008543807A (ja) * 2005-06-17 2008-12-04 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｐｄｅ１ｃ及びそのインヒビターの使用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008543807A (ja) * 2005-06-17 2008-12-04 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｐｄｅ１ｃ及びそのインヒビターの使用

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
GERMAIN M. ET AL.: "Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension", NATURE GENETICS, vol. 45, no. 5, May 2013 (2013-05-01), pages 518 - 521, XP055090109 *
MURRAY F. ET AL.: "Expression and activity of cAMP phosphodiesterase isoforms in pulmonary artery smooth muscle cells from patients with pulmonary hypertension: role for PDE1", AM J PHYSIOL LUNG CELL MOL PHYSIOL, vol. 292, 2007, pages L294 - L303, XP002556128 *
SCHERMULY R. T. ET AL.: "Phosphodiesterase 1 Upregulation in Pulmonary Arterial Hypertension Target for Reverse-Remodeling Therapy", CIRCULATION, vol. 115, 2007, pages 2331 - 2339, XP009149064 *
TIAN X. ET AL.: "Inhibition of CA 2+/calmodulin- dependent phosphodiesterasela attenuates right ventricular remodeling and dysfunction in two rat models", AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 183, no. 1, 2011 *
TIAN X. ET AL.: "Inhibition of Ca2+/Calmodulin- Dependent PhosphodiesteraselA Restores Right Ventricular Dysfunction in Experimental Pulmonary Hypertension", CIRCULATION, vol. 122, no. 21, 2010 *

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