Use of a c5ar1 antagonist and / or il-1ß inhibitor in the preparation of a medicament for treating a pulmonary blood reduction form of congenital heart disease

Abstract

This invention discloses the application of C5aR1 antagonists and / or IL-1β inhibitors in the preparation of drugs for treating congenital heart disease with pulmonary hypovascularity. This invention breaks through the limitations of traditional single surgical procedures, providing for the first time a targeted, effective, and safe drug treatment strategy from a novel perspective of immune inflammation regulation. This strategy not only effectively promotes lung development and improves patients' physiological indicators, but also safeguards high-risk surgeries, ultimately comprehensively improving the prognosis and quality of life for patients with congenital heart disease with pulmonary hypovascularity.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and in particular relates to the application of C5aR1 antagonists or IL-1β inhibitors in the preparation of drugs for treating congenital heart disease with reduced pulmonary blood flow. Background Technology

[0002] Congenital heart disease (CHD) refers to structural and functional abnormalities of the heart and great blood vessels in the thoracic cavity caused by abnormal embryonic development. As the most common birth defect globally, CHD is also the most common birth defect in my country, with an incidence rate of approximately 8.98‰, and has become the leading cause of death and disability in children under 5 years old. With advancements in surgical procedures and intensive care techniques, the perioperative survival rate of children with CHD has significantly improved, allowing more and more children to enter adolescence and adulthood, forming a growing population. Therefore, the long-term quality of life for these adult CHD patients or children with CHD has become a major public health concern.

[0003] Clinical studies have shown that the long-term exercise tolerance of children with congenital heart disease (CHD) is significantly lower than that of healthy children, with the most significant decline observed in children with reduced pulmonary blood flow (RPF) CHD. The incidence of RPF-CHD (such as tetralogy of Fallot, pulmonary atresia, and other complex malformations with pulmonary artery stenosis, such as double outlet ventricle, tricuspid atresia, and transposition of the great arteries) is approximately 0.08‰–0.12‰, accounting for 11.5‰ of all CHD cases. In this type of congenital heart disease, right ventricular outflow tract obstruction or pulmonary artery hypoplasia leads to a significant reduction in blood entering the pulmonary circulation. This reduced pulmonary blood flow hinders the development of the pulmonary vascular bed and alveoli, which is the main reason for the decline in long-term quality of life and exercise tolerance in children with CHD. Current main treatments (such as systemic-pulmonary shunts) aim to increase pulmonary blood flow, but their effectiveness is limited and they carry risks. Palliative surgeries such as Blalock-Taussing shunts have certain limitations, including: 1. High surgical trauma and risk, especially for low-weight and young children; 2. Unsatisfactory and uncontrollable results: shunts can only increase pulmonary blood flow to a certain extent, but cannot be precisely controlled, and have limited effect on promoting the active development of pulmonary vessels and alveoli; 3. Numerous complications: potentially leading to pulmonary artery tortuosity, congestive heart failure, and pulmonary vascular disease; 4. A treatment window exists, during which lung development continues to lag while the child awaits surgery. Therefore, finding an effective, non-invasive method to actively promote lung development and improve the long-term prognosis of children with these conditions is a pressing clinical challenge.

[0004] In recent years, studies have shown that, in addition to hemodynamic changes, immune inflammatory responses play a crucial role in organ development and disease progression, and the roles of inflammation and immune responses in organ development and repair have received increasing attention. The complement system is a core component of innate immunity. C5a is one of its most potent inflammatory mediators; by binding to its receptor (C5aR1), it recruits neutrophils, monocytes, and other cells, releasing large amounts of inflammatory factors and proteases, leading to a strong inflammatory response and tissue damage. The production of IL-1β can be induced by various signals, including C5a, and can strongly activate the NF-κB pathway, but its role in lung hypoplasia caused by reduced pulmonary blood flow remains unexplored.

[0005] The role of the complement C5a / C5aR1 signaling pathway in pulmonary hypoplasia caused by pulmonary hypovascular congenital heart disease has not yet been elucidated, and no studies have explored the use of this pathway to treat such diseases. Summary of the Invention

[0006] To address the technical problems existing in the prior art, this invention provides the application of C5aR1 antagonists and / or IL-1β inhibitors in the preparation of drugs for treating congenital heart disease with pulmonary hypovascularity. This invention reveals for the first time the application potential of C5aR1 antagonists and IL-1β in the treatment of congenital heart disease with pulmonary hypovascularity.

[0007] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0008] This invention provides, in one aspect, the use of C5aR1 antagonists and / or IL-1β inhibitors in the preparation of medicaments for treating congenital heart disease with reduced pulmonary blood flow.

[0009] In this invention, "Pulmonary Blood Flow Deficient Congenital Heart Disease" is a type of congenital heart malformation characterized by a pulmonary blood flow that is significantly lower than that of the systemic circulation. Essentially, it is caused by obstruction of the blood flow pathway from the right heart system to the pulmonary circulation (such as valvular stenosis, vascular atresia, or anatomical abnormalities), which leads to long-term insufficient blood supply to the lung tissue and subsequently causes a series of pathophysiological changes such as lung development disorders, hypoxia, and right heart remodeling.

[0010] In some embodiments of the present invention, the congenital heart disease with reduced pulmonary blood flow is selected from one or more of the following: tetralogy of Fallot, pulmonary atresia with intact ventricular septum, tricuspid atresia with pulmonary stenosis, Ebstein's anomaly with severe tricuspid regurgitation and reduced pulmonary blood flow, severe pulmonary stenosis, and other congenital heart diseases that are directly caused by right ventricular outflow tract obstruction or congenital malformation of the right heart system, resulting in reduced pulmonary blood flow and whose core pathological mechanism is consistent with the aforementioned diseases, and which have no other non-right heart system pathogenic factors.

[0011] In this invention, "other congenital heart diseases caused by right ventricular outflow tract obstruction or congenital malformation of the right heart system, directly leading to reduced pulmonary blood flow, with the core pathological mechanism consistent with the aforementioned diseases and without other non-right heart system pathogenic factors" refers to all congenital heart malformations that, apart from the aforementioned explicitly listed tetralogy of Fallot, pulmonary atresia with intact ventricular septum, tricuspid atresia with pulmonary stenosis, Ebstein's anomaly with severe tricuspid regurgitation and reduced pulmonary blood flow, and severe pulmonary stenosis, have right ventricular outflow tract obstruction or right heart system structural / functional malformation as the core pathological mechanism, ultimately leading to a pathological reduction in pulmonary circulation blood flow. These include, but are not limited to, congenital heart diseases with similar mechanisms such as supravalvular pulmonary stenosis, double outlet right ventricle with pulmonary stenosis, and single ventricle with reduced pulmonary blood flow.

[0012] In some embodiments of the present invention, patients with pulmonary hypovascular congenital heart disease can be identified by one or more of the following indicators: (1) McGoon index < 1.5 or Nakata index < 150 mm 2 / m 2 ; (2) Persistently low blood oxygen saturation (e.g., percutaneous blood oxygen saturation < 85% at rest); (3) Patients who rely on systemic lung shunt or prostaglandin E1 to maintain pulmonary blood flow.

[0013] In some embodiments of the present invention, the patients with pulmonary hypovascular congenital heart disease are children aged 0-3 years, such as newborns (0-28 days), infants (0-1 year), and toddlers (1-3 years).

[0014] Another aspect of the present invention provides the use of C5aR1 antagonists and / or IL-1β inhibitors in the preparation of medicaments for improving lung development.

[0015] In some embodiments of the present invention, the C5aR1 antagonist is selected from one or more of the following: substances that inhibit the expression of the C5aR1 gene, substances that can completely or partially inhibit the function of the C5aR1 protein.

[0016] In some embodiments of the present invention, the C5aR1 antagonist is selected from one or more of the following: nucleic acid molecules or gene editing tools that target and inhibit C5aR1 transcription, nucleic acid molecules or gene editing tools that target and inhibit C5a receptor 1 transcription, antibodies, cyclic peptides or synthetic molecules that directly neutralize or block the biological activity of C5aR1, and antibodies, cyclic peptides or synthetic molecules that directly neutralize or block the biological activity of C5a receptor 1.

[0017] In some embodiments of the present invention, the C5aR1 antagonist is selected from one or more of the following: Avdoralimab, ACT-1014-6470, VIS954, VQ-201, Izastobart, PMX-53, PMX-205, JPE-1375, NDT9513727, W-54011, and DF2593A.

[0018] In some embodiments of the present invention, the C5aR1 antagonist is PMX-53.

[0019] In some embodiments of the present invention, the IL-1β inhibitor includes one or more of the following: substances that inhibit IL-1β gene expression and substances that can completely or partially inhibit the function of IL-1β protein.

[0020] In some embodiments of the present invention, the IL-1β inhibitor is selected from one or more of the following: nucleic acid molecules that target and inhibit IL-1β transcription, gene editing tools, antibodies that directly neutralize or block the biological activity of IL-1β, cyclic peptides, and synthetic molecules.

[0021] In some embodiments of the present invention, the IL-1β inhibitor is selected from one or more of the following: Firsekibart, Canakinumab, Anakinra, VX-765, BMS-582949, Diacerein, Oridonin, and Parthenolide.

[0022] In some embodiments of the present invention, the IL-1β inhibitor is Diacerein.

[0023] In some embodiments of the present invention, the drug further includes prostaglandin E1 and / or a diuretic.

[0024] In some embodiments of the present invention, the medicament further includes a pharmaceutically acceptable carrier or excipient.

[0025] In some embodiments of the present invention, the dosage form of the drug is an oral preparation, a nasal preparation, an intramuscular preparation, or an intravenous preparation.

[0026] A third aspect of the invention provides a pharmaceutical composition comprising a C5aR1 antagonist and / or an IL-1β inhibitor, prostaglandin E1 and / or a diuretic.

[0027] In some embodiments of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable carrier or excipient.

[0028] In some embodiments of the present invention, the C5aR1 antagonist is defined as used in the applications described in the second aspect of the present invention.

[0029] In some embodiments of the present invention, the IL-1β inhibitor is as defined in the applications described in the second aspect of the present invention.

[0030] The fourth aspect of the invention provides the use of a selection of C5aR1 antagonists, IL-1β inhibitors, and pharmaceutical compositions described in the third aspect of the invention in the preparation of a medicament for improving the efficacy of palliative or radical surgery in the treatment of congenital heart disease with reduced pulmonary blood flow.

[0031] In some embodiments of the present invention, the pulmonary hypovascular congenital heart disease is defined as described in the application of the first aspect of the present invention.

[0032] In some embodiments of the present invention, the C5aR1 antagonist is defined as used in the applications described in the second aspect of the present invention.

[0033] In some embodiments of the present invention, the IL-1β inhibitor is as defined in the applications described in the second aspect of the present invention.

[0034] In some embodiments of the present invention, the drug is formulated for administration before and / or after palliative or radical surgery to patients with congenital heart disease characterized by pulmonary hypovascularity. Specifically, in the preoperative stage: the drug serves as an "induction therapy" or "preparatory therapy" to promote lung development, aiming to increase the diameter of the pulmonary artery and the number of alveoli, creating better anatomical and physiological conditions for subsequent radical surgeries (such as radical surgery, Fontan-type surgeries), and reducing surgical risks and mortality; in the postoperative stage: the drug serves as adjunctive therapy for patients who still have pulmonary hypoplasia, pulmonary hypertension, or hypoxemia after surgery, to further improve lung function and promote pulmonary vascular remodeling.

[0035] In some embodiments of the present invention, the timing of intervention with the above-mentioned drug is as follows: (1) At the time of initial diagnosis: Once the patient is diagnosed with severe pulmonary hypoxia type congenital heart disease, medication can be started.

[0036] (2) Before planned surgery: The medication is started some time before the scheduled palliative or radical surgery (e.g., 4-12 weeks before surgery) as “preoperative neoadjuvant therapy”.

[0037] (3) Postoperative recovery period: the period of preparation for subsequent surgeries after completing palliative surgery (such as BT shunt surgery or Glenn surgery).

[0038] In some embodiments of the present invention, the above-mentioned drug can achieve one or more of the following therapeutic effects: (1) Promotes pulmonary artery angiogenesis and growth; (2) Promotes alveolarization and lung parenchyma development; (3) Improves pulmonary vascular resistance; (4) Improve arterial blood oxygen saturation; (5) Reduce the mortality rate and complication rate of subsequent surgeries; (6) Improve long-term quality of life and exercise tolerance.

[0039] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0040] The reagents and raw materials used in this invention are all commercially available or can be prepared using conventional techniques in the field.

[0041] The positive and progressive effects of this invention are as follows: (1) This invention provides a non-surgical drug intervention program to reduce the suffering and surgical risks of children; (2) It directly targets the pathogenic pathway at the molecular level, which may more effectively improve lung development from the root; (3) It can be used in combination with existing palliative therapies to achieve synergistic effects and improve the long-term prognosis of patients.

[0042] Compared with the prior art, the application of the complement C5a receptor 1 antagonist and IL1β inhibitor provided by this invention in the treatment of congenital heart disease with reduced pulmonary blood flow has the following significance: 1. Theoretical innovation and mechanistic breakthrough: For the first time, new therapeutic targets and mechanisms of action have been revealed. 1.1 Opening a New Path: This invention is the first to link the complement C5a / C5aR1 signaling pathway with pulmonary hypoplasia in congenital heart disease with reduced pulmonary blood flow, and proposes treating the disease by antagonizing this pathway. This provides a completely new perspective for understanding the pathophysiological mechanism of this disease, moving beyond the traditional approach of simply increasing blood flow through surgical procedures.

[0043] 1.2 Novel Mechanism of Action: The effects of this invention are not simply symptomatic treatment, but rather intervention in disease progression at the molecular level. By blocking C5aR1 and IL1β, it can directly inhibit harmful local inflammatory responses, creating a favorable microenvironment for the active development and repair of pulmonary vessels and alveoli. This is a "root cause treatment" or "repair promotion" therapy.

[0044] 2. Significant improvement in clinical treatment efficacy

[0045] 2.1 Directly promotes lung development and improves surgical prognosis: Compared with palliative surgery (such as systemic-pulmonary shunt) which only increases blood flow to a limited extent, this invention actively promotes the growth of pulmonary arteries (angiogenesis) and the maturation of alveolar structures (alveolarization), thereby substantially improving objective indicators such as the McGoon index and Nakata index. This creates better anatomical conditions for subsequent radical surgery, significantly reducing surgical difficulty, mortality, and postoperative complications.

[0046] 2.2 Improve patients' physiological status: By promoting lung development, it can effectively improve patients' arterial blood oxygen saturation, relieve chronic hypoxia, improve their overall condition, buy valuable time for children's growth, and may improve their long-term quality of life and exercise tolerance.

[0047] 3. Advantages and safety of the treatment strategy

[0048] 3.1 Providing Non-Surgical / Minimally Invasive Treatment Options: This invention offers a drug therapy that may avoid or postpone high-risk, highly invasive open-chest surgery, or reduce its complexity. This is of great significance for critically ill newborns who cannot undergo immediate surgery or whose surgery carries extremely high risks.

[0049] 3.2 Strong targeting and fewer potential side effects: Compared with broad-spectrum anti-inflammatory drugs (such as glucocorticoids), C5a receptor 1 antagonists target specific pathogenic pathways, theoretically have higher safety and fewer off-target effects, and avoid systemic side effects such as growth inhibition and hyperglycemia caused by hormone drugs.

[0050] 3.3 Creating opportunities for synergistic treatment: This invention can be used as neoadjuvant therapy before surgery or adjuvant therapy after surgery, and can produce synergistic effects with existing standard therapies (such as prostaglandin E1 to maintain the opening of the ductus arteriosus, oxygen inhalation, etc.), forming a new comprehensive treatment model of "drug-promoted development + surgical reconstruction of structure", achieving a 1+1>2 effect.

[0051] 4. Social and economic benefits

[0052] 4.1 Filling a Market Gap: Currently, there are no approved targeted drugs worldwide for promoting lung development in patients with pulmonary hypoperfusion. This invention fills this critical clinical gap and has broad market prospects.

[0053] 4.2 Reduce medical costs: By improving patient conditions, reducing surgical complexity and complications, the overall length of hospital stay can be shortened and the number of repeat interventions can be reduced, thereby significantly reducing the long-term medical burden and having significant socio-economic value.

[0054] In summary, the significant advancement of this invention compared to existing technologies lies in its ability to overcome the limitations of traditional single surgical procedures. For the first time, it provides a targeted, highly effective, and safe drug treatment strategy from a novel perspective of immune-inflammatory regulation. This strategy not only effectively promotes lung development and improves patients' physiological indicators but also safeguards high-risk surgeries, ultimately comprehensively improving the prognosis and quality of life for patients with pulmonary hypovascularity-related congenital heart disease, thus possessing significant clinical value and social significance. Attached Figure Description

[0055] Figures 1-4 The results show the HE staining of alveoli and statistical results of alveolar size in P14-day-old suckling mice after PMX53 treatment, the immunofluorescence staining of RAGE receptor in ATI cells of P14-day-old suckling mice and statistical results, the immunofluorescence staining of SFTPC protein in AT2 cells of P14-day-old suckling mice and statistical results, and the immunofluorescence staining of Sema3a, the axonal guiding molecule of P14-day-old suckling mice and statistical results.

[0056] Figures 5-8 The results show the HE staining of alveoli and statistical results of alveolar size in P14 day-old suckling mice after Diacerein treatment, the immunofluorescence staining of RAGE receptor in ATI cells of P14 day-old suckling mice and statistical results, the immunofluorescence staining of SFTPC protein in AT2 cells of P14 day-old suckling mice and statistical results, and the immunofluorescence staining of Sema3a, the axonal guiding molecule of P14 day-old suckling mice and statistical results. Detailed Implementation

[0057] Based on a neonatal rat model of insufficient pulmonary perfusion constructed by the cardiothoracic surgery team at Shanghai Children's Medical Center using constricted pulmonary arteries, the inventors discovered through transcriptome sequencing that the complement pathway, particularly complement C5aR1 and IL-1β, was significantly elevated in the P7-day neonatal rat model with insufficient pulmonary perfusion, while the expression of the axonal guiding molecule Sema3a was significantly decreased. Through in-depth research, the inventors have for the first time revealed and verified the existence of a key pathogenic signaling pathway in a model of congenital heart disease with reduced pulmonary blood flow: C5a / C5aR1 → IL-1β → NF-κB → Sema3a.

[0058] The inventors have creatively proposed that in congenital heart disease with reduced pulmonary blood flow, the decreased pulmonary blood flow may trigger a local ischemic and hypoxic microenvironment, thereby abnormally activating the complement system (especially C5a). After C5a acts on mitochondrial C5aR1 in cells (such as immune cells or lung parenchymal cells), it shifts cellular energy metabolism from OXPHOS to glycolysis, thereby upregulating IL-1β gene expression at the transcriptional level. This abnormal inflammatory response further exacerbates the damage to pulmonary blood vessels and alveolar structures, inhibiting their development. Therefore, this invention aims to provide a novel pharmaceutical use for complement C5a receptor 1 antagonists and IL-1β inhibitors, namely, by antagonizing C5aR1 or IL-1β, blocking this harmful inflammatory signaling pathway, thereby reducing inflammatory damage to lung tissue, creating a favorable microenvironment for the development of pulmonary blood vessels and alveoli, and ultimately promoting lung development. This provides a novel, non-surgical drug treatment strategy for congenital heart disease with reduced pulmonary blood flow.

[0059] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0060] C5a receptor 1 antagonist PMX53, purchased from MedChemExpress China, product batch number 219639-75-5.

[0061] Diacerein, an IL-1β inhibitor, was purchased from APExBIO, lot number 13739-02-1.

[0062] Example 1

[0063] 1. Experimental Methods

[0064] 1.1 Experimental Animals and Model Establishment

[0065] Animals: Healthy newborn SD rats (day 0) were selected and randomly divided into the following three groups: (1) Sham group: only the chest was opened, the pulmonary artery was not ligated, and the animals were fed normally after the operation.

[0066] (2) Model control group (PAB group): The classic "reduced pulmonary blood flow" pulmonary dysplasia model - neonatal rat pulmonary artery constriction (PAB) model was established by surgically ligating the main pulmonary artery of newborn rats.

[0067] The specific steps are as follows: Thoracotomy: Make an incision of approximately 0.3 cm in the right second intercostal space. In newborn rats, only the right intercostal space is opened to preserve the integrity of the sternum. Absorb any oozing blood from the wound with cotton swabs.

[0068] Expose the pulmonary artery: Use a microsurgical retractor to lift the chest wall and fully expose the pleural cavity. After cutting the pericardium and aspirating the pericardial fluid, gently push the thymus to expose the pulmonary artery (located to the right of the aorta). Adjusting the position of the auricle and the animal's body position with gelatin sponge can further optimize the pulmonary artery field of view.

[0069] Pulmonary artery circumduction: The tip of a 12-0 suture needle is blunted to create a blunt needle, which is then passed transversely through the main pulmonary artery. A 28G inserter is placed parallel above the vessel, and the suture and inserter are then ligated together (three knots in total, with the second knot slightly loose). After ligation, the inserter is removed, and excess suture ends are trimmed, thus completing the quantitative circumduction of the pulmonary artery. The sham surgery group underwent the same procedure as the PAB group, except that this circumduction step was omitted.

[0070] Chest closure and marking: After confirming there is no active bleeding in the pleural cavity, the intercostal spaces, muscle layer, and skin layer are sutured sequentially using 9-0 sutures. The pups are immediately marked post-operatively using the toe-clipping method.

[0071] Postoperative care: After surgery, the pups should first be placed under an infrared heating lamp for rapid rewarming. Once they regain spontaneous breathing and limb movement, they should be transferred to a constant-temperature heating plate for continuous warmth. Only after their skin has returned to a healthy pinkish color and they are active again can they be returned to their mother's cage in batches to minimize frequent disturbance to the mother. Pups in the same cage should be operated on in two batches to ensure that at least half of the pups are always near the mother.

[0072] (3) Treatment group (PAB+PMX-53 or PAB+C5aR1 ant): After successfully establishing the left lung blood reduction model, the C5a receptor antagonist PMX-53 was injected intraperitoneally at a dose of 0.5 mg / kg. The PAB and Sham groups were given an intraperitoneal injection of physiological saline solution with the same volume equivalent to the C5a receptor 1 antagonist injection dose.

[0073] Group details: Sham surgery group: n=5; Model control group: n=5; Treatment group: n=5 1.2 Dosing regimen (1) Drug: C5a receptor antagonist PMX-53.

[0074] (2) Route of administration: Intraperitoneal injection.

[0075] (3) Dosage and frequency of administration: once every other day, 0.5 mg / kg each time.

[0076] (4) Dosing cycle: Starting from the first day after surgery, continue to administer the drug for 2 weeks (P14 days).

[0077] 1.3 Observation and Detection Indicators

[0078] General care: Observe the rats' activity, respiration, weight and survival status daily.

[0079] Sample collection: After the administration of the drug (approximately 14 days after the age of the rats), the rats were weighed and anesthetized. They were then sacrificed and their lungs were removed for subsequent testing (including lung volume and alveolar development (including alveolar size, type I and type II alveolar development indicators RAGE receptor and SFTPC protein), and expression of axonal guiding molecule Sema3a).

[0080] 2. Experimental Results

[0081] 2.1 Alveolar development in P14 day-old suckling mice: PMX53 can effectively improve lung development in P14 PAB suckling mice.

[0082] HE staining and immunofluorescence: alveolar size of PAX53-treated PAB suckling mice ( Figure 1 Type I alveoli () Figure 2 ) and type II alveolar development ( Figure 3 Compared to the placebo group, there was a significant improvement in the expression of the axonal guiding molecule Sema3a ( Figure 4 The levels were significantly higher in PAB suckling mice than in the placebo-treated group.

[0083] Example 2

[0084] 1. Experimental Methods

[0085] 1.1 Experimental Animals and Model Establishment

[0086] Animals: Healthy newborn SD rats (day 0) were selected and randomly divided into the following three groups: Sham group: only open the chest, without ligating the pulmonary artery, and feed normally after the operation.

[0087] Model control group (PAB group): The classic "reduced pulmonary blood flow" pulmonary dysplasia model - PAB model - was established by surgically ligating the main pulmonary artery of newborn mice.

[0088] Treatment group (PAB+Diacerein or PAB+IL1β inh): After successfully establishing the left lung blood reduction model, the IL1β inhibitor Diacerein was administered by gavage at a dose of 25 mg / kg. The PAB and Sham groups were given an intraperitoneal injection of physiological saline solution with the same volume equivalent to the C5a receptor antagonist injection dose.

[0089] Group details: Sham surgery group: n=5; Model control group: n=5; Treatment group: n=5 1.2 Dosing regimen (1) Drug: IL1β inhibitor Diacerein.

[0090] (2) Route of administration: gavage.

[0091] (3) Dosage and frequency of administration: once a day, 25 mg / kg each time.

[0092] (4) Dosing cycle: Starting from the first day after surgery, continue to administer the drug for 2 weeks (P14 days).

[0093] 1.3 Observation and Detection Indicators

[0094] (1) General conditions: Daily observation of rat activity, respiration, weight and survival.

[0095] (2) Sample collection: After the administration of the drug (i.e., about 14 days old), the rats were weighed and anesthetized. They were then sacrificed and their lungs were removed for subsequent testing (including lung volume and alveolar development (including alveolar size, type I alveolar and type II alveolar development indicators RAGE receptor and SFTPC protein), and expression of axonal guiding molecule Sema3a).

[0096] 2. Experimental Results

[0097] 2.1 Alveolar development in P14 day-old suckling mice: Diacerein can effectively improve lung development in P14 PAB suckling mice.

[0098] HE staining and immunofluorescence: alveolar size in PAB suckling mice treated with Diacerein ( Figure 5 Type I alveoli () Figure 6 ) and type II alveolar development ( Figure 7 Compared to the placebo group, there was a significant improvement, with Sema3a expression, axonal guiding molecule, being significantly higher in PAB suckling mice than in the placebo group. Figure 8 ).

Claims

1. Application of C5aR1 antagonists and / or IL-1β inhibitors in the preparation of drugs for treating congenital heart disease with reduced pulmonary blood flow.

2. The application as described in claim 1, characterized in that, The congenital heart disease with reduced pulmonary blood flow is selected from one or more of the following: Tetralogy of Fallot, pulmonary atresia with intact ventricular septum, tricuspid atresia with pulmonary stenosis, Ebstein's anomaly with severe tricuspid regurgitation and reduced pulmonary blood flow, severe pulmonary stenosis, and other congenital heart diseases that are directly caused by right ventricular outflow tract obstruction or congenital malformation of the right heart system, resulting in reduced pulmonary blood flow, and whose core pathological mechanism is consistent with the aforementioned diseases, and which have no other non-right heart system pathogenic factors. And / or, patients with the pulmonary hypovascular congenital heart disease can be identified by one or more of the following indicators: (1) McGoon index < 1.5 or Nakata index < 150 mm 2 / m 2 ; (2) Persistently low blood oxygen saturation (e.g., percutaneous blood oxygen saturation < 85% at rest); (3) Patients who rely on systemic lung shunt or prostaglandin E1 to maintain pulmonary blood flow.

3. Application of C5aR1 antagonists and / or IL-1β inhibitors in the preparation of drugs to improve lung development.

4. The application as described in any one of claims 1-3, characterized in that, The C5aR1 antagonist is selected from one or more of the following: substances that inhibit C5aR1 gene expression, substances that can completely or partially inhibit the function of C5aR1 protein; Preferably, the C5aR1 antagonist is selected from one or more of the following: nucleic acid molecules or gene editing tools that target and inhibit C5aR1 transcription, nucleic acid molecules or gene editing tools that target and inhibit C5a receptor 1 transcription, antibodies, cyclic peptides and synthetic molecules that directly neutralize or block the biological activity of C5aR1, and antibodies, cyclic peptides and synthetic molecules that directly neutralize or block the biological activity of C5a receptor 1. More preferably, the C5aR1 antagonist is selected from one or more of the following: Avdoralimab, ACT-1014-6470, VIS954, VQ-201, Izastobart, PMX-53, PMX-205, JPE-1375, NDT9513727, W-54011 and DF2593A; preferably PMX-53.

5. The application as described in any one of claims 1-4, characterized in that, The IL-1β inhibitors include one or more of the following: substances that inhibit IL-1β gene expression and substances that can completely or partially inhibit the function of IL-1β protein. Preferably, the IL-1β inhibitor is selected from one or more of the following: nucleic acid molecules that target and inhibit IL-1β transcription, gene editing tools, antibodies, cyclic peptides, and synthetic molecules that directly neutralize or block the biological activity of IL-1β; More preferably, the IL-1β inhibitor is selected from one or more of the following: Firsekibart, Canakinumab, Anakinra, VX-765, BMS-582949, Diacerein, Oridonin, and Parthenolide; preferably Diacerein.

6. The application as described in any one of claims 1-5, characterized in that, The drug also includes prostaglandin E1 and / or diuretics.

7. The application as described in any one of claims 1-6, characterized in that, The drug also includes pharmaceutically acceptable carriers or excipients; And / or, the dosage form of the drug is an oral preparation, a nasal preparation, an intramuscular preparation, or an intravenous preparation.

8. A pharmaceutical composition, characterized in that, The pharmaceutical composition includes a C5aR1 antagonist and / or an IL-1β inhibitor, prostaglandin E1 and / or a diuretic; Preferably, the C5aR1 antagonist is as defined in the application described in claim 4; And / or, as defined in the application described in claim 5, the IL-1β inhibitor.

9. Use of one or more selected from C5aR1 antagonists, IL-1β inhibitors, and pharmaceutical compositions as described in claim 8 in the preparation of a medicament for improving the efficacy of palliative or radical surgery for the treatment of congenital heart disease with reduced pulmonary blood flow.

10. The application as described in claim 9, characterized in that, The congenital heart disease with reduced pulmonary blood flow is as defined in the application described in claim 2; And / or, the C5aR1 antagonist as defined in the application described in claim 4; And / or, the IL-1β inhibitor as defined in the application described in claim 5; And / or, the drug is formulated for administration before and / or after palliative or radical surgery to patients with congenital heart disease with pulmonary hypovascularity.

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