WO2021227417A1 - 一种治疗脊髓性肌萎缩症的方法和药物 - Google Patents
一种治疗脊髓性肌萎缩症的方法和药物 Download PDFInfo
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- plasminogen
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Definitions
- the present invention relates to a method for treating spinal muscular atrophy (SMA) and related disorders, comprising administering an effective amount of plasminogen to a subject suffering from spinal muscular atrophy (SMA) and related disorders Components of the activation pathway or related compounds, such as plasminogen, to repair damaged nerves and improve clinical symptoms and signs.
- SMA spinal muscular atrophy
- Components of the activation pathway or related compounds, such as plasminogen to repair damaged nerves and improve clinical symptoms and signs.
- SMA Spinal Muscular Atrophy
- SMA spinal muscular atrophy
- spinal muscular atrophy also known as spinal muscular atrophy or spinal muscular atrophy. It is a type of disease in which muscle weakness and muscle atrophy are caused by the degeneration of the motor neurons in the anterior horn of the spinal cord. It is an autosomal recessive genetic disease.
- SMA survival motor neuron
- Symptoms include muscle weakness, hypotonia, weakness in crying, limp or falling tendency, difficulty sucking or swallowing, accumulation of secretions from the lungs or throat, difficulty eating, and susceptibility to respiratory infections.
- the legs are often weaker than the arms and fail to reach developmental signs, such as raising the head or sitting up. Generally, the earlier the symptoms appear, the shorter the life span.
- SMA Stret al. The process of SMA is directly related to the deterioration speed of motor neuron cells and the degree of weakness caused by it. Babies with severe forms of SMA often die from respiratory diseases due to weakness of the muscles that support breathing. Children with milder forms of SMA survive longer, but they may require extensive medical support.
- SMA is an autosomal recessive genetic disease. About 95% of SMA is caused by the mutation of SMN1 (Survival Motor Neuron 1) gene on chromosome 5, so it is also called 5q type SMA.
- Type 5q SMA is divided into 5 subtypes according to the patient's age of onset and the severity of the disease: Type 0 patients: generally more common in fetuses or newborns, the onset of fetal period is manifested as decreased fetal movement, and neonatal manifestations are Loss of muscle reflexes, facial paralysis, atrial septal defect and joint contractures. The most serious manifestations are respiratory failure. The life expectancy of sick children is greatly shortened, and most of them survive within 6 months.
- Type I patients infantile, also known as Werdnig-Hoffman disease accounts for 50% of SMA patients.
- the patient developed hypotonia, poor head control, and weakened or disappeared tendon reflexes within 6 months after birth.
- Severe hypotonia manifested as "frog leg" posture when lying down, lack of head control, unable to sit upright, weak intercostal muscles, relatively small diaphragm, patients often suffer from weakened swallowing function, respiratory muscle weakness and respiratory failure .
- 92% of children with type I SMA usually die of respiratory failure 20 months ago; type II patients: intermediate type, accounting for about 20% of SMA patients, usually 6-18 after birth
- the patient can sit alone at a certain stage in the development process, but cannot walk independently.
- Type III patients Juvenile type, also known as Kugelberg-Welander disease, accounts for about 30% of SMA patients. Patients usually develop onset within 18 months to 5 years after birth. It can walk with the help of material support. Unlike type II SMA, most of these people do not have complications such as scoliosis and respiratory muscle weakness. The cognition and life expectancy of this group are generally not affected by the disease; type IV patients: onset after adolescence, exercise ability gradually Decrease, accounting for about 5% of the total number of SMA patients.
- SMAs are not caused by mutations in the SMN1 gene. They are called non-5q SMAs, which means that their pathogenic genes are not located in the SMN region of chromosome 5. Similar to 5q type SMA, children with non-5q type SMA will also have symptoms of muscle weakness very early, but there will be some differences, including the distal muscle weakness rather than the proximal muscle weakness, and the earlier occurrence of distant muscle weakness.
- SMA is caused by inactivating mutations or deletions of telomere copies of genes (SMN1) on two chromosomes, resulting in loss of function of the SMN1 gene.
- SMN1 protein functions as a cofactor in RNA maturation and is required for the viability of all eukaryotic cells (Talbot and Tizzano (2017) Gene Ther 24(9):529-533).
- the SMN2 protein is almost the same as SMN1 except for a single mutation that plays a role in the splicing of RNA messages.
- SMA is usually diagnosed by a test that combines clinical symptoms with at least one copy of SMN1 gene.
- other tests such as electromyography (EMG) or muscle biopsy can also assist in the diagnosis.
- EMG electromyography
- the treatment of SMA is limited to supportive therapy, including breathing, nutrition and rehabilitation treatment and care. There is no medicine that can effectively treat this disease.
- plasminogen pathway activators such as plasminogen can significantly improve the symptoms of nerve injury in SMA subjects, improve lung function, prolong survival, promote the transcription and expression of SMN genes, and increase brain and muscle tissue.
- the level of SMN protein can promote the expression of NF- ⁇ B protein in brain tissue and muscle tissue, promote the formation of mature NGF in brain tissue, and improve lung tissue damage, thereby effectively preventing and treating SMA.
- the present invention relates to a method for treating spinal muscular atrophy (SMA) (including type 0, type I, type II, type III, type IV, and non-5q SMA), comprising administering a motor neuron disease
- spinal muscular atrophy SMA
- subjects with spinal muscular atrophy (SMA) have a therapeutically effective amount of one or more plasminogen pathway activators selected from the following: components of the plasminogen activation pathway, capable of directly activating fibrin Lysinogen or compounds that indirectly activate plasminogen by activating the upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, and can up-regulate plasminogen Or plasminogen activator-expressed compounds, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors.
- plasminogen pathway activators selected from the following: components of the plasminogen activation pathway, capable of directly activating fibrin Lysinogen or compounds that
- the plasminogen pathway activator is effective against spinal muscular atrophy (SMA) (including type 0, type I, type II, type III, type IV, and non-5q SMA).
- SMA spinal muscular atrophy
- the subject has one or more activities selected from: 1. Reduce or improve the severity of SMA; 2. Delay the onset of SMA; 3. Inhibit the progression of SMA; 4. Prolong the survival time of the subject; 5. Improve the quality of life of the subject and/or improve the mental state of the subject; 6. Reduce the number of SMA-related symptoms; 7. Reduce or improve the severity of one or more symptoms related to SMA; 8. Shorten the duration of SMA-related symptoms; 9. Prevent the recurrence of SMA-related symptoms; 10. Inhibit the development or onset of SMA symptoms; 11.
- the plasminogen pathway activator improves muscle atrophy, increases muscle strength, and/or improves muscle tone in the subject. In some specific embodiments, the plasminogen pathway activator prolongs the survival of the subject.
- the plasminogen pathway activator promotes the transcription and/or expression of the SMN gene. In some specific embodiments, the plasminogen pathway activator promotes the recovery of muscle function in the subject. In some specific embodiments, the plasminogen pathway activator promotes the repair of spinal cord anterior horn neurons in the subject. In some specific embodiments, the plasminogen pathway activator promotes the expression of NF- ⁇ B protein in the subject. In some specific embodiments, the plasminogen pathway activator promotes the formation of mature NGF in the subject. The plasminogen pathway activator promotes the formation of mature NGF in the subject.
- the plasminogen pathway activator is administered in combination with one or more other drugs and/or treatment methods.
- the treatment methods include cell therapy (eg stem cell therapy) and gene therapy , Such as antisense RNA, small molecule splicing modifiers.
- the plasminogen pathway activator is a component of the plasminogen activation pathway.
- the components of the plasminogen activation pathway are selected from plasminogen (abbreviation: plasminogen), recombinant human plasmin, Lys-plasminogen, Glu -Plasminogen, plasmin, plasminogen and plasmin variants and the like containing one or more kringle domains and protease domains of plasminogen and plasmin Substances, mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasmin Enzyme, delta-plasmin, plasminogen activator, tPA and uPA.
- plasminogen abbreviation: plasminogen
- the antagonist of the fibrinolysis inhibitor is PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin or ⁇ 2 macroglobulin antagonist, such as PAI-1, complement C1 inhibitor, ⁇ 2 anti-plasmin or ⁇ 2 macroglobulin antibody.
- the component of the plasminogen activation pathway is plasminogen.
- the plasminogen comprises or has an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96% identical to the amino acid sequence shown in SEQ ID NO: 2, 6, 8, 10 or 12. , 97%, 98% or 99% sequence identity of the amino acid sequence, and has plasminogen activity.
- the plasminogen activity is the proteolytic activity of plasminogen.
- the plasminogen activity is the lysine binding activity of plasminogen to the substrate molecule.
- the plasminogen activity is the proteolytic activity of plasminogen and the lysine binding activity of plasminogen to the substrate molecule.
- the plasminogen is added, deleted and/or substituted 1-100, 1-90, 1-80, 1-70 on the basis of sequence 2, 6, 8, 10 or 12. , 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1 -3, 1-2, 1 amino acid, and has plasminogen proteolytic activity and/or lysine binding activity protein.
- the plasminogen activity is the proteolytic activity of plasminogen.
- the plasminogen is a protein containing plasminogen active fragments and having the proteolytic activity and/or lysine binding activity of plasminogen.
- the active fragment of plasminogen comprises or has a serine protease domain of plasminogen or is called a plasminogen protease domain.
- the amino acid sequence of the active fragment of plasminogen is shown in SEQ ID NO: 14.
- the plasminogen is selected from Glu-plasminogen (human full-length plasminogen), Lys-plasminogen (after cleavage between amino acids 76-77) Human full-length plasminogen), microplasminogen (including Kringle 5 (K5) and serine protease domain), microplasminogen (including serine protease domain), delta-plasminogen (including Kringle 1 and serine protease domain) or their variants that retain plasminogen activity.
- the plasminogen is human full-length plasminogen, or a variant or fragment thereof that still retains plasminogen activity.
- the plasminogen activity is the proteolytic activity of plasminogen.
- the plasminogen activity is the lysine binding activity of plasminogen to the substrate molecule. In some embodiments, the plasminogen activity is the proteolytic activity of plasminogen and the lysine binding activity of plasminogen to the substrate molecule. In some embodiments, the plasminogen is a human plasminogen ortholog from a primate or rodent or it still retains the proteolytic activity of plasminogen and/or lysine Variants or fragments of binding activity. In some embodiments, the plasminogen comprises an amino acid sequence as shown in sequence 2, 6, 8, 10 or 12. In some embodiments, the plasminogen is natural human plasminogen.
- the plasminogen pathway activator is administered systemically or locally, for example in the form of intravenous, intramuscular, intrathecal, nasal inhalation, nebulization, nasal drops, or eye drops Administration.
- the subject is a human.
- the subject lacks or lacks plasminogen.
- the deficiency or deletion is congenital, secondary, and/or local.
- the plasminogen is 0.0001-2000mg/kg, 0.001-800mg/kg, 0.01-600mg/kg, 0.1-400mg/kg, 1-200mg/kg, 1-100mg/kg, daily 10-100mg / kg (calculated per kg body weight) or 0.0001-2000mg / cm 2, 0.001-800mg / cm 2, 0.01-600mg / cm 2, 0.1-400mg / cm 2, 1-200mg / cm 2, 1- 100mg / cm 2, 10-100mg / cm 2 ( calculated per square centimeter of body surface area) of the dose per day, administration every two days or every three days continuously.
- the aforementioned SMA is type 0, type I, type II, type III, type IV, or non-5q type SMA.
- this application also relates to pharmaceutical compositions, drugs, preparations, kits, and products for the treatment of spinal muscular atrophy (SMA), including the above-mentioned plasminogen pathway activator, such as the above-mentioned Components of the plasminogen activation pathway, such as the plasminogen described above.
- SMA spinal muscular atrophy
- the pharmaceutical composition, medicament, or formulation comprises a pharmaceutically acceptable carrier and a plasminogen pathway activator, such as the components of the plasminogen activation pathway described above, such as those described above Plasminogen.
- the kits and articles of manufacture include one or more containers that contain the pharmaceutical composition, drug, or formulation.
- the kit or product further comprises a label or instructions for use, the label or instructions for use indicate the use of a plasminogen pathway activator, such as the components of the plasminogen activation pathway described above, for example The above-mentioned method for treating spinal muscular atrophy with plasminogen.
- the kit or article of manufacture further comprises one or more additional containers containing one or more other drugs.
- the aforementioned SMA is type 0, type I, type II, type III, type IV or non-5q type SMA.
- the present application also relates to the above-mentioned plasminogen pathway activator for the treatment of spinal muscular atrophy (SMA), such as the above-mentioned plasminogen.
- SMA spinal muscular atrophy
- the aforementioned SMA is type 0, type I, type II, type III, type IV, or non-5q type SMA.
- the present application also relates to the above-mentioned plasminogen pathway activator, such as the use of the above-mentioned plasminogen for the treatment of spinal muscular atrophy (SMA).
- SMA spinal muscular atrophy
- the aforementioned SMA is type 0, type I, type II, type III, type IV, or non-5q type SMA.
- the present application also relates to a therapeutically effective amount of the above-mentioned plasminogen pathway activator (for example, the components of the above-mentioned plasminogen activation pathway, such as the above-mentioned plasminogen) for preparing the treatment of spinal cord.
- plasminogen pathway activator for example, the components of the above-mentioned plasminogen activation pathway, such as the above-mentioned plasminogen
- SMA muscular dystrophy
- the plasminogen pathway activator is selected from one or more of the following plasminogen pathway activators: components of the plasminogen activation pathway, capable of directly activating plasmin Pro or compounds that indirectly activate plasminogen by activating the upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, and can up-regulate plasminogen or fiber Compounds expressed by plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolytic inhibitors.
- the components of the plasminogen activation pathway are selected from plasminogen, recombinant human plasmin, Lys-plasminogen, Glu-plasminogen, Plasmin, plasminogen and plasmin variants and analogs, microplasmin containing one or more kringle domains and protease domains of plasminogen and plasmin Mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasminogen, delta-plasmin Enzyme (delta-plasmin), plasminogen activator, tPA and uPA.
- the antagonist of the fibrinolysis inhibitor is PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin or ⁇ 2 macroglobulin antagonist, such as PAI-1, complement C1 inhibitor, ⁇ 2 anti-plasmin or ⁇ 2 macroglobulin antibody.
- the plasminogen pathway activator is a component of the plasminogen activation pathway.
- the components of the plasminogen activation pathway are selected from plasminogen (abbreviation: plasminogen), recombinant human plasmin, Lys-plasminogen, Glu -Plasminogen, plasmin, plasminogen and plasmin variants and the like containing one or more kringle domains and protease domains of plasminogen and plasmin Substances, mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasmin Enzyme, delta-plasmin, plasminogen activator, tPA and uPA.
- plasminogen abbreviation: plasminogen
- the antagonist of the fibrinolysis inhibitor is PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin or ⁇ 2 macroglobulin antagonist, such as PAI-1, complement C1 inhibitor, ⁇ 2 anti-plasmin or ⁇ 2 macroglobulin antibody.
- the component of the plasminogen activation pathway is plasminogen.
- the plasminogen comprises or has an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96% identical to the amino acid sequence shown in SEQ ID NO: 2, 6, 8, 10 or 12. , 97%, 98% or 99% sequence identity of the amino acid sequence, and has plasminogen activity.
- the plasminogen activity is the proteolytic activity of plasminogen.
- the plasminogen activity is the lysine binding activity of plasminogen to the substrate molecule.
- the plasminogen activity is the proteolytic activity of plasminogen and the lysine binding activity of plasminogen to the substrate molecule.
- the plasminogen is added, deleted and/or substituted 1-100, 1-90, 1-80, 1-70 on the basis of sequence 2, 6, 8, 10 or 12. , 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1 -3, 1-2, 1 amino acid, and has plasminogen proteolytic activity and/or lysine binding activity protein.
- the plasminogen activity is the proteolytic activity of plasminogen.
- the plasminogen is a protein containing plasminogen active fragments and having the proteolytic activity and/or lysine binding activity of plasminogen.
- the active fragment of plasminogen comprises or has a serine protease domain of plasminogen or is called a plasminogen protease domain.
- the amino acid sequence of the active fragment of plasminogen is shown in SEQ ID NO: 14.
- the plasminogen is selected from Glu-plasminogen (human full-length plasminogen), Lys-plasminogen (after cleavage between amino acids 76-77) Human full-length plasminogen), microplasminogen (including Kringle 5 (K5) and serine protease domain), microplasminogen (including serine protease domain), delta-plasminogen (including Kringle 1 and serine protease domain) or their variants that retain plasminogen activity.
- the plasminogen is human full-length plasminogen, or a variant or fragment thereof that still retains plasminogen activity.
- the plasminogen activity is the proteolytic activity of plasminogen.
- the plasminogen activity is the lysine binding activity of plasminogen to the substrate molecule. In some embodiments, the plasminogen activity is the proteolytic activity of plasminogen and the lysine binding activity of plasminogen to the substrate molecule. In some embodiments, the plasminogen is a human plasminogen ortholog from a primate or rodent or it still retains the proteolytic activity of plasminogen and/or lysine Variants or fragments of binding activity. In some embodiments, the plasminogen comprises an amino acid sequence as shown in sequence 2, 6, 8, 10 or 12. In some embodiments, the plasminogen is natural human plasminogen.
- the plasminogen pathway activator such as a component of the above-mentioned plasminogen activation pathway, for example, the above-mentioned plasminogen is administered in combination with one or more other drugs and/or treatment methods.
- the plasminogen pathway activator for example, a component of the plasminogen activation pathway, such as plasminogen through intravenous, intramuscular, intrathecal, nasal inhalation, aerosol inhalation, drip It is administered in the form of nasal fluid or eye drops.
- the pharmaceutical composition, medicament, or formulation includes a pharmaceutically acceptable carrier and a plasminogen pathway activator, such as a component of the plasminogen activation pathway, such as plasminogen.
- the kits and articles of manufacture include one or more containers that contain the pharmaceutical composition, drug, or formulation.
- the kit or product further comprises a label or instructions for use, the label or instructions for use indicate the use of a plasminogen pathway activator, such as a component of the plasminogen activation pathway, such as plasminogen Methods of treating spinal muscular atrophy.
- the kit or article of manufacture further comprises one or more additional containers containing one or more other drugs.
- the aforementioned SMA is type 0, type I, type II, type III, type IV, or non-5q type SMA.
- the present invention clearly covers all combinations of technical features belonging to the embodiments of the present invention, and the technical solutions after these combinations have been clearly disclosed in this application, just as the above-mentioned technical solutions have been separately and clearly disclosed.
- the present invention also clearly covers the combinations between the various embodiments and their elements, and the technical solutions after the combination are clearly disclosed herein.
- Figure 1 shows the amplitude results of the motor EMG before and after treatment in the type II SMA patient described in Example 1.
- the results showed that the action potential amplitudes of the tibial nerve and common peroneal nerve of the patients were improved to varying degrees compared with before the medication.
- the results show that plasminogen can improve the conduction function of peripheral neurons in patients with type II SMA and improve neuromuscular damage.
- Figure 2 shows the results of the electromyogram amplitudes of the upper and lower limbs of the patient described in Example 2 before and after treatment. Compared with before medication, the action potential amplitudes of the patients' left femoral nerve, right ulnar nerve, bilateral common peroneal nerve and tibial nerve all improved to varying degrees. The results show that plasminogen can improve the conduction function of peripheral neurons in patients with type II SMA and improve neuromuscular damage.
- Figure 3 shows the results of the electromyogram amplitudes of the upper and lower limbs of the patient described in Example 3 before and after treatment. Compared with before medication, the patient's bilateral median nerve, tibial nerve, common peroneal nerve, and ulnar nerve action potential increased to varying degrees. The results show that plasminogen can improve the conduction function of peripheral neurons in patients with type II SMA and improve neuromuscular damage.
- FIG. 4A-4B Survival curve and survival time statistics of SMN ⁇ 7 SMA mice after plasminogen administration.
- A is the statistical result of survival curve
- B is the statistical result of survival time.
- FIG. 5 qPCR results of SMN gene in the spinal cord of SMN ⁇ 7 SMA mice after administration of plasminogen.
- the results showed that the spinal cord of the blank control group mice had a certain level of SMN gene transcription, the SMN gene transcription level of the mice in the solvent group was lower than that of the blank control mice, and the SMN gene transcription level of the mice in the administration group was significantly higher than that of the mice in the vehicle group. Blank control mice. This result suggests that plasminogen can promote SMN gene transcription.
- FIG. 6 Western blot detection results and optical density quantitative analysis results of SMN ⁇ 7 SMA mice brain NF- ⁇ B protein after plasminogen administration.
- FIG. 7 Western blot detection results and optical density quantitative analysis results of representative hindlimb muscle NF- ⁇ B protein of SMN ⁇ 7 SMA mice after administration of plasminogen.
- the results showed that the muscles of the blank control group mice had a certain amount of NF- ⁇ B protein, the muscle NF- ⁇ B protein levels of the mice in the vehicle group were lower than those of the blank control group, and the muscle NF- ⁇ B protein levels of the mice in the administration group were significantly higher than those of the control group. Mice in the vehicle group, and statistically significant differences (* means P ⁇ 0.05). This result suggests that plasminogen can promote the increase of muscle NF- ⁇ B protein level in SMN ⁇ 7 SMA mice.
- Figure 8 Western blot detection results and optical density (OD) value quantitative analysis results of representative brain SMN proteins in SMN ⁇ 7 SMA mice after plasminogen administration.
- the results showed that the brain of the blank control group mice expressed a certain amount of SMN protein, the SMN protein expression level of the mice in the vehicle group was lower than that of the blank control mice, and the SMN protein expression level of the mice in the administration group was significantly higher than that of the mice in the vehicle group. This result suggests that plasminogen can promote SMN protein expression in the brain of SMN ⁇ 7 SMA mice.
- FIG. 9 Western blot detection results and optical density (OD) quantitative analysis results of representative hindlimb muscle SMN protein of SMN ⁇ 7 SMA mice after plasminogen administration.
- the results showed that the muscles of the blank control group mice expressed a certain amount of SMN protein, the muscle SMN protein expression level of mice in the vehicle group was lower than that of the blank control group mice, and the muscle SMN protein expression level of the mice in the administration group was significantly higher than that of the vehicle group mice .
- This result suggests that plasminogen can promote the expression of SMN protein in the muscle of SMN ⁇ 7 SMA mice.
- FIG 10 Western blot detection results and the quantitative analysis results of the NGF/Pro-NGF optical density (OD) ratio of the brain tissue of SMA mice after administration of plasminogen.
- the results showed that the brain tissue of the blank control group had a certain ratio of NGF/ProNGF, the ratio of NGF/ProNGF in the brain tissue of the mice in the administration group was significantly higher than that of the mice in the vehicle group, and the statistical difference was extremely significant (*** means P ⁇ 0.001) . It is suggested that plasminogen can promote the transformation of ProNGF into NGF in the brain tissue of SMA model mice, and promote the formation of mature NGF.
- FIG. 11 H&E staining of representative lung tissue of SMA mice after administration of plasminogen.
- the results show that the terminal bronchiolar epithelial cells of the lung tissue of the blank control group are arranged neatly and clearly; the alveolar cavity is uniform in size and the alveolar space is not There is thickening, no inflammatory cell infiltration around the blood vessels; respiratory bronchiole epithelium in lung tissue of mice in the vehicle group falls off, alveolar ducts and alveolar sacs are enlarged, alveolar septums are widened, alveoli collapse to structural disorders, and eosinophils around the pulmonary vessels Cells, foam cells, lymphocytes; respiratory bronchiole epithelium in the lung tissue of mice in the administration group is arranged in an orderly manner, alveolar ducts and alveolar sacs are enlarged, and alveolar cavity is evenly enlarged, but alveolar walls composed of a single layer of alveolar epithelium can be seen. It is suggested
- spinal muscular atrophy refers to a disease caused by inactivating mutations or deletions of the SMN1 gene on two chromosomes, resulting in the loss of SMN1 gene function.
- Symptoms of SMA include muscle weakness, hypotonia, weak crying, weak coughing, limp or falling tendency, difficulty sucking or swallowing, difficulty breathing, accumulation of secretions in the lungs or throat, clenched fists and sweaty hands, and tongue shaking/ Vibration, head that tends to one side (even when lying down), legs that tend to be weaker than arms, legs that are often "frog legs", difficulty eating, increased sensitivity to respiratory infections, bowel/ Bladder weakness, lower than normal weight, inability to sit without support, inability to walk, inability to crawl, and hypotonia, loss of reflexes, and multiple congenital contractures (joint contractures) associated with loss of pre-hom cells.
- treatment of spinal muscular atrophy (SMA) or “treatment of spinal muscular atrophy (SMA)” in this application includes obtaining one or more of the following effects: 1. Reduce or improve the severity of SMA; 2. Delay The onset of SMA; 3. Inhibit the progression of SMA; 4. Prolong the survival time of the subject; 5. Improve the quality of life of the subject and/or improve the mental state of the subject; 6. Reduce the number of SMA-related symptoms; 7 Reduce or improve the severity of one or more symptoms associated with SMA; 8. Shorten the duration of symptoms associated with SMA; 9. Prevent the recurrence of symptoms associated with SMA; 10. Inhibit the development of SMA symptoms or Onset; 11. Inhibit the progression of symptoms related to SMA; 12. Improve lung function; 13.
- SMN gene Increase blood oxygen saturation; 14. Promote the transcription and expression of SMN gene; 15. Increase the level of SMN protein in brain tissue and muscle tissue; 16. Promote the expression of NF- ⁇ B protein in brain tissue and muscle tissue; 17. Promote the formation of mature NGF in brain tissue; 18. Reduce lung tissue damage; 19. Increase muscle strength; 20. Reduce muscle atrophy; 21. Reduce motor nerves Meta loss; 22. Promote growth and development; and/or 23. Improve motor function.
- components of the plasminogen activation pathway of the present application or related compounds thereof, such as the plasminogen described above, enhance the transcription and/or expression of SMN genes.
- the components of the plasminogen activation pathway of the present application or related compounds, such as the plasminogen described above, increase the expression of SMN protein in human subjects in need thereof.
- the components of the plasminogen activation pathway of the present application or related compounds, such as plasminogen can be used alone or in combination with other drugs to treat or prevent inactivating mutations in the SMN gene Or diseases caused by deletion and/or related to loss or defect of SMN gene function. These diseases include but are not limited to spinal muscular atrophy (SMA).
- SMA spinal muscular atrophy
- the application relates to a method for treating diseases caused by inactivating mutations or deletions of SMN gene and/or related to the loss or defect of SMN gene function, such as SMA, comprising administering to a subject a therapeutically effective amount A component of the plasminogen activation pathway or its related compounds, such as plasminogen.
- the application relates to a method of treating SMA, comprising administering to a subject a therapeutically effective amount of plasminogen.
- the present application relates to a method of treating SMA, comprising administering to a subject a therapeutically effective amount of plasminogen, the plasminogen having one or more activities selected from the following: 1. Less Reduce or improve the severity of SMA; 2. Delay the onset of SMA; 3. Inhibit the progression of SMA; 4. Prolong the survival time of the subject; 5. Improve the quality of life of the subject and/or improve the mental state of the subject 6. Reduce the number of SMA-related symptoms; 7. Reduce or improve the severity of one or more symptoms related to SMA; 8. Shorten the duration of symptoms related to SMA; 9. Prevent symptoms related to SMA Recurrence; 10. Inhibit the development or onset of SMA symptoms; 11.
- Fibrinolytic system also known as fibrinolytic system, is a system composed of a series of chemical substances involved in the process of fibrinolysis (fibrinolysis), mainly including fibrinolytic enzyme (plasminogen) and plasmin , Plasminogen activator, fibrinolysis inhibitor.
- Plasminogen activators include tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA).
- t-PA tissue-type plasminogen activator
- u-PA urokinase-type plasminogen activator
- t-PA activates plasminogen
- fibrin urokinase-type plasminogen activator
- u-PA urokinase-type plasminogen activator
- PLG Plasminogen
- Plasminase is a serine protease, which has the following functions: degrades fibrin and fibrinogen; hydrolyzes a variety of coagulation factors V, VIII, X, VII, XI, II, etc.; turns plasminogen into fibrinolysis Enzymes; hydrolysis of complement, etc.
- Fibrinolytic inhibitors including plasminogen activator inhibitor (PAI) and ⁇ 2 antiplasmin ( ⁇ 2-AP).
- PAI mainly has two forms, PAI-1 and PAI-2, which can specifically bind to t-PA in a ratio of 1:1 to inactivate it and activate PLG at the same time.
- ⁇ 2-AP is synthesized by the liver and combined with PL in a ratio of 1:1 to form a complex, inhibiting PL activity; FXIII makes ⁇ 2-AP covalently bond with fibrin, reducing the sensitivity of fibrin to PL.
- Substances that inhibit the activity of the fibrinolytic system in the body PAI-1, complement C1 inhibitor; ⁇ 2 anti-plasmin; ⁇ 2 macroglobulin.
- plasminogen pathway activator or "plasminogen pathway activator” of the present invention encompasses components of the plasminogen activation pathway, capable of directly activating plasminogen or by activating plasmin Compounds that indirectly activate plasminogen by activating upstream components of the pathway, compounds that mimic the activity of plasminogen or plasmin, and those that can up-regulate the expression of plasminogen or plasminogen activator Compounds, plasminogen analogs, plasmin analogs, tPA or uPA analogs and antagonists of fibrinolytic inhibitors.
- component of the plasminogen activation pathway or “component of the plasminogen activation pathway” of the present invention encompasses:
- Plasminogen activators such as tPA and uPA, and tPA or uPA variants and analogs containing one or more domains of tPA or uPA (such as one or more kringle domains and proteolytic domains) .
- antagonist of fibrinolysis inhibitor covers PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin or ⁇ 2 macroglobulin antagonist, such as PAI-1, complement C1 inhibitor, ⁇ 2 antifibrosis Antibodies to lysozyme or ⁇ 2 macroglobulin.
- variants of plasminogen, plasmin, tPA and uPA include all naturally occurring human genetic variants and other mammalian forms of these proteins, as well as by addition, deletion and/or substitution such as 1- 100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, Proteins of 1-10, 1-5, 1-4, 1-3, 1-2, 1 amino acid that still have plasminogen, plasmin, tPA or uPA activity.
- variants of plasminogen, plasmin, tPA, and uPA include those by, for example, 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1- 45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 conservative Mutant variants of these proteins obtained by amino acid substitutions.
- the "plasminogen variants" of the present invention encompasses those containing or having at least 75%, 80%, 85%, 90%, 95%, 96%, and the amino acid sequence shown in sequence 2, 6, 8, 10 or 12. A protein with 97%, 98%, or 99% sequence identity, and has plasminogen proteolytic activity and/or lysine binding activity.
- the "plasminogen variant” of the present invention can be added, deleted and/or substituted 1-100, 1-90, 1-80, 1- on the basis of sequence 2, 6, 8, 10 or 12.
- the plasminogen variants of the present invention include all naturally occurring human genetic variants and other mammalian forms of these proteins, as well as through conservative amino acid substitutions such as 1-100, 1-90, 1-80, 1- 70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, Mutant variants of these proteins obtained from 1-3, 1-2, 1 amino acids.
- the plasminogen of the present invention may be a human plasminogen ortholog from a primate or rodent or a variant that still retains the proteolytic activity and/or lysine binding activity of plasminogen.
- plasminogen, plasmin, tPA, and uPA include compounds that provide substantially similar effects to plasminogen, plasmin, tPA, or uPA, respectively.
- variants and analogs of plasminogen, plasmin, tPA and uPA encompass fibers comprising one or more domains (for example, one or more kringle domains and proteolytic domains) "Variants” and “analogs" of plasminogen, plasmin, tPA and uPA.
- the "variants” and “analogs” of plasminogen encompass the inclusion of one or more plasminogen domains (e.g., one or more kringle (k) domains and proteolytic domains (or serine)).
- Protease domain, or plasminogen protease domain plasminogen variants and analogs, such as mini-plasminogen.
- plasminogens encompasses "variants” and “analogs” of plasmin comprising one or more plasmin domains (for example, one or more kringle domains and proteolytic domains), such as fibrinolytic enzymes. Enzyme (mini-plasmin) and delta-plasmin (delta-plasmin).
- plasminogen, plasmin, tPA or uPA have the activity of plasminogen, plasmin, tPA or uPA respectively, or whether they provide the same
- the substantially similar effects of plasminogen, plasmin, tPA or uPA can be detected by methods known in the art, for example, by methods based on enzymography, ELISA (enzyme-linked immunosorbent assay) and FACS ( Fluorescence-activated cell sorting method) is measured by the level of activated plasmin activity, for example, it can be measured with reference to a method selected from the following documents: Ny, A., Leonardsson, G., Hagglund, AC, Hagglof, P.
- the "component of plasminogen activation pathway" of the present invention is plasminogen, selected from Glu-plasminogen, Lys-plasminogen, and microplasmin Pro, microplasminogen, delta-plasminogen or their variants that retain plasminogen activity.
- the plasminogen is natural or synthetic human plasminogen, or a conservative mutant variant or fragment thereof that still retains plasminogen activity and/or lysine binding activity.
- the plasminogen is a human plasminogen ortholog from a primate or rodent or one that still retains plasminogen activity and/or lysine binding activity Conservative mutant variants or fragments thereof.
- the amino acid sequence of the plasminogen comprises or has an amino acid sequence as shown in sequence 2, 6, 8, 10 or 12.
- the plasminogen is human full-length plasminogen.
- the plasminogen is human full-length plasminogen as shown in sequence 2.
- a compound capable of directly activating plasminogen or indirectly activating plasminogen by activating upstream components of the plasminogen activation pathway refers to a compound capable of directly activating plasminogen or by activating plasminogen Any compound that activates upstream components of the pathway and indirectly activates plasminogen, such as tPA, uPA, streptokinase, saruplase,reteplase, reteplase, tenecteplase, aniplase, Monteplase, Lanoteplase, Pamideplase, Staphylokinase.
- the "antagonist of the fibrinolysis inhibitor" of the present invention is a compound that antagonizes, weakens, blocks, and prevents the action of the fibrinolysis inhibitor.
- the fibrinolysis inhibitors are, for example, PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin, and ⁇ 2 macroglobulin.
- the antagonist such as PAI-1, complement C1 inhibitor, ⁇ 2 anti-plasmin or ⁇ 2 macroglobulin antibody, or blocking or down-regulating such as PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin or ⁇ 2 macroglobulin Antisense RNA or small RNA expressed by globulin, or occupy the binding site of PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin or ⁇ 2 macroglobulin but without PAI-1, complement C1 inhibitor, ⁇ 2 anti-fibrosis Compounds that function as lysozyme or ⁇ 2 macroglobulin", or compounds that block the binding domain and/or active domain of PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin or ⁇ 2 macroglobulin.
- Plasmin is a key component of the plasminogen activation system (PA system). It is a broad-spectrum protease that can hydrolyze several components of the extracellular matrix (ECM), including fibrin, gelatin, fibronectin, laminin, and proteoglycan. In addition, plasmin can activate some metalloprotease precursors (pro-MMPs) to form active metalloproteases (MMPs). Therefore, plasmin is considered to be an important upstream regulator of extracellular proteolysis. Plasmin is formed by proteolysis of plasminogen through two physiological PAs: tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA).
- tPA tissue-type plasminogen activator
- uPA urokinase-type plasminogen activator
- PAs Due to the relatively high levels of plasminogen in plasma and other body fluids, it is traditionally believed that the regulation of the PA system is mainly achieved through the synthesis and activity levels of PAs.
- the synthesis of PA system components is strictly regulated by different factors, such as hormones, growth factors and cytokines.
- the main inhibitor of plasmin is ⁇ 2-antiplasmin ( ⁇ 2-antiplasmin).
- the activity of PAs was inhibited by both uPA and tPA plasminogen activator inhibitor-1 (PAI-1) and mainly inhibited uPA lysinogen activator inhibitor-2 (PAI-2).
- PAI-1 uPA and tPA plasminogen activator inhibitor-1
- PAI-2 mainly inhibited uPA lysinogen activator inhibitor-2
- Certain cell surfaces have uPA-specific cell surface receptors (uPAR) with direct hydrolytic activity.
- Plasminogen is a single-chain glycoprotein consisting of 791 amino acids and a molecular weight of approximately 92kDa. Plasminogen is mainly synthesized in the liver and exists in large amounts in the extracellular fluid. Plasminogen content in plasma is about 2 ⁇ M. Therefore, plasminogen is a huge potential source of proteolytic activity in tissues and body fluids. Plasminogen exists in two molecular forms: Glu-plasminogen and Lys-plasminogen. The naturally secreted and uncleaved form of plasminogen has an amino terminal (N-terminal) glutamate and is therefore called glutamate-plasminogen.
- glutamate-plasminogen is hydrolyzed at Lys76-Lys77 to lysine-plasminogen.
- lysine-plasminogen has a higher affinity for fibrin and can be activated by PAs at a higher rate.
- the Arg560-Val561 peptide bond of these two forms of plasminogen can be cleaved by uPA or tPA, resulting in the formation of a disulfide bond-linked double-chain protease plasmin.
- the amino terminal part of plasminogen contains five homologous tricyclic rings, so-called kringles, and the carboxy terminal part contains the protease domain.
- Some kringles contain lysine binding sites that mediate the specific interaction of plasminogen with fibrin and its inhibitor ⁇ 2-AP.
- Plasmin also has substrate specificity for several components of ECM, including laminin, fibronectin, proteoglycan and gelatin, indicating that plasmin also plays an important role in ECM reconstruction.
- plasmin can also degrade other components of ECM by converting certain protease precursors into active proteases, including MMP-1, MMP-2, MMP-3 and MMP-9. Therefore, it has been suggested that plasmin may be an important upstream regulator of extracellular proteolysis.
- plasmin has the ability to activate certain latent forms of growth factors. In vitro, plasmin can also hydrolyze components of the complement system and release chemotactic complement fragments.
- Pulminin is a very important enzyme present in the blood, which can hydrolyze fibrin clots into fibrin degradation products and D-dimers.
- “Plasminogen” is the zymogen form of plasmin. According to the sequence in swiss prot, it is composed of 810 amino acids and the molecular weight is about 90kD, a glycoprotein mainly synthesized in the liver and able to circulate in the blood. The cDNA sequence encoding this amino acid sequence is shown in sequence 3. The full-length plasminogen contains seven domains: a serine protease domain at the C-terminus, a Pan Apple (PAp) domain at the N-terminus, and five Kringle domains (Kringle1-5).
- PAp Pan Apple
- Kringle1 includes residues Cys103-Cys181
- Kringle2 includes residues Glu184-Cys262
- Kringle3 includes residues Cys275-Cys352
- Kringle4 Including residues Cys377-Cys454
- Kringle5 includes residues Cys481-Cys560.
- the serine protease domain includes residues Val581-Arg804.
- Glu-plasminogen is a natural full-length plasminogen consisting of 791 amino acids (without the signal peptide of 19 amino acids).
- the cDNA sequence encoding this sequence is shown in sequence 1, and its amino acid sequence is shown in sequence 2. Shown. In the body, there is also a Lys-plasminogen formed by hydrolysis from amino acids 76-77 of Glu-plasminogen. As shown in sequence 6, the cDNA sequence encoding this amino acid sequence is as shown in sequence 5. Shown.
- Delta-plasminogen is a fragment of the full-length plasminogen without the Kringle2-Kringle5 structure, and only contains Kringle1 and serine protease (structure) domain (also called proteolytic domain, or fiber The lysinogen protease domain), the amino acid sequence of delta-plasminogen (sequence 8) has been reported in the literature, and the cDNA sequence encoding this amino acid sequence is as sequence 7.
- Mini-plasminogen Mini-plasminogen is composed of Kringle5 and serine protease domain.
- Micro-plasminogen (Micro-plasminogen) only contains the serine protease domain, and it has been reported in the literature that its amino acid sequence includes residues Ala543-Asn791 (starting with the Glu residue of the Glu-plasminogen sequence without the signal peptide).
- CN102154253A also reported that its sequence includes residues Lys531-Asn791 (the Glu residue of the Glu-plasminogen sequence without the signal peptide is used as the starting amino acid).
- residues Lys531-Asn791 the Glu residue of the Glu-plasminogen sequence without the signal peptide is used as the starting amino acid.
- the amino acid sequence is shown in Sequence 12
- the cDNA sequence encoding the amino acid sequence is shown in Sequence 11.
- the meaning or activity of the "deficiency" of plasminogen means that the content of plasminogen in the subject is lower than that of a normal person, and is low enough to affect the normal physiological function of the subject;
- the meaning or activity of "deletion" of plasminogen is that the content of plasminogen in the subject is significantly lower than that of normal people, even the activity or expression is minimal, and normal physiological functions can only be maintained through external sources.
- plasminogen of the present invention covers both plasminogen and plasmin.
- plasminogen activator PA
- PA plasminogen activator
- the active plasmin can further hydrolyze the fibrin clot into fibrin degradation products and D-dimers, and then dissolve the thrombus.
- the PAp domain of plasminogen contains important determinants that maintain plasminogen in an inactive closed conformation, while the KR domain can bind to lysine residues present on the receptor and substrate.
- a variety of enzymes that can act as plasminogen activators are known, including: tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and coagulation factor XII (Hager Man factor) and so on.
- Plasminogen active fragments are included in this application: 1) In the plasminogen protein, active fragments capable of binding to the target sequence in the substrate, also known as lysine-binding fragments, such as Kringle 1, Fragments of Kringle 2, Kringle 3, Kringle 4, and/or Kringle 5 (for the plasminogen structure, see Aisina R B, Mukhametova L I. Structure and function of plasminogen/plasmin system [J].
- the plasminogen is a protein comprising the active fragment of plasminogen shown in SEQ ID NO: 14.
- the plasminogen is a protein comprising lysine binding fragments of Kringle 1, Kringle 2, Kringle 3, Kringle 4, and/or Kringle 5.
- the plasminogen active fragment of the present application comprises sequence 14, an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, 99% homology with sequence 14 Protein. Therefore, the plasminogen of the present invention includes a protein that contains the active fragment of the plasminogen and still maintains the activity of the plasminogen.
- the plasminogen of the present application includes Kringle 1, Kringle 2, Kringle 3, Kringle 4, and/or Kringle 5, or has at least 80 percent with Kringle 1, Kringle 2, Kringle 3, Kringle 4, or Kringle 5. Proteins with %, 90%, 95%, 96%, 97%, 98%, 99% homology and still have lysine binding activity.
- the methods for measuring plasminogen and its activity in blood include: the detection of tissue plasminogen activator activity (t-PAA), the detection of plasma tissue plasminogen activator antigen (t-PAAg), Detection of plasma tissue plasminogen activity (plgA), detection of plasma tissue plasminogen antigen (plgAg), detection of plasma tissue plasminogen activator inhibitor activity, plasma tissue plasminogen activator inhibition Detection of substance antigens, plasma plasmin-antiplasmin complex detection (PAP).
- t-PAA tissue plasminogen activator activity
- t-PAAg the detection of plasma tissue plasminogen activator antigen
- plgA Detection of plasma tissue plasminogen activity
- plgAg detection of plasma tissue plasminogen antigen
- PAP plasma tissue plasminogen activator inhibition
- the most commonly used detection method is the chromogenic substrate method: adding streptokinase (SK) and chromogenic substrate to the tested plasma, the PLG in the tested plasma is transformed into PLM under the action of SK, and the latter acts on The chromogenic substrate is subsequently measured with a spectrophotometer, and the increase in absorbance is proportional to the activity of plasminogen.
- SK streptokinase
- immunochemical methods, gel electrophoresis, immunoturbidimetry, radioimmuno-diffusion methods, etc. can also be used to determine the plasminogen activity in the blood.
- orthologs or orthologs refer to homologs between different species, including both protein homologs and DNA homologs, and are also called orthologs and vertical homologs. It specifically refers to proteins or genes in different species that evolved from the same ancestor gene.
- the plasminogen of the present invention includes human natural plasminogen, and also includes plasminogen orthologs or orthologs derived from different species that have plasminogen activity.
- Constant substitution variant refers to a given amino acid residue that changes but does not change the overall conformation and function of the protein or enzyme. This includes, but is not limited to, those with similar characteristics (such as acidic, basic, hydrophobic, etc.) Amino acids replace amino acids in the amino acid sequence of the parent protein. Amino acids with similar properties are well known. For example, arginine, histidine, and lysine are hydrophilic basic amino acids and can be interchanged. Similarly, isoleucine is a hydrophobic amino acid and can be replaced by leucine, methionine or valine. Therefore, the similarity of two proteins or amino acid sequences with similar functions may be different.
- Constant substitution variants also include polypeptides or enzymes that are determined by BLAST or FASTA algorithms to have more than 60% amino acid identity. If it can reach more than 75%, it is better, preferably more than 85%, or even more than 90%. It is the best, and has the same or substantially similar properties or functions compared with the natural or parent protein or enzyme.
- isolated plasminogen refers to plasminogen protein separated and/or recovered from its natural environment.
- the plasminogen will be purified (1) to a purity (by weight) greater than 90%, greater than 95%, or greater than 98%, as determined by the Lowry method, for example, greater than 99% (By weight), (2) to a degree sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by using a rotating cup sequence analyzer, or (3) to homogeneity, which is achieved by using Coomassie blue or silver staining is determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing or non-reducing conditions.
- the isolated plasminogen also includes plasminogen prepared from recombinant cells by bioengineering technology and separated by at least one purification step.
- polypeptide refers to polymerized forms of amino acids of any length, which can include genetically encoded and non-genetically encoded amino acids, chemically or biochemically modified or derived Modified amino acids, and polypeptides with modified peptide backbones.
- the term includes fusion proteins, including but not limited to fusion proteins with heterologous amino acid sequences, fusions with heterologous and homologous leader sequences (with or without an N-terminal methionine residue); and so on.
- the “percent amino acid sequence identity (%)" with respect to the reference polypeptide sequence is defined as when gaps are introduced when necessary to achieve the maximum percent sequence identity, and any conservative substitutions are not considered as part of the sequence identity, the candidate sequence is Refers to the percentage of amino acid residues that are identical to amino acid residues in the polypeptide sequence.
- the comparison for the purpose of determining percent amino acid sequence identity can be achieved in a variety of ways within the technical scope of the art, for example, using publicly available computer software, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for the alignment of the sequences, including any algorithm that achieves the maximum alignment requirements over the entire length of the sequence being compared. However, for the purposes of the present invention, the percent amino acid sequence identity value is generated using the sequence comparison computer program ALIGN-2.
- the% amino acid sequence identity of a given amino acid sequence A relative to a given amino acid sequence B (or can be expressed as having or containing relative to, with, or against a given amino acid sequence)
- a given amino acid sequence A) of a certain% amino acid sequence identity of B is calculated as follows:
- X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in the program's A and B alignment
- Y is the total number of amino acid residues in B. It should be appreciated that in the case where the length of the amino acid sequence A is not equal to the length of the amino acid sequence B, the% amino acid sequence identity of A relative to B may not be equal to the% amino acid sequence identity of B relative to A. Unless expressly stated otherwise, all% amino acid sequence identity values used herein are obtained using the ALIGN-2 computer program as described in the previous paragraph.
- mice rats, mice
- non-human primates humans
- dogs and cats
- Hoofed animals such as horses, cows, sheep, pigs, goats
- a “therapeutically effective amount” or “effective amount” refers to an amount of plasminogen sufficient to achieve the prevention and/or treatment of the disease when administered to a mammal or other subject to treat the disease.
- the “therapeutically effective amount” will vary depending on the plasminogen used, the severity of the disease and/or symptoms of the subject to be treated, age, weight, and the like.
- treatment of a disease state includes inhibiting or preventing the development of the disease state or its clinical symptoms, or alleviating the disease state or symptoms, so that the disease state or its clinical symptoms are temporarily or permanently regressed.
- muscle strength refers to the force of muscle contraction during voluntary movement of the limbs or the force of active muscle movement. According to the situation of muscle strength, muscle strength is usually divided into the following 0-5 grades: grade 0, completely paralyzed, muscle contraction cannot be measured; grade 1, only muscle contraction is measured, but no movement can be produced; grade 2, limb physical ability Move in parallel on the bed, but cannot resist its own gravity, that is, cannot lift off the bed; level 3, the limb can overcome gravity, can lift off the bed, but cannot resist resistance; level 4, the limb can do exercises against external resistance , But not complete; grade 5, normal muscle strength.
- muscle tone refers to the degree of tension of a muscle in a resting and relaxed state. Muscle tone is the basis for maintaining various postures and normal movements of the body. Muscle tension manifests in many forms. For example, when a person is lying and resting, the tension of various muscles of the body is called resting muscle tension. When the body is standing, although no significant muscle contraction is seen, the muscles in the front and back of the body also maintain a certain tension to maintain the standing posture and body stability, which is called postural muscle tension. The tension of muscles during exercise, called motor muscle tension, is an important factor to ensure continuous and smooth muscle movement (without tremor, twitching, or spasm). Under pathological conditions, muscle tension increases or decreases, which affects the normal posture or movement of the human body.
- Plasminogen can be isolated from nature and purified for further therapeutic use, or it can be synthesized by standard chemical peptide synthesis techniques. When a polypeptide is synthesized chemically, it can be synthesized via a liquid phase or a solid phase.
- Solid phase peptide synthesis (SPPS) (where the C-terminal amino acid of the sequence is attached to an insoluble support, followed by sequential addition of the remaining amino acids in the sequence) is a suitable method for the chemical synthesis of plasminogen.
- SPPS Solid phase peptide synthesis
- Various forms of SPPS, such as Fmoc and Boc can be used to synthesize plasminogen.
- the attached solid phase free N-terminal amine is coupled to a single N-protected amino acid unit. Then, the unit is deprotected, exposing a new N-terminal amine that can be attached to other amino acids.
- the peptide remains immobilized on the solid phase, after which it is cut off.
- Standard recombinant methods can be used to produce the plasminogen of the present invention.
- a nucleic acid encoding plasminogen is inserted into an expression vector so that it is operably linked to the regulatory sequence in the expression vector.
- Expression control sequences include, but are not limited to, promoters (such as naturally associated or heterologous promoters), signal sequences, enhancer elements, and transcription termination sequences.
- Expression control can be a eukaryotic promoter system in a vector that can transform or transfect eukaryotic host cells (such as COS or CHO cells). Once the vector is incorporated into a suitable host, the host is maintained under conditions suitable for high-level expression of the nucleotide sequence and collection and purification of plasminogen.
- Suitable expression vectors are usually replicated in the host organism as an episome or as an integrated part of the host chromosomal DNA.
- the expression vector contains a selection marker (for example, ampicillin resistance, hygromycin resistance, tetracycline resistance, kanamycin resistance, or neomycin resistance) to facilitate the transformation of the desired DNA sequence for exogenous use Those cells are tested.
- Escherichia coli is an example of a prokaryotic host cell that can be used to clone plasminogen-encoding polynucleotides.
- Other microbial hosts suitable for use include bacilli, such as Bacillus subtilis and other enterobacteriaceae, such as Salmonella, Serratia, and various pseudomonas. Genus (Pseudomonas) species.
- expression vectors can also be produced, which usually contain expression control sequences compatible with the host cell (for example, an origin of replication).
- promoters such as the lactose promoter system, the tryptophan (trp) promoter system, the beta-lactamase promoter system, or the promoter system from bacteriophage lambda. Promoters usually control expression, optionally in the case of manipulating gene sequences, and have ribosome binding site sequences, etc., to initiate and complete transcription and translation.
- yeast can also be used for expression.
- Yeast such as S. cerevisiae
- Pichia Pichia
- suitable yeast host cells in which suitable vectors have expression control sequences (such as promoters), origins of replication, termination sequences, etc., as required.
- suitable promoters include 3-phosphoglycerate kinase and other glycolytic enzymes.
- Inducible yeasts are initiated by specifically including promoters from alcohol dehydrogenase, isocytochrome C, and enzymes responsible for the utilization of maltose and galactose.
- mammalian cells e.g., mammalian cells cultured in an in vitro cell culture
- the plasminogen of the present invention e.g., a polynucleotide encoding plasminogen.
- Suitable mammalian host cells include CHO cell lines, various Cos cell lines, HeLa cells, myeloma cell lines, and transformed B cells or hybridomas.
- Expression vectors used in these cells may contain expression control sequences such as an origin of replication, promoters and enhancers (Queen et al., Immunol. Rev.
- ribosome binding Site RNA splice site
- polyadenylation site RNA splice site
- transcription terminator sequence RNA splice site
- suitable expression control sequences are promoters derived from white immunoglobulin gene, SV40, adenovirus, bovine papilloma virus, cytomegalovirus and the like. See Co et al., J. Immunol. 148:1149 (1992).
- Plasminogen is substantially pure, for example at least about 80% to 85% pure, at least about 85% to 90% pure, at least about 90% to 95% pure, or 98% to 99% pure Or purer, for example free of contaminants such as cell debris, macromolecules other than plasminogen, etc.
- a freeze-dried formulation can be formed by mixing plasminogen with the required purity with optional pharmaceutical carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A.ed. (1980)) Or aqueous solutions to prepare therapeutic formulations.
- Acceptable carriers, excipients, and stabilizers are non-toxic to recipients at the dose and concentration used, and include buffers such as phosphate, citrate and other organic acids; antioxidants include ascorbic acid and methionine; preservatives (such as Octadecyl dimethyl benzyl ammonium chloride; hexane diamine chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl p-hydroxybenzoic acid Esters such as methyl or propyl parabens; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight polypeptides (less than about 10 residues) ; Proteins such as serum albumin, gelatin or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine,
- the formulations of the present invention may also contain more than one active compound required for the specific condition to be treated, preferably those with complementary activities and no side effects between each other.
- active compound required for the specific condition to be treated, preferably those with complementary activities and no side effects between each other.
- the plasminogen of the present invention can be encapsulated in microcapsules prepared by techniques such as coacervation or interfacial polymerization, for example, can be placed in a colloidal drug delivery system (e.g., liposomes, albumin microspheres, microemulsions, Nanoparticles and nanocapsules) or placed in hydroxymethyl cellulose or gel-microcapsules and poly-(methyl methacrylate) microcapsules in a coarse emulsion.
- colloidal drug delivery system e.g., liposomes, albumin microspheres, microemulsions, Nanoparticles and nanocapsules
- hydroxymethyl cellulose or gel-microcapsules and poly-(methyl methacrylate) microcapsules in a coarse emulsion.
- the plasminogen of the present invention for in vivo administration must be sterile. This can be easily achieved by filtration through a sterile filter before or after freeze-drying and reformulation.
- the plasminogen of the present invention can be used to prepare sustained-release preparations.
- sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers having a certain shape and containing glycoproteins, such as films or microcapsules.
- sustained-release matrices include polyesters, hydrogels such as poly(2-hydroxyethyl-methacrylate) (Langer et al., J. Biomed. Mater.
- Polymers such as ethylene- Vinyl acetate and lactic-glycolic acid can continue to release molecules for more than 100 days, but some hydrogels release proteins for a short time.
- a reasonable strategy for stabilizing the protein can be designed according to the relevant mechanism. For example, if the mechanism of aggregation is found to be The formation of intermolecular SS bonds through the exchange of thiodisulfide bonds can be stabilized by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling humidity, using appropriate additives, and developing specific polymer matrix compositions .
- the administration of the pharmaceutical composition of the present invention can be achieved in different ways, such as intravenously, intraperitoneally, subcutaneously, intracranially, intrathecal, intraarterial (e.g. via carotid artery), intramuscular.
- Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
- non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, or fixed oils.
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, and so on. Preservatives and other additives may also be present, such as, for example, antimicrobial agents, antioxidants, chelating agents, and inert gases, among others.
- the dosage range of the pharmaceutical composition containing plasminogen of the present invention can be about 0.0001 to 2000 mg/kg, or about 0.001 to 500 mg/kg (for example, 0.02 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg per day). /kg, 10mg/kg, 50mg/kg, etc.) the weight of the subject.
- the dosage may be 1 mg/kg body weight or 50 mg/kg body weight or in the range of 1-50 mg/kg, or at least 1 mg/kg. Doses above or below this exemplified range are also covered, especially taking into account the factors mentioned above.
- the intermediate dose in the above range is also included in the scope of the present invention.
- the subject can administer such doses every day, every other day, every week, or according to any other schedule determined through empirical analysis.
- An exemplary dosage schedule includes 1-10 mg/kg for consecutive days. During the administration of the drug of the present invention, it is necessary to evaluate the therapeutic effect and safety in real time.
- One embodiment of the present invention relates to a product or a kit containing the plasminogen or plasmin of the present invention that can be used to treat cardiovascular diseases and related disorders caused by diabetes.
- the article preferably includes a container, label or package insert. Suitable containers are bottles, vials, syringes, etc.
- the container can be made of various materials such as glass or plastic.
- the container contains a composition that can effectively treat the disease or condition of the present invention and has a sterile access (for example, the container may be an intravenous solution pack or a vial, which contains a stopper that can be penetrated by a hypodermic injection needle of). At least one active agent in the composition is plasminogen/plasmin.
- the label on or attached to the container indicates that the composition is used for the treatment of cardiovascular disease and related disorders caused by diabetes according to the present invention.
- the preparation may further comprise a second container containing a pharmaceutically acceptable buffer, such as phosphate buffered saline, Ringer's solution, and dextrose solution. It may further contain other substances required from a commercial and user point of view, including other buffers, diluents, filters, needles and syringes.
- the article contains a package insert with instructions for use, including, for example, instructing the user of the composition to administer the plasminogen composition and other medications for the treatment of concomitant diseases to the patient.
- the human plasminogen used in all the following examples is derived from donor plasma, based on the method described in the literature [1-3] and optimized by the process, purified from human donor plasma, of which human Lys-plasminogen (Lys-plasminogen) and Glu-plasminogen (Glu-plasminogen)>98%.
- nebulized inhalation or intravenous injection All the patients in the following Examples 1-7 signed informed consent, voluntarily accepted the treatment of plasminogen purified from human plasma, and were approved by the hospital ethics committee. According to the severity and course of the disease, adjust the usage and dosage.
- the mode of administration is nebulized inhalation or intravenous injection.
- the drug concentration of nebulized inhalation and intravenous injection are both 5mg/ml, and physiological saline is used as the solvent.
- Intravenous injection 100-200 mg/time; frequency: once every 1 day, every 2 days or every 3 days; 2 weeks is a course of treatment; each course is 2-3 weeks apart. A total of 6 courses of treatment.
- the Hammersmith Functional Motor Scale (Expanded Hammersmith Functional Motor Scale, HFMSE) is specifically used to assess the motor function of patients with type II and type III SMA, reflecting the severity of the disease. It is defined compared to the change in the baseline, assessing the changes in the children's motor function, the higher the score, the better the motor function [4-6].
- Neuro-EMG examination is the main diagnosis and identification method of motor neuron disease.
- the amplitude of compound muscle action potential reflects neuronal axon damage.
- SMA is a motor neuron degenerative disease, a large number of motor neurons die, muscle weakness and compound muscle action potential amplitude is reduced or even undetectable [7].
- HFMSE score 20 points before medication, 21 points after the first course of treatment. For the second course of treatment, the score was 23 points before treatment and 24 points after treatment. After the 6th course of treatment, the score was 25 points.
- the patient Before treatment, the patient cannot stand without assistance. After 2 courses of treatment, the patient can assist standing. After 3 courses of treatment, the patient achieves assisted walking, and the patient's head control ability is significantly improved. As the treatment progresses, the patient's motor function is further improved, including the extension of the auxiliary standing time and the increase of the auxiliary walking distance.
- Electromyography The amplitude of the action potentials of the bilateral tibial nerve, common peroneal nerve and femoral nerve increased significantly after treatment compared with that before treatment ( Figure 1).
- plasminogen can improve the HFMSE score of patients with type II SMA, improve the patient's motor function, and improve the patient's neuromuscular function and mental state.
- the first time intravenous injection, 50mg
- the second time intravenous injection, 50mg
- the third and fourth time intravenous injection, 100mg.
- the frequency of medication is once every 2 days or once every 3 days, sharing the medicine for 2 weeks.
- the HFMSE score sheet before the medication is 2 points, and the HFMSE score is 8 points after the fourth medication.
- the patient can sit alone and raise his hands.
- the EMG results showed that the action potential amplitude of the left femoral nerve, right ulnar nerve, common peroneal nerve, and tibial nerve increased after treatment compared with before treatment ( Figure 2).
- plasminogen can improve the HFMSE score of patients with type II SMA, improve the patient's motor function, and improve the neuromuscular function, and there are no drug-related side effects during the treatment.
- Intravenous injection dose: 50mg-100mg each time; frequency: once every 1 day or once every 3 days; 2 weeks is a course of treatment, each course is 3-4 weeks apart, a total of 8 courses of treatment.
- HFMSE score 23 points before treatment, 24 points after the first course of treatment. There was an interval of approximately two months between the patient's first course of treatment and the second course of treatment. The second course of treatment is 23 minutes before treatment and 24 minutes after treatment. After the 8th course of treatment, the score was 28 points.
- Electromyography After treatment, the amplitude of the action potentials of the median nerve, tibial nerve, common peroneal nerve, and ulnar nerve increased to varying degrees (Figure 3).
- plasminogen can increase the HFMSE score of patients with type II SMA, improve the patient's motor function, and improve neuromuscular function.
- the first time intravenous injection, 50mg; the second time: intravenous injection, 50mg; the third time: intravenous injection, 100mg; the fourth time: intravenous injection, 150mg, each time interval of 3 days, medication for 2 weeks.
- the leg strength increased significantly, the breathing improved, the voice became louder, the pectus excavatum improved significantly, the signs of rib valgus improved, the strength of the arms and hands increased, but he could not grasp the adult's hand and was pulled up.
- the arm elevation has been degraded. Previously, the arm could be raised to the top of the head by itself, but it could only reach the face in the following treatments.
- the patient male, 11 months old, was diagnosed as type I SMA by genetic testing at 6 months; when the doctor was diagnosed, he informed that the average life cycle of patients with this type of disease was 2 years old, and the family did not take any treatment measures.
- Symptoms Weak head support; Weak upper limbs and arms, unable to lift, less swinging hands, weak grasping, weak middle finger; Weak lower limbs, less swinging, movable toes; unable to sit alone, involuntary turning over, low sucking power, difficulty swallowing , Perform blood oxygen monitoring 24 hours a day, the blood oxygen saturation is 92-97%, and the chest fluctuates weakly when breathing.
- the dose of nebulized inhalation is 5-10mg, and the dose of intravenous injection is 50-200mg.
- the CHOP INTEND scale (Children's Hospital of Philadelphia Infant Neuromuscular Disease Test Scale) was used to evaluate the improvement of motor function in patients with type I SMA. A higher score indicates better motor function [8].
- CHOP INTEND score Before treatment, the CHOP INTEND score was 30 points, and the score increased to 50 points after 5 courses of treatment. For some reasons, the interval between the 5th and 6th courses of treatment was about 2 months, and the score dropped to 36 points. After the 6th course of treatment, the score was 44 points. The interval between the 6th course of treatment and the 7th course of treatment is approximately 2 months. The 7th course of treatment is 44 minutes before medication and 45 minutes after medication. After the 10th course of treatment, the score was 46 points.
- Swallowing function After the medication, the patient's coughing frequency is reduced when eating and drinking, and the speech function is good.
- plasminogen can improve the CHOP INTEND score of patients with type I SMA, improve the patient’s motor function, and achieve a milestone improvement of 30 seconds of sitting without assisted support and 30 seconds of head support; it can also improve the patient’s swallowing function and Speaking ability; improve the patient's chest collapse signs, improve lung function, increase blood oxygen saturation; and improve the patient's mental state and sleep.
- the second course of treatment will be carried out 2 months after the end of the first course of treatment.
- the first course of treatment the time of hanging and shaking both hands is increased, the amplitude is increased, and the strength is increased.
- the left upper arm can move inward autonomously under the condition of supporting it.
- the lower limbs assisted with bending the knees and standing up for 30 minutes, the facial expressions increase, the eyes can be blinked, and the mouth can twitch spontaneously.
- Second course of treatment occasionally swallowing soup, sleep improvement
- the third course of treatment normal bowel movements, the head can be swayed left and right, with auxiliary support, the head can be raised for a few seconds.
- the wrist is slightly stronger, the fingertips can be rotated cyclically, and the left arm can be swayed autonomously for a greater range.
- the blood oxygen was maintained at 97%, and no oxygen was given.
- the fourth course of treatment the left arm has better coordination, the right arm has a small movement range, but the swing frequency is fast.
- the muscles of the lower limbs are soft and not stiff, the facial expressions increase, and they can defecate spontaneously.
- plasminogen can improve the motor function of patients with non-5q SMA, including increasing the strength, amplitude and range of limb movement, enriching the patient’s facial expression; improving the patient’s lung function and respiratory function, reducing oxygen transfusion, and increasing blood oxygen saturation To improve the patient’s swallowing function; to improve the patient’s sleep quality.
- Examples 8-15 are drug studies on animal models, and the plasminogen is still the above-mentioned plasminogen protein purified from human donor plasma.
- FVB.Cg-Grm7Tg(SMN2)89AhmbSmn1tm1MsdTg(SMN2*delta7)4299Ahmb/J gene mutant mice (hereinafter referred to as SMN ⁇ 7SMA mice) have homozygous mutations in the SMN1 gene and express the human SMN2 gene. The clinical and pathological manifestations of this mouse Similar to human SMA.
- the breeding rat was purchased from the Jackson Laboratory in the United States (pedigree number: 005025).
- mice SMN ⁇ 7 SMA mice were weighed at birth and randomly divided into vehicle group (6 mice) and drug group (5 mice) according to their body weight. The mice were administered 3 days after birth. The mice in the vehicle group were injected intraperitoneally with 6ml/kg of vehicle per day, and the mice in the administration group were injected with 60mg/kg intraperitoneally per day of plasminogen. Record the survival of the mice.
- mice Take out 7 SMN ⁇ 7 SMA mice 3 days old, 4 mice in the vehicle group, and give 6 ⁇ l bovine serum albumin solution (5mg/ml) by intraperitoneal injection every morning and afternoon every day for the first 9 days, starting from day 10, every day 6 ⁇ l bovine serum albumin solution (10mg/ml) was given by intraperitoneal injection once; 3 mice in the administration group were given plasminogen by 30 ⁇ g/6 ⁇ l intraperitoneal injection once a day in the morning and afternoon for the first 9 days, starting on the 10th day , Plasminogen was injected intraperitoneally at 60 ⁇ g/6 ⁇ l once a day; 4 wild-type mice were taken as blank control group, and 6 ⁇ l bovine serum albumin solution (5mg/ml ), starting from day 10, 6 ⁇ l bovine serum albumin solution (10mg/ml) was given by intraperitoneal injection once a day.
- 6 ⁇ l bovine serum albumin solution 5mg/ml
- mice On the 12th day, the mice were sacrificed and brain tissues were collected, brain tissue homogenates were prepared, and Western blot detection of NF- ⁇ B protein was performed.
- a 10% gel was prepared according to the gel preparation instructions of the SDS-PAGE gel preparation kit (Solarbio, P1320).
- the samples of each group were mixed with 4 ⁇ loading buffer (TaKaRa, e2139) at a volume ratio of 3:1, heated at 100°C for 5 minutes, cooled and centrifuged for 2 minutes, and then 20 ⁇ L was loaded.
- the electrophoresis conditions are 30V running gel for 30min, and then 100V electrophoresis to the bottom of the gel.
- the gel was stripped and transferred to an activated PVDF membrane (GE, A29433753).
- the electroporation conditions were 15V, 2.5h.
- the transferred PVDF membrane was immersed in a blocking solution (5% degreasing emulsion) and sealed overnight in a refrigerator at 4°C.
- TBST 0.01M Tris-NaCl, pH7.6 buffer
- rabbit anti-mouse NF- ⁇ B antibody (Cell Signaling Technology, 8242) was incubated at room temperature for 3 hours, TBST was washed 4 times, and goat anti-rabbit IgG (HRP) antibody (Abcam, ab6721) was added to incubate at room temperature for 1 hour.
- Nuclear factor kappa-B is a key nuclear transcription factor.
- the members of the NF- ⁇ B family mainly include RelA (p65), c-Rel, RelB, NF- ⁇ B1 (p50 protein and its precursor p105) and NF- ⁇ B2 (p52 protein and its precursor p100), each member can form homology Or a heterodimer to perform its function.
- the most common in mammalian cells is the combination of p65 and p50 to form a p65/p50 dimer.
- the NF- ⁇ B transcription factor binds to the inhibitor of kappa B (Inhibitor of kappa B) protein and is thus trapped in the cytoplasm.
- I ⁇ B protein The stimulation of the upstream signal causes I ⁇ B protein to be phosphorylated and modified under the action of IKK (I ⁇ B kinase), and then recognized by the ubiquitin ligase complex, which promotes the degradation of I ⁇ B protein in a proteasome-dependent manner, and NF- ⁇ B is released thereby , Enter the nucleus and initiate the expression of target genes [11].
- IKK I ⁇ B kinase
- NF- ⁇ B ubiquitin ligase complex
- NF- ⁇ B can be found in almost all animal cells. They participate in the cell's response to external stimuli, and play a key role in the cell's inflammatory response, immune response and other processes. NF- ⁇ B is also related to synaptic plasticity and memory [12].
- mice in the blank control group had a certain amount of NF- ⁇ B protein
- the levels of NF- ⁇ B protein in the brains of mice in the vehicle group were lower than those in the control group
- the levels of NF- ⁇ B protein in the brains of mice in the administration group were significantly higher than those in the control group.
- the muscles were obtained from the sacrificed mice in the foregoing Example 10, and the Western blot detection of NF- ⁇ B protein was performed according to the method described in the foregoing Example 10.
- Example 12 Plasminogen promotes the increase of SMN protein level in brain tissue of SMA model mice
- mice Two SMN ⁇ 7 SMA mice aged 3 days were taken out, one was in the vehicle group, and 6 ⁇ l bovine serum albumin solution (5mg/ml) was given by intraperitoneal injection every morning and afternoon; one was in the administration group. According to 30 ⁇ g/6 ⁇ l intraperitoneal injection once a day in the morning and afternoon to give plasminogen; take 2 wild-type (FVB) mice as a blank control group, intraperitoneal injection once a day in the morning and afternoon to give 6 ⁇ l bovine serum albumin solution ( 5mg/ml). After 9 days of treatment, the mice were sacrificed and brain tissues were collected, and brain tissue homogenates were prepared for Western blot detection of SMN protein.
- 6 ⁇ l bovine serum albumin solution 5mg/ml
- mice The hind limb muscle tissues of the sacrificed mice were obtained as described in Example 12, and a tissue homogenate was prepared for Western blot detection of SMN protein. The detection method was as described in Example 12.
- Brain tissues were taken from the sacrificed mice in Example 12, tissue homogenates were prepared, and Western blot detection of NGF protein was performed.
- the samples of each group were mixed with 4 ⁇ loading buffer (TaKaRa, e2139) at a volume ratio of 3:1, heated at 100°C for 5 minutes, cooled and centrifuged for 2 minutes, and then 20 ⁇ L was loaded.
- the electrophoresis conditions were 30V running for 30min, and then 100V electrophoresis to the bottom of the gel. After the electrophoresis, the gel was stripped and transferred to an activated PVDF membrane (GE, A29433753).
- the electroporation conditions were 15V, 2.5h.
- the transferred PVDF membrane is soaked in a blocking solution (5% degreasing emulsion) and sealed overnight in a refrigerator at 4°C. After washing 4 times with TBST (0.01M Tris-NaCl, pH7.6 buffer), add rabbit anti-mouse NGF antibody Incubate at room temperature for 3 hours. After washing 4 times with TBST, add goat anti-rabbit IgG (HRP) antibody (Abcam, ab6721) and incubate at room temperature for 1 hour.
- TBST 0.01M Tris-NaCl, pH7.6 buffer
- Immobilon Western HRP Substrate develops color, takes pictures under a biomolecular imager and uses Image J software to obtain the optical density value of each band for quantitative analysis.
- Lung tissues were taken from the sacrificed mice in Example 12 and fixed in 10% neutral formalin fixative for 24 hours.
- the fixed lung tissue was dehydrated by alcohol gradient and transparent with xylene before embedding in paraffin.
- the thickness of the tissue section was 5 ⁇ m.
- the section was deparaffinized and rehydrated and stained with hematoxylin and eosin (H&E staining), differentiated with 1% hydrochloric acid and alcohol, turned blue with ammonia, and mounted with alcohol gradient dehydration. The section was observed under a microscope at 200 times.
- the terminal bronchiole epithelial cells in the lung tissue of the blank control group were neatly arranged and clearly distinguishable; the alveolar cavity was uniform in size, the alveolar compartment was not thickened, and there was no inflammatory cell infiltration around the blood vessels; the lung tissue of the vehicle group was breathing Bronchiolar epithelium is shed, alveolar ducts and alveolar sacs are enlarged, alveolar septums are widened, alveoli collapse to structural disorders, and pulmonary blood vessels are surrounded by eosinophils, foam cells, and lymphocytes; respiratory bronchioles in lung tissue of mice in the administration group
- the epithelium is arranged in an orderly manner, the alveolar ducts and alveolar sacs are enlarged, and the alveolar cavity is evenly enlarged, but the alveolar wall composed of a single layer of alveolar epithelium can be seen (Figure 11). It is suggested that plasminogen can improve lung tissue damage in SMA model mice.
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Claims (15)
- 一种治疗脊髓性肌萎缩症(SMA)的方法,包括给药患脊髓性肌萎缩症(SMA)的受试者治疗有效量的纤溶酶原途径激活剂。
- 权利要求1的方法,其中所述纤溶酶原途径激活剂促进SMN基因的转录和/或表达。
- 权利要求1或2的方法,其中所述纤溶酶原途径激活剂改善受试者的肌力。
- 权利要求1-3任一项的方法,其中所述纤溶酶原途径激活剂延长受试者生存期。
- 权利要求1-4任一项的方法,其中所述纤溶酶原途径激活剂改善受试者的肌张力。
- 权利要求1-6任一项的方法,其中所述纤溶酶原途径激活剂促进受试者生长发育。
- 权利要求1-7任一项的方法,其中所述纤溶酶原途径激活剂与一种或多种其它药物或治疗方法联合施用。
- 权利要求1-8任一项的方法,其中所述纤溶酶原途径激活剂通过静脉内、肌肉内、鞘内、鼻腔吸入、雾化吸入、滴鼻液或滴眼液形式给药。
- 权利要求1-9任一项的方法,其中所述纤溶酶原途径激活剂为纤溶酶原激活途径的组分。
- 权利要求1-10任一项的方法,所述纤溶酶原途径激活剂为纤溶酶原。
- 权利要求11的方法,其中所述纤溶酶原包含与序列2、6、8、10或12所示氨基酸序列具有至少80%、85%、90%、95%、96%、97%、98%或99%的序列同一性的氨基酸序列,并且具有纤溶酶原活性。
- 权利要求11的方法,所述纤溶酶原为包含纤溶酶原活性片段、并且具有纤溶酶原活性的蛋白质。
- 权利要求11的方法,所述纤溶酶原选自Glu-纤溶酶原、Lys-纤溶酶原、小纤溶酶原、微纤溶酶原、delta-纤溶酶原或它们的保留纤溶酶原活 性的变体。
- 权利要求11的方法,所述纤溶酶原包含序列2、6、8、10或12所示氨基酸序列。
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TW202142256A (zh) | 2021-11-16 |
TWI811675B (zh) | 2023-08-11 |
JP2023525256A (ja) | 2023-06-15 |
CA3182911A1 (en) | 2021-11-18 |
US20230190891A1 (en) | 2023-06-22 |
WO2021228086A1 (zh) | 2021-11-18 |
EP4140498A4 (en) | 2023-11-01 |
KR20230004752A (ko) | 2023-01-06 |
JP2023525257A (ja) | 2023-06-15 |
EP4144364A4 (en) | 2023-11-22 |
CN115697385A (zh) | 2023-02-03 |
CA3183106A1 (en) | 2021-11-18 |
CN115551535A (zh) | 2022-12-30 |
TW202200192A (zh) | 2022-01-01 |
EP4144364A1 (en) | 2023-03-08 |
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EP4140498A1 (en) | 2023-03-01 |
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