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CN-121550436-B - Composition and combination mode

CN121550436BCN 121550436 BCN121550436 BCN 121550436BCN-121550436-B

Abstract

The invention belongs to the technical field of biological medicines, and relates to application of a new target spot in epilepsia related to tuberous sclerosis, a composition and a combined medication mode. The invention proves that when the combination of the high-dose SLC6A1 inhibitor, the medium-dose GAD1 function enhancer and the low-dose SLC1A2 activator is adopted, the average epileptic seizure frequency of experimental animals is lower than that of a combined administration group with the same dose or close to the same dose, and is also lower than that of a single-drug experimental group, and the effectiveness of the combination of SLC6A1 serving as a core and GAD1 and SLC1A2 serving as synergistic targets is proved.

Inventors

  • CHEN LEI
  • LI WANLING

Assignees

  • 四川大学华西医院

Dates

Publication Date
20260512
Application Date
20260123

Claims (3)

  1. 1. A pharmaceutical composition for targeted treatment of tuberous sclerosis-related epilepsy, wherein the pharmaceutical composition comprises an SLC6A1 inhibitor, a GAD1 function enhancer, and an SLC1A2 activator; The SLC6A1 inhibitor is tiagabine; The GAD1 function enhancer is vitamin B6; the SLC1A2 activator is ceftriaxone sodium; The dosage ratio of the SLC6A1 inhibitor, the GAD1 function enhancer and the SLC1A2 activator is 3:2:1, 4:2:1 or 5:3:1.
  2. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises other pharmaceutically acceptable excipients.
  3. 3. The application of the drug combination in preparing the drug for targeted treatment of the epilepsia related to the tuberous sclerosis is characterized in that the drug combination is combination of an SLC6A1 inhibitor, a GAD1 function enhancer and an SLC1A2 activator, wherein the SLC6A1 inhibitor is tiagabine, the GAD1 function enhancer is vitamin B6, the SLC1A2 activator is ceftriaxone sodium, and the dosage ratio of the SLC6A1 inhibitor, the GAD1 function enhancer and the SLC1A2 activator is 3:2:1, 4:2:1 or 5:3:1.

Description

Composition and combination mode Technical Field The invention belongs to the technical field of biological medicines, relates to application of a new target spot in epilepsia related to tuberous sclerosis, a composition and a combined medication mode, and in particular relates to new application of SLC6A1, GAD1 and SLC1A2 genes as potential treatment targets of epilepsia related to tuberous sclerosis, and a composition and a combined medication mode based on the target spot. Background Tuberous sclerosis (Tuberous sclerosis complex, TSC) is an autosomal dominant inherited rare disease in which mutations in the TSC1 or TSC2 genes cause aberrant activation of mTOR signaling pathways, epilepsy being the most common neurological manifestation of TSC. TSC-related seizures often occur early and frequently, more likely resulting in delayed neurological development and cognitive dysfunction in the patient. The pathogenesis of TSC-related epilepsy is closely related to abnormal activation of the mTOR pathway, ultimately leading to high excitation and abnormal discharge of the cerebral cortex network, leading to seizures. MTOR inhibitors (e.g., sirolimus, everolimus) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of TSC-related epilepsy, but have significant limitations in clinical application, namely, the response rate of therapeutic effects is low, only about 40% of TSC patients are effectively controlled after receiving treatment, the individual differences in therapeutic effects among different patients are significant, the safety risk is prominent, the drugs may cause adverse reactions such as immunosuppression, metabolic disorders, stomatitis, and the like, and in addition, the drugs directly act on cell proliferation and growth regulation pathways, so that the long-term administration of infants will significantly increase the risk of tumorigenesis, and the long-term application of the infants in low-age patient groups is limited. In addition, traditional antiepileptic drugs (e.g., levetiracetam, oxcarbazepine) are often directed against neurotransmitter receptors or ion channels, and about 70% of patients are not treated with drugs, and develop drug-refractory epilepsy (the refractory ratio is twice that of normal epilepsy). Furthermore, prior art studies on mTOR pathway inhibitors, mostly single-target interventions, have not yet formed synergistic regulatory strategies for the "neurotransmitter synthesis-transport-clearance" full chain. In summary, the exploration of new targets for epilepsy related to Tuberous Sclerosis (TSC), the development of new drugs or new drug combination methods, is an urgent need in the current field of TSC-related epilepsy treatment. Disclosure of Invention The invention aims to provide a novel strategy for treating epilepsy related to tuberous sclerosis based on multi-target synergism, so as to partially solve or relieve the problems of limited curative effect, large side effect, insufficient control on refractory epilepsy and the like of a single-target medicament in the prior art. The invention aims to more comprehensively and effectively restore the excitation-inhibition balance of the central nervous system by simultaneously targeting the SLC6A1 gene, the GAD1 gene and the SLC1A2 gene to synergistically regulate the steady state and the glutamate clearance capacity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), thereby controlling epileptic seizure. The invention adopts the following technical scheme. In one aspect, the invention provides the use of the SLC6A1 gene, the GAD1 gene and the SLC1A2 gene as combined markers in the preparation of a medicament or a reagent for treating epilepsy related to Tuberous Sclerosis (TSC). Further, the combination marker is used for the development of a medicament or agent indicative of the tuberous sclerosis-related epilepsy. Through simultaneous targeting of SLC6A1 gene, GAD1 gene and SLC1A2 gene, GABA synthesis, transport and glutamic acid removal can be simultaneously interfered, a synergistic antiepileptic effect is generated, and the method has great value for guiding development of novel antiepileptic drugs. In another aspect, the invention provides novel target compositions that target TSC-related epilepsy. A marker combination targeting a tuberous sclerosis-related epilepsy, the marker combination being a combination of a SLC6A1 gene, a GAD1 gene and a SLC1A2 gene. In another aspect, the invention provides compositions and combinations for targeted treatment of TSC-related epilepsy. A pharmaceutical composition targeted for the treatment of tuberous sclerosis-related epilepsy, the pharmaceutical composition comprising an SLC6A1 inhibitor, a GAD1 function enhancer, and an SLC1A2 activator. Further, the SLC6A1 inhibitor is a GAT-1 selective inhibitor. Further, the GAD1 function enhancer includes pyridoxal phosphate (PLP) and precursor compounds thereof. The precursor compounds