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Preparation method and application of a mitochondrial gene therapy vector mi-linker-u-binding

A mitochondria and carrier technology, applied in gene therapy, medical preparations with inactive ingredients, pharmaceutical formulations, etc., can solve the problems of low efficiency, high price, and high immunogenicity, and achieve the effect of avoiding low efficiency

Active Publication Date: 2022-07-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since LHON is caused by mutations in mtDNA, and ordinary gene carriers cannot pass through the mitochondrial double membrane structure, the current gene therapy for LHON is mainly achieved through ectopic expression of viral vectors such as adeno-associated virus. The strategy has problems such as low efficiency, high immunogenicity, and high price

Method used

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  • Preparation method and application of a mitochondrial gene therapy vector mi-linker-u-binding
  • Preparation method and application of a mitochondrial gene therapy vector mi-linker-u-binding
  • Preparation method and application of a mitochondrial gene therapy vector mi-linker-u-binding

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] The preparation scheme of the mitochondrial targeting vector is as follows:

[0061] (1) Synthesis of SUH: The thioketal bond, undecafluorohexylamine and histamine were dissolved in anhydrous dimethyl sulfoxide in a molar ratio of 1.2:0.2:0.8, and the reaction was carried out under the condition of an oil bath at 90 °C 48h to obtain SUH at the end of the double bond; then, take out half of the volume of SUH and set aside, add 37 μL of capping molecule 122 to the remaining half volume of SUH, react at 40°C for 24h, and finally obtain the amino terminal by ether precipitation SUH;

[0062] (2) Synthesis of TPP-SUH: The activated mitochondrial targeting group TPP and the amino-terminal SUH are mixed and stirred, and reacted at a temperature of 25°C-35°C for 24 hours, and then TPP-SUH is obtained;

[0063] (3) Synthesis of Ide-SUH: add 5 times the molar amount of idebenone to the SUH on hold; react at 40°C for 24h to obtain Ide-SUH;

[0064] (4), the preparation of TISUH:...

Embodiment 2

[0066] The structures of SUH, TPP-SUH and Ide-SUH were identified by hydrogen NMR spectroscopy, and the results were as follows figure 1 shown.

Embodiment 3

[0068] The mitochondrial gene therapy vectors SUH, TPP-SUH and Ide-SUH synthesized according to Example 1 were tested for their ability to bind to genes. The synthetic material was diluted to 0.2μg / μL, 0.4μg / μL, 1μg / μL, 2μg / μL and 4μg / μL, and incubated with 2μL (0.2μg / μL) gene solution for 30min, and finally the material was detected by gel electrophoresis Binding ability to genes. The experimental results are as figure 2 shown.

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Abstract

The invention discloses a preparation method and application of a mitochondrial gene therapy carrier MI-linker-U-binding. The invention belongs to the technical field of pharmaceutical preparations. The present invention enters the mitochondrial matrix through the mitochondrial targeting group and the penetrating ability of the fluorinated material membrane, and releases functional genes and therapeutic drugs Ide in response to the high ROS level of the diseased mitochondria, so as to achieve the treatment of mitochondrial gene mutation-related diseases (such as: LHON) specimens In addition, the present invention avoids the problems of low efficiency, high immunogenicity, high price and the like of the current viral vector-mediated ectopic expression system, and the vector can efficiently deliver functional genes and drugs into the mitochondrial matrix, so as to achieve both symptoms and symptoms of LHON. The mitochondrial gene therapy vector can also be used for diseases caused by other mitochondrial gene mutations, such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like seizure syndrome (MELAS), myoclonic epilepsy and irregular erythrofibrosis (MERRF) et al.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a co-delivery system of a mitochondrial targeted drug and a functional gene, so as to achieve the purpose of treating both the symptoms and root causes of diseases related to mitochondrial gene mutation. Background technique [0002] Leber Hereditary Optic Neuropathy (LHON) is a rare disease caused by mitochondrial DNA (mtDNA) mutation, and it is also one of the most common diseases that cause blindness in young adults in the world. LHON is more common in young and middle-aged men, with an average age of onset of 24 years. Once the disease occurs, the main symptoms of patients are acute vision loss or loss within a few weeks, and this vision damage is difficult to recover, which not only brings great pain to the patient, but also causes a very heavy burden to the family and society. Because the disease is harmful and there is no effective treatmen...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/34A61K48/00A61P27/02A61P25/00A61P25/08C08G69/42
CPCA61K47/34A61K48/005A61P27/02A61P25/00A61P25/08C08G69/42
Inventor 姜虎林王译胡力凡邢磊
Owner CHINA PHARM UNIV