-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
Loss of iNature dystrophin (dystrophin) can lead to Duchenne muscular dystrophy (DMD), which is characterized by progressive degeneration of the heart and skeletal muscle, and mortality in adolescence or young adults
.
Although heart failure has become the leading cause of death in DMD patients, effective therapeutic interventions are still incomplete, partly due to the lack of suitable preclinical models
.
On October 26, 2021, the Changxing team of West Lake University published a research paper entitled "Therapeutic Exon Skipping via a CRISPR-guided Cytidine Deaminase Rescues Dystrophic Cardiomyopathy In Vivo" in Circulation (IF=30) online.
The deletion was introduced into exon 4 to create a new type of DMD mouse model, which is one of the exons encoding dystrophin actin binding domain 1 (called Dmd E4* mice)
.
AAV9-based CRISPR/Cas9-AID (eTAM) and AAV9-sgRNA were injected into newborn Dmd E4* mice, and they were analyzed 2 or 12 months after treatment to assess exon skipping, The degree of dystrophin recovery and improvement of myocardial and skeletal muscle phenotype
.
Dmd E4* mice reproduce many aspects of human DMD, including shortened lifespan (approximately 50%), progressive cardiomyopathy, kyphosis, severe loss of muscle strength, and muscle cell degeneration
.
A single dose of AAV9-eTAM produced more than 50% of targeted exon skipping in Dmd transcripts and restored up to 90% of dystrophin in the heart
.
As a result, early ventricular remodeling was prevented and heart and skeletal muscle function was improved, thereby prolonging the lifespan of Dmd E4* mice
.
Although the expression of AAV vectors and base editors gradually declined, the recovery of dystrophin and the pathophysiological rescue of muscular dystrophy lasted for at least one year
.
Duchenne muscular dystrophy (DMD) is the most serious form of muscular dystrophy, affecting 1 in 3,500 to 5,000 boys at birth globally
.
Due to the loss of dystrophin encoded by the DMD gene on chromosome Xp21, the patient's skeletal muscle and cardiac muscle gradually atrophy
.
With the improvement of respiratory support in DMD patients, heart failure has become the main cause of morbidity and death
.
As early as 6-10 years old, the heart of DMD patients showed abnormal electrocardiogram, and they often progressed to dilated cardiomyopathy and heart failure in their 20s, and no therapeutic intervention was available
.
Most of the mutations found in the DMD gene disrupt its reading frame, resulting in the complete loss of dystrophin, which is essential for maintaining the integrity of muscle cells
.
At the same time, early observations of in-frame mutations in the DMD gene lead to less severe Becker muscular dystrophy (BMD), which inspired the treatment of restoring the open reading frame (ORF) through exon skipping, which can be achieved through antisense oligomerism.
Nucleotide (ASO) or CRISPR technology is implemented
.
Dystrophin (427-kDa) consists of the N-terminal actin binding domain (ABD) that anchors the protein to the cytoskeleton, the central rod domain, and the cysteine-rich b-actin glycan.
Domain and C-terminal domain
.
In the DMD animal model carrying various mutations in the central rod domain, the application of the above technology shows that the truncated dystrophin protein lacking part of the rod domain has the function of repairing skeletal muscle defects in vivo
.
However, whether this remodeling strategy can ameliorate the fatal cardiomyopathy associated with DMD is still largely uncertain, because so far, no murine model can summarize the genetic and cardiological characteristics observed in patients.
.
The most commonly used animal model of DMD (mdx mouse) has a nonsense point mutation in exon 23, and only a slight cardiac phenotype appears at the end of the life of the mouse
.
When combined with other genetic defects, mdx mice show more severe cardiac dysfunction, however, this is inconsistent with human Duchenne genetics (only DMD mutations)
.
In order to test the feasibility and effectiveness of TAM-based therapy, the study constructed a new preclinical model of DMD, which produced a frameshift deletion of exon 4 of the Dmd gene, called Dmd E4* mice
.
Compared with the widely used mdx model, the Dmd E4* model is similar to the progression of cardiology observed in human DMD
.
Single-dose treatment of newborn mice can restore dystrophin, prevent deterioration of heart function and extend the lifespan of Dmd E4* mice
.
Therefore, this study proved the feasibility and effectiveness of using CRISPR-guided cytidine deaminase as a therapeutic strategy to "install" beneficial splicing changes to treat human diseases (such as DMD)
.
Reference message: https://
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
Loss of iNature dystrophin (dystrophin) can lead to Duchenne muscular dystrophy (DMD), which is characterized by progressive degeneration of the heart and skeletal muscle, and mortality in adolescence or young adults
.
Although heart failure has become the leading cause of death in DMD patients, effective therapeutic interventions are still incomplete, partly due to the lack of suitable preclinical models
.
On October 26, 2021, the Changxing team of West Lake University published a research paper entitled "Therapeutic Exon Skipping via a CRISPR-guided Cytidine Deaminase Rescues Dystrophic Cardiomyopathy In Vivo" in Circulation (IF=30) online.
The deletion was introduced into exon 4 to create a new type of DMD mouse model, which is one of the exons encoding dystrophin actin binding domain 1 (called Dmd E4* mice)
.
AAV9-based CRISPR/Cas9-AID (eTAM) and AAV9-sgRNA were injected into newborn Dmd E4* mice, and they were analyzed 2 or 12 months after treatment to assess exon skipping, The degree of dystrophin recovery and improvement of myocardial and skeletal muscle phenotype
.
Dmd E4* mice reproduce many aspects of human DMD, including shortened lifespan (approximately 50%), progressive cardiomyopathy, kyphosis, severe loss of muscle strength, and muscle cell degeneration
.
A single dose of AAV9-eTAM produced more than 50% of targeted exon skipping in Dmd transcripts and restored up to 90% of dystrophin in the heart
.
As a result, early ventricular remodeling was prevented and heart and skeletal muscle function was improved, thereby prolonging the lifespan of Dmd E4* mice
.
Although the expression of AAV vectors and base editors gradually declined, the recovery of dystrophin and the pathophysiological rescue of muscular dystrophy lasted for at least one year
.
Duchenne muscular dystrophy (DMD) is the most serious form of muscular dystrophy, affecting 1 in 3,500 to 5,000 boys at birth globally
.
Due to the loss of dystrophin encoded by the DMD gene on chromosome Xp21, the patient's skeletal muscle and cardiac muscle gradually atrophy
.
With the improvement of respiratory support in DMD patients, heart failure has become the main cause of morbidity and death
.
As early as 6-10 years old, the heart of DMD patients showed abnormal electrocardiogram, and they often progressed to dilated cardiomyopathy and heart failure in their 20s, and no therapeutic intervention was available
.
Most of the mutations found in the DMD gene disrupt its reading frame, resulting in the complete loss of dystrophin, which is essential for maintaining the integrity of muscle cells
.
At the same time, early observations of in-frame mutations in the DMD gene lead to less severe Becker muscular dystrophy (BMD), which inspired the treatment of restoring the open reading frame (ORF) through exon skipping, which can be achieved through antisense oligomerism.
Nucleotide (ASO) or CRISPR technology is implemented
.
Dystrophin (427-kDa) consists of the N-terminal actin binding domain (ABD) that anchors the protein to the cytoskeleton, the central rod domain, and the cysteine-rich b-actin glycan.
Domain and C-terminal domain
.
In the DMD animal model carrying various mutations in the central rod domain, the application of the above technology shows that the truncated dystrophin protein lacking part of the rod domain has the function of repairing skeletal muscle defects in vivo
.
However, whether this remodeling strategy can ameliorate the fatal cardiomyopathy associated with DMD is still largely uncertain, because so far, no murine model can summarize the genetic and cardiological characteristics observed in patients.
.
The most commonly used animal model of DMD (mdx mouse) has a nonsense point mutation in exon 23, and only a slight cardiac phenotype appears at the end of the life of the mouse
.
When combined with other genetic defects, mdx mice show more severe cardiac dysfunction, however, this is inconsistent with human Duchenne genetics (only DMD mutations)
.
In order to test the feasibility and effectiveness of TAM-based therapy, the study constructed a new preclinical model of DMD, which produced a frameshift deletion of exon 4 of the Dmd gene, called Dmd E4* mice
.
Compared with the widely used mdx model, the Dmd E4* model is similar to the progression of cardiology observed in human DMD
.
Single-dose treatment of newborn mice can restore dystrophin, prevent deterioration of heart function and extend the lifespan of Dmd E4* mice
.
Therefore, this study proved the feasibility and effectiveness of using CRISPR-guided cytidine deaminase as a therapeutic strategy to "install" beneficial splicing changes to treat human diseases (such as DMD)
.
Reference message: https://