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Written byWang Cong
EditorWang Duoyu
TypesettingShui Chengwen
Duchenne muscular dystrophy (DMD) is a single-gene disease with a relatively high incidence, Mutations in the gene encoding dystrophin on the X chromosome, resulting in the inability to produce enough dystrophin, the patient's muscle tissue is gradually replaced by fat and fibrotic tissue, and about 1 in 5,000 newborn male babies is affected
.
In recent years, several antisense oligonucleotide (ASO) drugs for the treatment of DMD have been approved for marketing to achieve therapeutic goals through exon skipping, but these drugs can only cover DMD patients
with a few specific mutation sites.
In addition to the exon skipping method, gene substitution is a better option, however, the Dystrophin gene is very large, with up to 79 exons and transcripts up to 14 kb, far beyond the loading limit of viral delivery vectors.
Therefore, therapeutic approaches that deliver the correctly encoded Dystrophin gene directly do not work
.
To solve this puzzle, a miniature Dystrophin gene has been developed that is still functional and small enough to be delivered
using AAV viral vectors.
Recently, researchers from Texas A&M University, the University of Florida, and Solid Biosciences published a report in the journal Science Translational Medicine titled Research paper of Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy.
The study showed that AAV-delivered microtype Dystrophin gene improved symptoms in the Golden Retriever Canine Muscular Dystrophy (GRMD) model without serious adverse events
。 This suggests that administration of Dystrophin protein through the AAV system may be a safe gene therapy
that provides therapeutic benefits to DMD patients.
Studies of DMD are usually conducted on mouse models of DMD, but in large animals such as Golden Retriever Muscular Dystrophy (GRMD) The model's findings are more easily translated to humans
.
In this study, the research team used adeno-associated virus type 9 (AAV9) to deliver the micro-Dystrophin gene (μDys5) in Golden Retriever canine muscular dystrophy (GRMD) model has undergone preclinical studies
.
The 12 GRMD dogs were randomly divided into four groups - control group, 1×10E13vg/kg dose group, 1×10E14vg/kg dose group, and 2 × 10E13vg/kg dose group, 3 in
each group.
The dogs were injected with the microscopic Dystrophin gene by intravenous injection of AAV9 when they were 3 months old (μDys5) and followed up for 90 days
after administration.
All dogs received prednisone (1 mg/kg, a hormone therapy for DMD) for a total of 5 weeks
from day 7 to day 28.
It is worth mentioning that in previous gene therapy studies, CMV promoters were often used to initiate the expression of the gene of interest , but CMV promoters may initiate higher levels of expression in non-muscle tissue and generate associated immune responses
.
To reduce the immune response to the miniature Dystrophin protein, the study provided a proof of concept showing that using a muscle-specific promoter, the expression of the micro-Dystrophin protein was initiated only in muscle tissue, and the results showed that GRMD dogs exhibited protein expression
for 8 weeks in the absence of immunosuppression.
The results showed that the genome copy number in the tissues of the treated dogs increased dose-dependently, μDys5 protein was expressed in muscle tissue and heart, the limb and respiratory muscle functions of dogs were improved, and histopathological lesions were reduced
.
As expected, phenotypic and histopathological lesions did not fully return to normal
due to the expression of the micro-Dystrophin protein.
In addition, different dose groups were well tolerated with no adverse events
.
These data suggest that the micro-Dystrophin protein delivered by systematic administration of AAV is safe and offers therapeutic benefits
for DMD patients.
Currently, there are four DMD clinical trials underway for AAV delivery of micro-Dystrophin proteins, from Pfizer, Sarepta, Genethon, and Solid Biosciences, a participant in the paper.
Solid conducted a clinical trial SGT-001 for the treatment of DMD in 2017 to evaluate its safety, tolerability, and efficacy
in adolescents and children with Duchenne muscular dystrophy (DMD).
But the clinical trial was ill-fated and was twice suspended
by the FDA due to safety concerns.
The related clinical trials of the other three companies have also had serious safety problems
.
Thesis.
Link: style="color: rgb(136, 136, 136);font-size: 12px;letter-spacing: normal;" _mstmutation="1" _istranslated="1">
Open reprint, welcome to forward to Moments and WeChat groups
EditorWang Duoyu
TypesettingShui Chengwen
Duchenne muscular dystrophy (DMD) is a single-gene disease with a relatively high incidence, Mutations in the gene encoding dystrophin on the X chromosome, resulting in the inability to produce enough dystrophin, the patient's muscle tissue is gradually replaced by fat and fibrotic tissue, and about 1 in 5,000 newborn male babies is affected
.
In recent years, several antisense oligonucleotide (ASO) drugs for the treatment of DMD have been approved for marketing to achieve therapeutic goals through exon skipping, but these drugs can only cover DMD patients
with a few specific mutation sites.
In addition to the exon skipping method, gene substitution is a better option, however, the Dystrophin gene is very large, with up to 79 exons and transcripts up to 14 kb, far beyond the loading limit of viral delivery vectors.
Therefore, therapeutic approaches that deliver the correctly encoded Dystrophin gene directly do not work
.
To solve this puzzle, a miniature Dystrophin gene has been developed that is still functional and small enough to be delivered
using AAV viral vectors.
Recently, researchers from Texas A&M University, the University of Florida, and Solid Biosciences published a report in the journal Science Translational Medicine titled Research paper of Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy.
The study showed that AAV-delivered microtype Dystrophin gene improved symptoms in the Golden Retriever Canine Muscular Dystrophy (GRMD) model without serious adverse events
。 This suggests that administration of Dystrophin protein through the AAV system may be a safe gene therapy
that provides therapeutic benefits to DMD patients.
Studies of DMD are usually conducted on mouse models of DMD, but in large animals such as Golden Retriever Muscular Dystrophy (GRMD) The model's findings are more easily translated to humans
.
In this study, the research team used adeno-associated virus type 9 (AAV9) to deliver the micro-Dystrophin gene (μDys5) in Golden Retriever canine muscular dystrophy (GRMD) model has undergone preclinical studies
.
The 12 GRMD dogs were randomly divided into four groups - control group, 1×10E13vg/kg dose group, 1×10E14vg/kg dose group, and 2 × 10E13vg/kg dose group, 3 in
each group.
The dogs were injected with the microscopic Dystrophin gene by intravenous injection of AAV9 when they were 3 months old (μDys5) and followed up for 90 days
after administration.
All dogs received prednisone (1 mg/kg, a hormone therapy for DMD) for a total of 5 weeks
from day 7 to day 28.
It is worth mentioning that in previous gene therapy studies, CMV promoters were often used to initiate the expression of the gene of interest , but CMV promoters may initiate higher levels of expression in non-muscle tissue and generate associated immune responses
.
To reduce the immune response to the miniature Dystrophin protein, the study provided a proof of concept showing that using a muscle-specific promoter, the expression of the micro-Dystrophin protein was initiated only in muscle tissue, and the results showed that GRMD dogs exhibited protein expression
for 8 weeks in the absence of immunosuppression.
The results showed that the genome copy number in the tissues of the treated dogs increased dose-dependently, μDys5 protein was expressed in muscle tissue and heart, the limb and respiratory muscle functions of dogs were improved, and histopathological lesions were reduced
.
As expected, phenotypic and histopathological lesions did not fully return to normal
due to the expression of the micro-Dystrophin protein.
In addition, different dose groups were well tolerated with no adverse events
.
These data suggest that the micro-Dystrophin protein delivered by systematic administration of AAV is safe and offers therapeutic benefits
for DMD patients.
Currently, there are four DMD clinical trials underway for AAV delivery of micro-Dystrophin proteins, from Pfizer, Sarepta, Genethon, and Solid Biosciences, a participant in the paper.
Solid conducted a clinical trial SGT-001 for the treatment of DMD in 2017 to evaluate its safety, tolerability, and efficacy
in adolescents and children with Duchenne muscular dystrophy (DMD).
But the clinical trial was ill-fated and was twice suspended
by the FDA due to safety concerns.
The related clinical trials of the other three companies have also had serious safety problems
.
Thesis.
Link: style="color: rgb(136, 136, 136);font-size: 12px;letter-spacing: normal;" _mstmutation="1" _istranslated="1">
Open reprint, welcome to forward to Moments and WeChat groups
