Paper a day Archives • World Duchenne

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#apaperaday: Bridging the Gap With Clinical Pharmacology in Innovative Rare Disease Treatment Modalities: Targeting DNA to RNA to Protein

Bridging the Gap With Clinical Pharmacology in Innovative Rare Disease Treatment Modalities: Targeting DNA to RNA to Protein

#apaperaday: Electrical Impedance Myography Correlates with Functional Measures of Disease Progression in D2-mdx Mice and Boys with Duchenne Muscular Dystrophy

Electrical Impedance Myography Correlates with Functional Measures of Disease Progression in D2-mdx Mice and Boys with Duchenne Muscular Dystrophy

#apaperaday: Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation

Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation

#apaperaday: Cardiac and Skeletal Muscle Pathology in the D2/mdx Mouse Model and Caveats Associated with the Quantification of Utrophin.

Cardiac and Skeletal Muscle Pathology in the D2/mdx Mouse Model and Caveats Associated with the Quantification of Utrophin.

#apaperaday: RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European Union legislation

RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European Union legislation

#apaperaday: Early Developmental Changes of Muscle Acetylcholine Receptors Are Little Influenced by Dystrophin Absence in mdx Mouse.

Early Developmental Changes of Muscle Acetylcholine Receptors Are Little Influenced by Dystrophin Absence in mdx Mouse.

#apaperaday: Associations Between Self-Reported Behavioral and Learning Concerns and DMD Isoforms in Duchenne Muscular Dystrophy

Associations Between Self-Reported Behavioral and Learning Concerns and DMD Isoforms in Duchenne Muscular Dystrophy

#apaperaday: Systemic PPMO-mediated dystrophin expression in the Dup2 mouse model of Duchenne muscular dystrophy

Systemic PPMO-mediated dystrophin expression in the Dup2 mouse model of Duchenne muscular dystrophy

#apaperaday: Clinical, muscle imaging, and genetic characteristics of dystrophinopathies with deep-intronic DMD variants

Clinical, muscle imaging, and genetic characteristics of dystrophinopathies with deep-intronic DMD variants

#apaperaday: Sulfur amino acid supplementation displays therapeutic potential in a C. elegans model of Duchenne muscular dystrophy

Sulfur amino acid supplementation displays therapeutic potential in a C. elegans model of Duchenne muscular dystrophy

#apaperaday: Quantitative Evaluation of Exon Skipping in Urine-Derived Cells for Duchenne Muscular Dystrophy

Quantitative Evaluation of Exon Skipping in Urine-Derived Cells for Duchenne Muscular Dystrophy

#apaperaday: Research participants: critical friends, agents for change

Research participants: critical friends, agents for change

#apaperaday: Prime editing optimized RTT permits the correction of the c.8713C>T mutation in DMD gene

Prime editing optimized RTT permits the correction of the c.8713C>T mutation in DMD gene

#apaperaday: Transplantation of Differentiated Tonsil-Derived Mesenchymal Stem Cells Ameliorates Murine Duchenne Muscular Dystrophy via Autophagy Activation

Transplantation of Differentiated Tonsil-Derived Mesenchymal Stem Cells Ameliorates Murine Duchenne Muscular Dystrophy via Autophagy Activation

#apaperaday: Phenotype predictions for exon deletions/duplications: A user guide for professionals and clinicians using Becker and Duchenne muscular dystrophy as examples

Phenotype predictions for exon deletions/duplications: A user guide for professionals and clinicians using Becker and Duchenne muscular dystrophy as examples

#apaperaday: A Nonsense Variant in the DMD Gene Causes X-Linked Muscular Dystrophy in the Maine Coon Cat

A Nonsense Variant in the DMD Gene Causes X-Linked Muscular Dystrophy in the Maine Coon Cat

#apaperaday: Perioperative Care for Patients with Neuromuscular Disorders in the Netherlands - A Questionnaire Study Among Anaesthesiologists, Neurologists and Clinical Geneticists

Perioperative Care for Patients with Neuromuscular Disorders in the Netherlands

#apaperaday: Improving Interpretation of Evidence Relating to Quality of Life in Health Technology Assessments of Rare Disease Treatments

Improving Interpretation of Evidence Relating to Quality of Life in Health Technology Assessments of Rare Disease Treatments

#apaperaday: Pregabalin synchronizes the regeneration of nerve and muscle fibers optimizing the gait recovery of MDX dystrophic mice

Pregabalin synchronizes the regeneration of nerve and muscle fibers optimizing the gait recovery of MDX dystrophic mice

#apaperaday: Abnormal Expression of Synaptic and Extrasynaptic GABAA Receptor Subunits in the Dystrophin-Deficient mdx Mouse

Abnormal Expression of Synaptic and Extrasynaptic GABAA Receptor Subunits in the Dystrophin-Deficient mdx Mouse

#apaperaday: Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts

Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: CRISPR-Based Therapeutic Gene Editing for Duchenne Muscular Dystrophy: Advances, Challenges and Perspectives Today's pick is a review paper on CRISPR based genome editing approaches for Duchenne by Chen et al in MDPI Cells. The review gives an introduction to Duchenne and dystrophin and genome editing, but I'll focus on the editing types and challenges. Doi 10.3390/cells11192964 The review contains an overview of many CRISPR approaches tested in vitro and in vivo for Duchenne in case people are interested in an overview table. I'll outline the different editing types authors discuss for Duchenne starting with the exon excision double cut. This uses 2 CRISPR (guides) to cut at both sides of an exon to cause this exon to be deleted in order to restore the reading frame (readability of the dystrophin transcript). This allows production of a Becker-type dystrophin. This can also be used to delete multiple exons. This double cut approach has been shown feasible for removing one and multiple exons. However, removing one exon is more efficient. The challenge of this approach is that using two CRISPRS can lead to more unexpected events than using just one. Single cut genome editing for Duchenne can be done in 2 ways to restore readability of the dystrophin gene transcript. 1. Making the exon invisible for the splicing machinery by destroying the exon recognition site (cutting at the splice site, which is then mutated during repair) The second approach is to cut inside the exon and then change the shape of the exon such that the readability is restored. This would in theory happen in 1/3 of cases, but for some targets the desired shape occurs more often (and in others it occurs less often). Both single cut approaches rely on the fact that after cutting DNA, the DNA repair mechanism of the cell will repair the DNA, but this will be with errors. Normally that is bad, but here the errors are used to make the exon invisible or to reshape it so readability is restored Knockin approaches aim to add DNA to replace missing parts for deletion mutations. This means that you have to deliver yet another component: 1. The cas9 (scissor), 2. The guide RNAs (CRISPR) 3. The template you want to be inserted into the DNA. This approach is feasible in cultured cells and animal models but very high doses of AAV were needed to achieve dystrophin restoration in vivo. Finally authors discuss approaches that rely on a single stranded break and that are less likely to cause permanent unwanted DNA changes First base editing allows changing 1 base pair in the DNA. This can be used to correct point mutations OR to make exons invisible. Prime editing allows reshaping of exons, but also correcting small deletion or insertion mutations. Both approaches are currently very inefficient. Authors discuss 4 challenges: 1. Safety related to AAV. The doses currently needed to deliver genome editing components are not tolerable by humans. So either the efficiency needs to improve (or I personally add, we need better AAV that go to muscle more specifically) 2. Immunogenicity to AAV and to Cas proteins. About 20-50% of people have preexisting immunity to AAV and about 60-80% of people have preexisting immunity to Cas9. It is clear that for AAV this is a problem, what the effect of Cas9 immunity will be in humans is not sure. However, Dongshengh Duan already showed that it leads to lower efficiency in a mouse model. 3. Off target activity - it is known there will be cuts at unwanted regions. Authors outline that attempts are made to improve specificity. Personally I think that for systemic treatment with a viral vector, long term Cas9 expression in multiple tissues is a risk. There is no undo button for unwanted edits. Authors suggest using tissue specific promotors to ensure Cas9 is only expressed in muscle 4. Durability. Authors correctly point out that with genome editing partially functional dystrophins are produced, so likely there will be turnover of muscle and a transient effect. They propose targeting the satellite cells to generate a permanent pool of reframed cells If that were possible it would be a very good solution. However, until now it has been very difficult to target the satellite cells. They are inactive and thus do not participate in taking up stuff. Authors are positive these challenges can be overcome and there will be a clinical translation in the near future. Near future is a flexible term of course...Regardless, I am not so sure that systemic genome editing will be in clinical trials for Duchenne soon. Hope I'm wrong... Finally, a comment about the introduction: the authors use the 'c-word' (cure). Genome editing can in theory cure Duchenne. No it cannot! First, approaches mainly aim at restoring a partially functional dystrophin. That is not curative. But more importantly, even when normal dystrophin is restored (e.g. with duplications), the accumulated damage will not be undone. All muscle lost will remain lost. Function lost will remain lost. That is not the definition of a cure. Given the risks involved with genome editing (not certain it will be effective, there are risks of unwanted edits), it is important we (researchers) paint a realistic picture of the potential benefit so IF a trial comes, patients/families can make an informed decision. Overpromising can lead to patients and families taking on risks they would never find acceptable had they known this is not a cure.

#apaperaday: CRISPR-Based Therapeutic Gene Editing for Duchenne Muscular Dystrophy: Advances, Challenges and Perspectives

CRISPR-Based Therapeutic Gene Editing for Duchenne Muscular Dystrophy: Advances, Challenges and Perspectives

#apaperaday: The Role of Associations in Reducing the Emotional and Financial Impact on Parents Caring for Children with Duchenne Muscular Dystrophy

The Role of Associations in Reducing the Emotional and Financial Impact on Parents Caring for Children with Duchenne Muscular Dystrophy

#apaperaday: Dystrophin Restoration after Adeno-Associated Virus U7–Mediated Dmd Exon Skipping Is Modulated by Muscular Exercise in the Severe D2-Mdx Duchenne Muscular Dystrophy Murine Model

Dystrophin Restoration after Adeno-Associated Virus U7–Mediated Dmd Exon Skipping Is Modulated by Muscular Exercise in the Severe D2-Mdx Duchenne Muscular Dystrophy Murine Model

#apaperaday: Cardiac care of children with dystrophinopathy and females carrying DMD-gene variations

Cardiac care of children with dystrophinopathy and females carrying DMD-gene variations

#apaperaday: The Relation Between Nutritional Intake and Weight in 4-18 Year Old Patients with Duchenne Muscular Dystrophy

The Relation Between Nutritional Intake and Weight in 4-18 Year Old Patients with Duchenne Muscular Dystrophy

#apaperaday: Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy

Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy

#apaperaday: Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties

Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties

#apaperaday: Gene Therapy for Duchenne Muscular Dystrophy: Unlocking the Opportunities in Countries in the Middle East and Beyond

Gene Therapy for Duchenne Muscular Dystrophy: Unlocking the Opportunities in Countries in the Middle East and Beyond

#apaperaday: Perspectives on the advances in the pharmacotherapeutic management of Duchenne muscular dystrophy

Perspectives on the advances in the pharmacotherapeutic management of Duchenne muscular dystrophy

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#apaperaday: Bridging the Gap With Clinical Pharmacology in Innovative Rare Disease Treatment Modalities: Targeting DNA to RNA to Protein

#apaperaday: Electrical Impedance Myography Correlates with Functional Measures of Disease Progression in D2-mdx Mice and Boys with Duchenne Muscular Dystrophy

#apaperaday: Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation

#apaperaday: Cardiac and Skeletal Muscle Pathology in the D2/mdx Mouse Model and Caveats Associated with the Quantification of Utrophin.

#apaperaday: RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European Union legislation

#apaperaday: Early Developmental Changes of Muscle Acetylcholine Receptors Are Little Influenced by Dystrophin Absence in mdx Mouse.

#apaperaday: Associations Between Self-Reported Behavioral and Learning Concerns and DMD Isoforms in Duchenne Muscular Dystrophy

#apaperaday: Systemic PPMO-mediated dystrophin expression in the Dup2 mouse model of Duchenne muscular dystrophy

#apaperaday: Clinical, muscle imaging, and genetic characteristics of dystrophinopathies with deep-intronic DMD variants

#apaperaday: Sulfur amino acid supplementation displays therapeutic potential in a C. elegans model of Duchenne muscular dystrophy

#apaperaday: Quantitative Evaluation of Exon Skipping in Urine-Derived Cells for Duchenne Muscular Dystrophy

#apaperaday: Research participants: critical friends, agents for change

#apaperaday: Prime editing optimized RTT permits the correction of the c.8713C>T mutation in DMD gene

#apaperaday: Transplantation of Differentiated Tonsil-Derived Mesenchymal Stem Cells Ameliorates Murine Duchenne Muscular Dystrophy via Autophagy Activation

#apaperaday: Phenotype predictions for exon deletions/duplications: A user guide for professionals and clinicians using Becker and Duchenne muscular dystrophy as examples

#apaperaday: A Nonsense Variant in the DMD Gene Causes X-Linked Muscular Dystrophy in the Maine Coon Cat

#apaperaday: Perioperative Care for Patients with Neuromuscular Disorders in the Netherlands - A Questionnaire Study Among Anaesthesiologists, Neurologists and Clinical Geneticists

#apaperaday: Improving Interpretation of Evidence Relating to Quality of Life in Health Technology Assessments of Rare Disease Treatments

#apaperaday: Pregabalin synchronizes the regeneration of nerve and muscle fibers optimizing the gait recovery of MDX dystrophic mice

#apaperaday: Abnormal Expression of Synaptic and Extrasynaptic GABAA Receptor Subunits in the Dystrophin-Deficient mdx Mouse

#apaperaday: Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts

#apaperaday: CRISPR-Based Therapeutic Gene Editing for Duchenne Muscular Dystrophy: Advances, Challenges and Perspectives

#apaperaday: The Role of Associations in Reducing the Emotional and Financial Impact on Parents Caring for Children with Duchenne Muscular Dystrophy

#apaperaday: Dystrophin Restoration after Adeno-Associated Virus U7–Mediated Dmd Exon Skipping Is Modulated by Muscular Exercise in the Severe D2-Mdx Duchenne Muscular Dystrophy Murine Model

#apaperaday: Cardiac care of children with dystrophinopathy and females carrying DMD-gene variations

#apaperaday: The Relation Between Nutritional Intake and Weight in 4-18 Year Old Patients with Duchenne Muscular Dystrophy

#apaperaday: Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy

#apaperaday: Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties

#apaperaday: Gene Therapy for Duchenne Muscular Dystrophy: Unlocking the Opportunities in Countries in the Middle East and Beyond

#apaperaday: Perspectives on the advances in the pharmacotherapeutic management of Duchenne muscular dystrophy

Road to independence: Documentary about young people with NMD

Webinar Recording: Understanding the role of dystrophin in the brain in DMD/BMD

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