Dystrophinopathy patient data as a guide to interpretation of pregestational female population screening for DMD gene variants.

Pregestational population screening of healthy females for copy number variants in DMD gene has raised numerous challenges regarding the interpretation and disclosure of these findings. Our objective was to analyze data from a local dystrophinopathy patient database, in comparison to population screening results. Utilizing the "Little steps" association registry for children with dystrophinopathy, we classified genetic findings (out-of-frame, in-frame, or difficult-to-predict) in 231 DMD and 90 BMD male patients.

The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap.

In recent years, a small number of people with rare diseases caused by unique genetic variants have been treated with therapies developed specifically for them. This pioneering field of genetic N-of-1 therapies is evolving rapidly, giving hope for the individualized treatment of people living with very rare diseases. In this Review, we outline the concept of N-of-1 individualized therapies, focusing on genetic therapies, and illustrate advances and challenges in the field using cases for which therapies have been successfully developed.

Joining forces to develop individualized antisense oligonucleotides for patients with brain or eye diseases: the example of the Dutch Center for RNA Therapeutics.

Antisense oligonucleotides (ASOs) offer versatile tools to modify the processing and expression levels of gene transcripts. As such, they have a high therapeutic potential for rare genetic diseases, where applicability of each ASO ranges from thousands of patients worldwide to single individuals based on the prevalence of the causative pathogenic variant. It was shown that development of individualized ASOs was feasible within an academic setting, starting with Milasen for the treatment of a patient with CLN7 Batten's disease in the USA.

A Guide to Chemical Considerations for the Pre-Clinical Development of Oligonucleotides.

Oligonucleotide therapeutics, a pioneering category of modern medicinal drugs, are at the forefront of utilizing innate mechanisms to modulate gene expression. With 18 oligonucleotide-based FDA-approved medicines currently available for treating various clinical conditions, this field showcases an innovative potential yet to be fully explored. Factors such as purity, formulation, and endotoxin levels profoundly influence the efficacy and safety of these therapeutics.

Learning, memory and blood-brain barrier pathology in Duchenne muscular dystrophy mice lacking Dp427, or Dp427 and Dp140.

Duchenne muscular dystrophy is a severe neuromuscular disorder that is caused by mutations in the DMD gene, resulting in a disruption of dystrophin production. Next to dystrophin expression in the muscle, different isoforms of the protein are also expressed in the brain and lack of these isoforms leads to cognitive and behavioral deficits in patients. It remains unclear how the loss of the shorter dystrophin isoform Dp140 affects these processes.

Antisense Oligonucleotide-Mediated Downregulation of IGFBPs Enhances IGF-1 Signaling.

Insulin-like growth factor-1 (IGF-1) has been considered as a therapeutic agent for muscle wasting conditions including Duchenne muscular dystrophy as it stimulates muscle regeneration, growth and function. Several preclinical and clinical studies have been conducted to show the therapeutic potential of IGF-1, however, delivery issues, short half-life and isoform complexity have impose challenges. Antisense oligonucleotides (AONs) are able to downregulate target proteins by interfering with their transcripts.

Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders.

Antisense oligonucleotides (ASOs) are incredibly versatile molecules that can be designed to specifically target and modify RNA transcripts to slow down or halt rare genetic disease progression. They offer the potential to target groups of patients or can be tailored for individual cases. Nonetheless, not all genetic variants and disorders are amenable to ASO-based treatments, and hence, it is important to consider several factors before embarking on the drug development journey.

Report of the European Medicines Agency Conference on RNA-Based Medicines.

RNA-based medicines have potential to treat a large variety of diseases, and research in the field is very dynamic. Proactively, The European Medicines Agency (EMA) organized a virtual conference on February 2, 2023 to promote the development of RNA-based medicines. The initiative addresses the goal of the EMA Regulatory Science Strategy to 2025 to "catalyse the integration of science and technology in medicines development.

Networking to Optimize exon 53 Skipping in the Brain of Mouse Model.

Duchenne muscular dystrophy (DMD) is caused by mutations in the gene that disrupt the open reading frame and thus prevent production of functional dystrophin proteins. Recent advances in DMD treatment, notably exon skipping and AAV gene therapy, have achieved some success aimed at alleviating the symptoms related to progressive muscle damage. However, they do not address the brain comorbidities associated with DMD, which remains a critical aspect of the disease.

Challenges of Assessing Exon 53 Skipping of the Human Transcript with Locked Nucleic Acid-Modified Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy.

Antisense oligonucleotide (AON)-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy (DMD) patients to restore dystrophin expression by reframing the disrupted open reading frame of the transcript. However, the treatment efficacy of the already conditionally approved AONs remains low. Aiming to optimize AON efficiency, we assessed exon 53 skipping of the transcript with different chemically modified AONs, all with a phosphorothioate backbone: 2'-O-methyl (2'OMe), locked nucleic acid (LNA)-2'OMe, 2'-fluoro (FRNA), LNA-FRNA, αLNA-FRNA, and FANA-LNA-FRNA.

Lessons learned from the first national population-based genetic carrier-screening program for Duchenne muscular dystrophy.

Purpose: To summarize the results of first year implementation of pan-ethnic screening testing for Duchenne muscular dystrophy (DMD) and present the ensuing challenges.

Methods: Data acquisition for this study was performed by retrospective search of Ministry of Health registry for reports of all laboratories performing genetic screening tests. DMD testing was performed by multiplex ligation-dependent probe amplification technology.

antisense oligonucleotide mediated exon skipping efficiency correlates with flanking intron retention time and target position within the exon.

Mutations in the gene are causative for Duchenne muscular dystrophy (DMD). Antisense oligonucleotide (AON) mediated exon skipping to restore disrupted dystrophin reading frame is a therapeutic approach that allows production of a shorter but functional protein. As DMD causing mutations can affect most of the 79 exons encoding dystrophin, a wide variety of AONs are needed to treat the patient population.

Spatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models.

Duchenne muscular dystrophy is caused by mutations in the DMD gene, leading to lack of dystrophin. Chronic muscle damage eventually leads to histological alterations in skeletal muscles. The identification of genes and cell types driving tissue remodeling is a key step to developing effective therapies.

The IRDiRC Chrysalis Task Force: making rare disease research attractive to companies.

Background: The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to use research to facilitate rapid diagnosis and treatment of rare diseases.

Objective: IRDiRC launched the Chrysalis Task Force to identify key financial and nonfinancial factors that make rare disease research and development attractive to companies.

Methods: The Chrysalis Task Force was comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders.

Diffusion-tensor magnetic resonance imaging captures increased skeletal muscle fibre diameters in Becker muscular dystrophy.

Background: Becker muscular dystrophy (BMD) is an X-linked disorder characterized by slow, progressive muscle damage and muscle weakness. Hallmarks include fibre-size variation and replacement of skeletal muscle with fibrous and adipose tissues, after repeated cycles of regeneration. Muscle histology can detect these features, but the required biopsies are invasive, are difficult to repeat and capture only small muscle volumes.

Next Generation Exon 51 Skipping Antisense Oligonucleotides for Duchenne Muscular Dystrophy.

In the last two decades, antisense oligonucleotides (AONs) that induce corrective exon skipping have matured as promising therapies aimed at tackling the dystrophin deficiency that underlies the severe and progressive muscle fiber degeneration in Duchenne muscular dystrophy (DMD) patients. Pioneering first generation exon 51 skipping AONs like drisapersen and eteplirsen have more recently been followed up by AONs for exons 53 and 45, with, to date, a total of four exon skipping AON drugs having reached (conditional) regulatory US Food and Drug Administration (FDA) approval for DMD. Nonetheless, considering the limited efficacy of these drugs, there is room for improvement.

Multiomic characterization of disease progression in mice lacking dystrophin.

Duchenne muscular dystrophy (DMD) is caused by genetic mutations leading to lack of dystrophin in skeletal muscle. A better understanding of how objective biomarkers for DMD vary across subjects and over time is needed to model disease progression and response to therapy more effectively, both in pre-clinical and clinical research. We present an in-depth characterization of disease progression in 3 murine models of DMD by multiomic analysis of longitudinal trajectories between 6 and 30 weeks of age.

The Future of Exon Skipping for Duchenne Muscular Dystrophy.

Antisense oligonucleotide (ASO)-mediated exon skipping can restore the open reading frame of dystrophin transcripts for Duchenne muscular dystrophy (DMD) patients. This allows production of internally deleted dystrophin proteins as found in the later onset, less severely progressive Becker muscular dystrophy. At present, ASOs that induce exon skipping and dystrophin restoration are approved for the treatment of DMD by the regulatory agencies of the United States and Japan.

The Dilemma of Choice for Duchenne Patients Eligible for Exon 51 Skipping The European Experience.

Antisense oligonucleotide (ASO) mediated exon skipping aims to reframe dystrophin transcripts for patients with Duchenne muscular dystrophy (DMD). Currently 4 ASOs have been approved by the Food and Drug Administration targeting exon 45, 51 and 53 based on low level dystrophin restoration. Additional studies to confirm functional effects are ongoing.

Development of tailored splice-switching oligonucleotides for progressive brain disorders in Europe: development, regulation, and implementation considerations.

Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting.