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Nature Reviews. Disease Primers Feb 2021Duchenne muscular dystrophy is a severe, progressive, muscle-wasting disease that leads to difficulties with movement and, eventually, to the need for assisted... (Review)
Review
Duchenne muscular dystrophy is a severe, progressive, muscle-wasting disease that leads to difficulties with movement and, eventually, to the need for assisted ventilation and premature death. The disease is caused by mutations in DMD (encoding dystrophin) that abolish the production of dystrophin in muscle. Muscles without dystrophin are more sensitive to damage, resulting in progressive loss of muscle tissue and function, in addition to cardiomyopathy. Recent studies have greatly deepened our understanding of the primary and secondary pathogenetic mechanisms. Guidelines for the multidisciplinary care for Duchenne muscular dystrophy that address obtaining a genetic diagnosis and managing the various aspects of the disease have been established. In addition, a number of therapies that aim to restore the missing dystrophin protein or address secondary pathology have received regulatory approval and many others are in clinical development.
Topics: Animals; Disease Models, Animal; Dystrophin; Humans; Muscular Dystrophy, Duchenne
PubMed: 33602943
DOI: 10.1038/s41572-021-00248-3 -
Continuum (Minneapolis, Minn.) Aug 2019This article reviews the symptoms, laboratory and neuroimaging diagnostic tests, genetics, and management of cerebellar ataxia. (Review)
Review
PURPOSE OF REVIEW
This article reviews the symptoms, laboratory and neuroimaging diagnostic tests, genetics, and management of cerebellar ataxia.
RECENT FINDINGS
Recent advances in genetics have led to the identification of novel genetic causes for ataxia and a more comprehensive understanding of the biological pathways critical for normal cerebellar function. When these molecular pathways become dysfunctional, patients develop cerebellar ataxia. In addition, several ongoing clinical trials for Friedreich ataxia and spinocerebellar ataxia will likely result in novel symptomatic and disease-modifying therapies for ataxia. Antisense oligonucleotides for spinocerebellar ataxias associated with CAG repeat expansions might be a promising therapeutic strategy.
SUMMARY
Cerebellar ataxias include heterogeneous disorders affecting cerebellar function, leading to ataxic symptoms. Step-by-step diagnostic workups with genetic investigations are likely to reveal the underlying causes of ataxia. Some disease-specific therapies for ataxia exist, such as vitamin E for ataxia with vitamin E deficiency and thiamine for Wernicke encephalopathy, highlighting the importance of recognizing these forms of ataxia. Finally, genetic diagnosis for patients with ataxia will accelerate clinical trials for disease-modifying therapy and will have prognostic value and implications for family planning for these patients.
Topics: Ataxia; Cerebellar Ataxia; Dopamine Agents; Female; Friedreich Ataxia; Humans; Male; Middle Aged; Physical Therapy Modalities
PubMed: 31356292
DOI: 10.1212/CON.0000000000000753 -
Molecular Therapy : the Journal of the... Dec 2021Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the... (Review)
Review
Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the difficulty of accessing both the brain and spinal cord. Recent advances in our understanding of disease mechanism and ALS genetics, however, have combined with tremendous strides in CNS targeting, gene delivery, and gene editing and knockdown techniques to open new horizons of therapeutic possibility. Gene therapy clinical trials are currently underway for ALS patients with SOD1 mutations, C9orf72 hexanucleotide repeat expansions, ATXN2 trinucleotide expansions, and FUS mutations, as well as sporadic disease without known genetic cause. In this review, we provide an in-depth exploration of the state of ALS-directed gene therapy, including antisense oligonucleotides, RNA interference, CRISPR, adeno-associated virus (AAV)-mediated trophic support, and antibody-based methods. We discuss how each of these approaches has been implemented across known genetic causes as well as sporadic ALS, reviewing preclinical studies as well as completed and ongoing human clinical trials. We highlight the transformative potential of these evolving technologies as the gene therapy field advances toward a true disease-modifying treatment for this devastating illness.
Topics: Amyotrophic Lateral Sclerosis; C9orf72 Protein; Dependovirus; Genetic Therapy; Humans; Oligonucleotides, Antisense
PubMed: 33839324
DOI: 10.1016/j.ymthe.2021.04.008 -
The Lancet. Neurology Jul 2022Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this... (Review)
Review
Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.
Topics: Humans; Huntingtin Protein; Huntington Disease; Neurodegenerative Diseases; Oligonucleotides; Oligonucleotides, Antisense; RNA Splicing
PubMed: 35716694
DOI: 10.1016/S1474-4422(22)00121-1 -
Journal of Neuromuscular Diseases 2021Duchenne muscular dystrophy (DMD) is an X-linked, muscle wasting disease that affects 1 in 5000 males. Affected individuals become wheelchair bound by the age of twelve... (Review)
Review
Duchenne muscular dystrophy (DMD) is an X-linked, muscle wasting disease that affects 1 in 5000 males. Affected individuals become wheelchair bound by the age of twelve and eventually die in their third decade due to respiratory and cardiac complications. The disease is caused by mutations in the DMD gene that codes for dystrophin. Dystrophin is a structural protein that maintains the integrity of muscle fibres and protects them from contraction-induced damage. The absence of dystrophin compromises the stability and function of the muscle fibres, eventually leading to muscle degeneration. So far, there is no effective treatment for deteriorating muscle function in DMD patients. A promising approach for treating this life-threatening disease is gene transfer to restore dystrophin expression using a safe, non-pathogenic viral vector called adeno-associated viral (AAV) vector. Whilst microdystrophin gene transfer using AAV vectors shows extremely impressive therapeutic success so far in large animal models of DMD, translating this advanced therapy medicinal product from bench to bedside still offers scope for many optimization steps. In this paper, the authors review the current progress of AAV-microdystrophin gene therapy for DMD and other treatment strategies that may apply to a subset of DMD patients depending on the mutations they carry.
Topics: Animals; Dependovirus; Dystrophin; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne
PubMed: 34511510
DOI: 10.3233/JND-210678 -
Nucleic Acids Research Apr 2023Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides... (Review)
Review
Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), RNA interference (RNAi) and an RNA aptamer against a protein. Among the diseases targeted by this new class of drugs are homozygous familial hypercholesterolemia, spinal muscular atrophy, Duchenne muscular dystrophy, hereditary transthyretin-mediated amyloidosis, familial chylomicronemia syndrome, acute hepatic porphyria, and primary hyperoxaluria. Chemical modification of DNA and RNA was central to making drugs out of oligonucleotides. Oligonucleotide therapeutics brought to market thus far contain just a handful of first- and second-generation modifications, among them 2'-fluoro-RNA, 2'-O-methyl RNA and the phosphorothioates that were introduced over 50 years ago. Two other privileged chemistries are 2'-O-(2-methoxyethyl)-RNA (MOE) and the phosphorodiamidate morpholinos (PMO). Given their importance in imparting oligonucleotides with high target affinity, metabolic stability and favorable pharmacokinetic and -dynamic properties, this article provides a review of these chemistries and their use in nucleic acid therapeutics. Breakthroughs in lipid formulation and GalNAc conjugation of modified oligonucleotides have paved the way to efficient delivery and robust, long-lasting silencing of genes. This review provides an account of the state-of-the-art of targeted oligo delivery to hepatocytes.
Topics: Humans; Morpholinos; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense; RNA; RNA Interference
PubMed: 36881759
DOI: 10.1093/nar/gkad067 -
International Journal of Molecular... May 2020Since the early days of its conceptualization and application, human gene transfer held the promise of a permanent solution to genetic diseases including cystic fibrosis... (Review)
Review
Since the early days of its conceptualization and application, human gene transfer held the promise of a permanent solution to genetic diseases including cystic fibrosis (CF). This field went through alternated periods of enthusiasm and distrust. The development of refined technologies allowing site specific modification with programmable nucleases highly revived the gene therapy field. CRISPR nucleases and derived technologies tremendously facilitate genome manipulation offering diversified strategies to reverse mutations. Here we discuss the advancement of gene therapy, from therapeutic nucleic acids to genome editing techniques, designed to reverse genetic defects in CF. We provide a roadmap through technologies and strategies tailored to correct different types of mutations in the cystic fibrosis transmembrane regulator ( gene, and their applications for the development of experimental models valuable for the advancement of CF therapies.
Topics: Animals; CRISPR-Cas Systems; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Gene Editing; Genetic Therapy; Genome, Human; Humans; Mice; Mutation; Oligonucleotides, Antisense; Phenotype
PubMed: 32486152
DOI: 10.3390/ijms21113903 -
Nature Reviews. Drug Discovery Aug 2021Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of... (Review)
Review
Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of cancers, as well as many other diseases. Over the past decade, substantial effort has been made towards the clinical application of RNA-based therapeutics, employing mostly antisense oligonucleotides and small interfering RNAs, with several gaining FDA approval. However, trial results have so far been ambivalent, with some studies reporting potent effects whereas others demonstrated limited efficacy or toxicity. Alternative entities such as antimiRNAs are undergoing clinical testing, and lncRNA-based therapeutics are gaining interest. In this Perspective, we discuss key challenges facing ncRNA therapeutics - including issues associated with specificity, delivery and tolerability - and focus on promising emerging approaches that aim to boost their success.
Topics: Animals; Genetic Therapy; Humans; Molecular Targeted Therapy; Neoplasms; RNA, Long Noncoding
PubMed: 34145432
DOI: 10.1038/s41573-021-00219-z -
Human Molecular Genetics Oct 2019Sensorineural hearing loss (SNHL) is the most common sensory disorder. Its underlying etiologies include a broad spectrum of genetic and environmental factors that can... (Review)
Review
Sensorineural hearing loss (SNHL) is the most common sensory disorder. Its underlying etiologies include a broad spectrum of genetic and environmental factors that can lead to hearing loss that is congenital or late onset, stable or progressive, drug related, noise induced, age related, traumatic or post-infectious. Habilitation options typically focus on amplification using wearable or implantable devices; however exciting new gene-therapy-based strategies to restore and prevent SNHL are actively under investigation. Recent proof-of-principle studies demonstrate the potential therapeutic potential of molecular agents delivered to the inner ear to ameliorate different types of SNHL. Correcting or preventing underlying genetic forms of hearing loss is poised to become a reality. Herein, we review molecular therapies for hearing loss such as gene replacement, antisense oligonucleotides, RNA interference and CRISPR-based gene editing. We discuss delivery methods, techniques and viral vectors employed for inner ear gene therapy and the advancements in this field that are paving the way for basic science research discoveries to transition to clinical trials.
Topics: Animals; Biomarkers; Clinical Trials as Topic; Disease Management; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Expression; Genetic Predisposition to Disease; Genetic Therapy; Genetic Vectors; Hearing Loss; Humans; Transgenes; Treatment Outcome
PubMed: 31227837
DOI: 10.1093/hmg/ddz129 -
Neurotherapeutics : the Journal of the... Jul 2022Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease for which there is currently no robust therapy. Recent progress in understanding ALS disease... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease for which there is currently no robust therapy. Recent progress in understanding ALS disease mechanisms and genetics in combination with innovations in gene modulation strategies creates promising new options for the development of ALS therapies. In recent years, six gene modulation therapies have been tested in ALS patients. These target gain-of-function pathology of the most common ALS genes, SOD1, C9ORF72, FUS, and ATXN2, using adeno-associated virus (AAV)-mediated microRNAs and antisense oligonucleotides (ASOs). Here, we review the latest clinical and preclinical advances in gene modulation approaches for ALS, including gene silencing, gene correction, and gene augmentation. These techniques have the potential to positively impact the direction of future research trials and transform ALS treatments for this grave disease.
Topics: Humans; Amyotrophic Lateral Sclerosis; Superoxide Dismutase-1; C9orf72 Protein; Oligonucleotides, Antisense; MicroRNAs
PubMed: 36068427
DOI: 10.1007/s13311-022-01285-w