-
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 -
Cell Metabolism Apr 2018RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding... (Review)
Review
RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform.
Topics: Animals; Drug Discovery; Genetic Therapy; Humans; Molecular Targeted Therapy; Muscular Atrophy, Spinal; Oligoribonucleotides, Antisense; RNA, Small Interfering
PubMed: 29617640
DOI: 10.1016/j.cmet.2018.03.004 -
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 -
Journal of the American College of... Nov 2021Detecting familial hypercholesterolemia (FH) early and "normalizing" low-density lipoprotein (LDL) cholesterol values are the 2 pillars for effective cardiovascular... (Review)
Review
Detecting familial hypercholesterolemia (FH) early and "normalizing" low-density lipoprotein (LDL) cholesterol values are the 2 pillars for effective cardiovascular disease prevention in FH. Combining lipid-lowering therapies targeting synergistic/complementary metabolic pathways makes this feasible, even among severe phenotypes. For LDL receptor-dependent treatments, PCSK9 remains the main target for adjunctive therapy to statins and ezetimibe through a variety of approaches. These include protein inhibition (adnectins), inhibition of translation at mRNA level (antisense oligonucleotides or small interfering RNA), and creation of loss-of-function mutations through base-pair editing. For patients with little LDL receptor function, LDL receptor-independent treatment targeting ANGPTL3 through monoclonal therapies are now available, or in the future, antisense/small interfering RNA-based approaches offer alternative approaches. Finally, first-in-human studies are ongoing, testing adenovirus-mediated gene therapy transducing healthy LDLR DNA in patients with HoFH. Further development of the CRISPR cas technology, which has shown promising results in vivo on introducing PCSK9 loss-of-function mutations, will move a single-dose, curative treatment for FH closer.
Topics: Cardiovascular Diseases; Cholesterol, LDL; Drug Development; Early Diagnosis; Humans; Hyperlipoproteinemia Type II; Lipid Regulating Agents; Therapies, Investigational
PubMed: 34711342
DOI: 10.1016/j.jacc.2021.09.004