Article
Pharmacology & Pharmacy
Hannah A. Blair
Summary: Tofersen (Qalsody(TM)) is an antisense oligonucleotide developed by Biogen to treat amyotrophic lateral sclerosis (ALS). It was approved in the USA on April 25, 2023, for the treatment of ALS in adults with a mutation in the superoxide dismutase 1 (SOD1) gene. This article summarizes the developmental milestones of tofersen leading to its first approval for ALS.
Review
Clinical Neurology
Sean W. Willemse, Michael A. van Es
Summary: The purpose of this review is to outline how advances in genetic studies of ALS are being translated into novel therapeutic strategies. Recent findings show that specific therapeutic targeting of mutant genes, such as antisense oligonucleotide therapy, have led to successful gene therapy for SOD1-ALS and multiple other gene-targeted trials are underway.
CURRENT OPINION IN NEUROLOGY
(2023)
Article
Clinical Neurology
Lucas Vu, Krystine Garcia-Mansfield, Antonio Pompeiano, Jiyan An, Victoria David-Dirgo, Ritin Sharma, Vinisha Venugopal, Harkeerat Halait, Guido Marcucci, Ya-Huei Kuo, Lisa Uechi, Russell C. Rockne, Patrick Pirrotte, Robert Bowser
Summary: The objective of this study was to identify biomarkers and assess their temporal response in predicting fast progression (FP) and slow progression (SP) of amyotrophic lateral sclerosis (ALS) using longitudinal cerebrospinal fluid (CSF) samples. Mass spectrometry was used to identify candidate biomarkers, and immunoassays were used to quantify and validate their levels. A mathematical model based on the longitudinal CSF proteome data was created to predict FP versus SP.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2023)
Review
Clinical Neurology
Benjamin D. Boros, Kathleen M. Schoch, Collin J. Kreple, Timothy M. Miller
Summary: This review discusses the current state of ASO therapies for ALS, outlining their successes from preclinical development to early clinical trials.
Review
Biochemistry & Molecular Biology
Valentina Rubino, Giuliana La Rosa, Flavia Carriero, Luca Pipicelli, Simona Damiano, Mariarosaria Santillo, Giuseppe Terrazzano, Giuseppina Ruggiero, Paolo Mondola
Summary: Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neurodegenerative disease with unclear pathogenesis involving astrocytes, microglial cells, and ROS.
Article
Biochemistry & Molecular Biology
Baris Genc, Boram Nho, Hana Seung, Benjamin Helmold, Huiwon Park, Oege Gozutok, Seunghyun Kim, Jinil Park, Sanghyun Ye, Haneul Lee, Nayeon Lee, Seung-Shin Yu, Sunyoung Kim, Junghun Lee, Hande Oezdinler
Summary: Recombinant adeno-associated virus (rAAV)-based gene therapies have great potential for treating rare diseases like amyotrophic lateral sclerosis (ALS). In this study, a new vector system was developed to express the active form of hepatocyte growth factor (HGF) for intrathecal injections, which has been shown to promote motor neuron survival. The results demonstrate that intrathecal delivery of HGF reduces astrogliosis and microgliosis in the motor cortex and helps restore ongoing upper motor neuron degeneration in ALS with TDP-43 pathology.
Article
Pharmacology & Pharmacy
Sebastian Peters, Eva Wirkert, Sabrina Kuespert, Rosmarie Heydn, Siw Johannesen, Anita Friedrich, Susanne Mailaender, Sven Korte, Lars Mecklenburg, Ludwig Aigner, Tim-Henrik Bruun, Ulrich Bogdahn
Summary: Through the study of the pharmacology, safety, and tolerability of LNA Gapmer Antisense Oligonucleotide NVP-13 in nonhuman primates, we found that it effectively reduces the expression of TGFBR2, decreases TGF beta signal transduction, and enhances neurogenic niche activity. The use of NVP-13 in cynomolgus monkeys did not result in any adverse events.
Article
Clinical Neurology
Cindy V. Ly, Margaret D. Ireland, Wade K. Self, James Bollinger, Jennifer Jockel-Balsarotti, Hillary Herzog, Peggy Allred, Leah Miller, Michael Doyle, Isabel Anez-Bruzual, Bhavesh Trikamji, Ted Hyman, Tyler Kung, Katherine Nicholson, Robert C. Bucelli, Bruce W. Patterson, Randall J. Bateman, Timothy M. Miller
Summary: Using stable isotope labeling and mass spectrometry, this study showed that SOD1 mutations affect the kinetics and stability of SOD1 protein, but similar changes were not observed in sporadic ALS patients. These findings highlight the potential of stable isotope labeling and peptide deamidation to optimize the design of gene and molecular therapies for neurological disorders.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2023)
Review
Chemistry, Medicinal
Maria Zakharova
Summary: Motor neuron disorders are a group of neurodegenerative diseases that often lead to muscle weakness, loss of ambulation, and respiratory insufficiency, ultimately causing early death. Recent advancements in gene therapy, including the approval of innovative drugs like nusinersen (Spinraza) and onasemnogene abeparvovec (Zolgensma), have shown promising results in treating spinal muscular atrophy. The molecular and genetic overlaps between different neurodegenerative diseases play a crucial role in the development of new therapeutic strategies, such as viral vector therapy and RNA modulating approaches.
MEDICINAL RESEARCH REVIEWS
(2021)
Review
Biotechnology & Applied Microbiology
Richard J. Mead, Ning Shan, H. Joseph Reiser, Fiona Marshall, Pamela J. Shaw
Summary: Amyotrophic lateral sclerosis (ALS) is a devastating disease with degeneration of motor neurons. Despite the challenges, ALS has seen progress in the development of disease-modifying therapies. Significant advancements have been made in ALS research and novel therapeutic approaches are being applied to address unmet medical needs. This review discusses how advanced knowledge and new approaches can lead to effective translation of therapies for ALS and potentially impact drug discovery for neurodegenerative disorders.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Article
Pharmacology & Pharmacy
Donna M. Lisi
Summary: Tofersen has recently been granted accelerated approval by the FDA to treat ALS associated with a mutation in the SOD1 gene. While study data have not shown significant benefit compared to placebo, trends suggest that early administration of toferson may reduce disease progression. Confirmatory studies are needed to verify the clinical benefit of toferson in familial ALS.
Article
Medicine, Research & Experimental
Leon Tejwani, Youngseob Jung, Hiroshi Kokubu, Sowmithra Sowmithra, Luhan Ni, Changwoo Lee, Benjamin Sanders, Paul J. Lee, Yangfei Xiang, Kimberly Luttik, Armand Soriano, Jennifer Yoon, Junhyun Park, Hannah H. Ro, Hyoungseok Ju, Clara Liao, Sofia Massaro Tieze, Frank Rigo, Paymaan Jafar-Nejad, Janghoo Lim
Summary: Reduction of Nemo-like kinase (Nlk) can increase lysosome formation and clearance of aggregated TDP-43, improving pathological, behavioral, and lifespan deficits in neurodegenerative disorders.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Cell Biology
Konstantinos Tsioras, Kevin C. Smith, Seby L. Edassery, Mehraveh Garjani, Yichen Li, Chloe Williams, Elizabeth D. Mckenna, Wenxuan Guo, Anika P. Wilen, Timothy J. Hark, Stefan L. Marklund, Lyle W. Ostrow, Jonathan D. Gilthorpe, Justin K. Ichida, Robert G. Kalb, Jeffrey N. Savas, Evangelos Kiskinis
Summary: This study investigates the effects of mutSOD1 on protein degradation using induced pluripotent stem cell-derived MNs and mass spectrometry, and identifies the altered interactome of VCP in mutSOD1 MNs. By overexpressing VCP, the toxicity of mutSOD1 in MNs is successfully rescued in vitro and in a C. elegans model.
Article
Multidisciplinary Sciences
C. M. Alejandra Zeballos, Hayden J. Moore, Tyler J. Smith, Jackson E. Powell, Najah S. Ahsan, Sijia Zhang, Thomas Gaj
Summary: TDP-43 proteinopathies are devastating neurodegenerative disorders. RNA-targeting CRISPR effector proteins can be used to mitigate TDP-43 pathology by targeting ataxin-2, thereby improving survival and reducing the severity of neuropathological hallmarks.
NATURE COMMUNICATIONS
(2023)
Review
Cell & Tissue Engineering
Hideyuki Okano, Satoru Morimoto
Summary: This review outlines the advances in iPSC modeling and therapeutic development for major neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease.
Article
Biochemistry & Molecular Biology
Annemieke Aartsma-Rus, Elizabeth Vroom, Daniel O'Reilly
Summary: The involvement of patients and patient representatives is crucial in the drug development process, as they can provide valuable insights into symptom burdens and key benefits. Success factors include finding the right partners, bilateral education, and maintaining realistic expectations.
NUCLEIC ACID THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Matthis Synofzik, Willeke M. C. Van Roon-Mom, Georg Marckmann, Hermine A. van Duyvenvoorde, Holm Graessner, Rebecca Schule, Annemieke Aartsma-Rus
Summary: ASO therapies offer a promising disease-modifying approach for rare neurological diseases, but there is a need to focus on ultrarare or private variants to provide treatment for a larger share of patients. The emerging field of n-of-1 ASO treatment approaches requires systematic guidance and standards to allow global scaling, particularly in the European context. Genetic, regulatory, and ethical perspectives are essential for preparing and implementing n-of-1 ASO treatments to ensure both individual patient benefit and knowledge gain.
NUCLEIC ACID THERAPEUTICS
(2022)
Letter
Cardiac & Cardiovascular Systems
Dongsheng Duan, Kevin M. Flanigan, Annemieke Aartsma-Rus
Article
Biochemistry & Molecular Biology
Sarah Engelbeen, Svetlana Pasteuning-Vuhman, Joke Boertje-van der Meulen, Rubina Parmar, Klaus Charisse, Laura Sepp-Lorenzino, Muthiah Manoharan, Annemieke Aartsma-Rus, Maaike van Putten
Summary: This study investigates the therapeutic effect of chemically modified siRNA delivery targeting the Alk4 gene, demonstrating it can effectively suppress the expression of Alk4 in muscles, with potential clinical implications for the treatment of muscular dystrophy.
NUCLEIC ACID THERAPEUTICS
(2023)
Editorial Material
Genetics & Heredity
Jerry Vockley, Annemieke Aartsma-Rus, Jennifer L. Cohen, Lex M. Cowsert, R. Rodney Howell, Timothy W. Yu, Melissa P. Wasserstein, Thomas Defay
Summary: Rare genetic disorders affect a certain percentage of newborn babies, and early diagnosis and treatment are challenging. The advancement of whole-genome sequencing (WGS) technology provides the possibility of early diagnosis and opens up new avenues for the treatment of rare genetic disorders. However, there are still several challenges to overcome. This article summarizes the impact of WGS on the diagnosis and treatment of rare genetic disorders.
AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS
(2023)
Article
Biotechnology & Applied Microbiology
Galina Filonova, Annemieke Aartsma-Rus
Summary: The exon-skipping approach is a potential therapy for Duchenne muscular dystrophy (DMD) patients, but the current levels of dystrophin restoration are low. Efforts are being made to improve the efficiency of exon skipping through chemical modifications of antisense oligonucleotides (AONs). Several approved and newly developed AONs are under preclinical and clinical investigation for their safety and effectiveness.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2023)
Editorial Material
Biochemistry & Molecular Biology
Annemieke Aartsma-Rus, Willeke van Roon-Mom, Marlen Lauffer, Christine Siezen, Britt Duijndam, Tineke Coenen-de Roo, Rebecca Schuele, Matthis Synofzik, Holm Graessner
Summary: Splice-modulating antisense oligonucleotides (ASOs) provide treatment options for rare neurological diseases with rare mutations, and patient-specific ASOs need to be developed. The 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop and treat eligible patients with patient-specific ASOs in Europe and the Netherlands, respectively, under a named patient setting.
Article
Biochemistry & Molecular Biology
Annemieke Aartsma-Rus, Alejandro Garanto, Willeke Van Roon-Mom, Erin M. McConnell, Victoria Suslovitch, Winston X. Yan, Jonathan K. Watts, Timothy W. Yu
Summary: The N = 1 Collaborative (N1C) recently organized a workshop to discuss and advance standards for the design and testing of splice-switching ASOs for individualized medicine. In this study, guidelines are presented, including the dissemination of standardized experimental designs, use of standardized reference ASOs, and a commitment to data sharing and exchange.
NUCLEIC ACID THERAPEUTICS
(2023)
Article
Biotechnology & Applied Microbiology
Annemieke Aartsma-Rus
Summary: Antisense oligonucleotide (ASO)-mediated exon skipping can restore the open reading frame of dystrophin transcripts for Duchenne muscular dystrophy (DMD) patients. Ways to improve ASO efficiency and applicability of this mutation-specific approach are evaluated in this expert perspective.
HUMAN GENE THERAPY
(2023)
Article
Multidisciplinary Sciences
Mirko Signorelli, Roula Tsonaka, Annemieke Aartsma-Rus, Pietro Spitali
Summary: Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by a lack of dystrophin in skeletal muscle. To better understand the disease progression and response to therapy, a study analyzed longitudinal multiomic data from 3 murine models of DMD. Integration of RNA-seq, metabolomic, and lipidomic data revealed 8 latent factors that explained a large portion of the variance in the dataset. These factors could distinguish between healthy and dystrophic mice, as well as different time-points. The study also connected gene expression changes in dystrophic muscles to inflammation and lipid signatures in the blood.
Article
Biochemistry & Molecular Biology
Remko Goossens, Nisha Verwey, Yavuz Ariyurek, Fred Schnell, Annemieke Aartsma-Rus
Summary: The study reveals that the non-sequential splicing of DMD transcript and the retention time of adjacent introns have an impact on the efficiency of AON. Targeting an out-of-frame exon flanked by a "slow" intron at its 5'-end leads to higher exon skipping efficiency. Furthermore, placing AON closer to the 5'-end of the target exon results in better skipping efficiency regardless of the splicing speed of adjacent introns.
Article
Multidisciplinary Sciences
L. G. M. Heezen, T. Abdelaal, M. van Putten, A. Aartsma-Rus, A. Mahfouz, P. Spitali
Summary: Using spatial transcriptomics, the authors identified gene expression signatures related to the histopathological changes in Duchenne mouse models. This study provides valuable insights into the underlying pathology and potential therapeutic targets for Duchenne muscular dystrophy.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Sarah Engelbeen, Daniel O'Reilly, Davy van de Vijver, Ingrid Verhaart, Maaike van Putten, Vignesh Hariharan, Matthew Hassler, Anastasia Khvorova, Masad J. Damha, Annemieke Aartsma-Rus
Summary: In this study, the researchers aimed to optimize the efficiency of antisense oligonucleotide (AON) therapy for Duchenne muscular dystrophy (DMD) patients. They evaluated exon 53 skipping of the DMD transcript with different chemically modified AONs and found that FRNA, LNA-FRNA, and LNA-2'O-Me AONs were the most efficient in human control myoblast cultures. However, in a mouse experiment, treatment with LNA-FRNA and LNA-2'O-Me AONs resulted in high levels of exon 53 skipping but no restoration of dystrophin, mainly due to the strong binding nature of LNA modifications to RNA interfering with amplification of unskipped product.
NUCLEIC ACID THERAPEUTICS
(2023)
Article
Medicine, Research & Experimental
Yu C. J. Chey, Jayshen Arudkumar, Annemieke Aartsma-Rus, Fatwa Adikusuma, Paul Q. Thomas
Summary: CRISPR gene-editing technology allows for the generation of animal disease models and has the potential to revolutionize the treatment of genetic disorders, such as Duchenne muscular dystrophy. It enables the generation of animal models that closely simulate disease-causing mutations, providing a platform for testing interventions like CRISPR therapy.
WIRES MECHANISMS OF DISEASE
(2023)