Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases

Karpe, Yashashree; Chen, Zhenyu; Li, Xue-Jun

doi:10.3390/ph14060565

Cited by 10 publications

(6 citation statements)

References 150 publications

(169 reference statements)

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“…The first of these techniques, NHEJ, is a fast but error-prone process that often leads to insertions and deletions at the breakpoint, thereby knocking out the gene encoding the protein. In contrast, HR induces insertions or replaces DNA fragments with a donor template, while being relatively error-free Figure 3 [ 142 , 143 , 144 , 145 , 146 ].…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives

Lejman

Panuciak

Nowicka

et al. 2023

IJMS

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Gene therapy is defined as the administration of genetic material to modify, manipulate gene expression or alter the properties of living cells for therapeutic purposes. Recent advances and improvements in this field have led to many breakthroughs in the treatment of various diseases. As a result, there has been an increasing interest in the use of these therapies to treat motor neuron diseases (MNDs), for which many potential molecular targets have been discovered. MNDs are neurodegenerative disorders that, in their most severe forms, can lead to respiratory failure and death, for instance, spinal muscular atrophy (SMA) or amyotrophic lateral sclerosis (ALS). Despite the fact that SMA has been known for many years, it is still one of the most common genetic diseases causing infant mortality. The introduction of drugs based on ASOs—nusinersen; small molecules—risdiplam; and replacement therapy (GRT)—Zolgensma has shown a significant improvement in both event-free survival and the quality of life of patients after using these therapies in the available trial results. Although there is still no drug that would effectively alleviate the course of the disease in ALS, the experience gained from SMA gene therapy gives hope for a positive outcome of the efforts to produce an effective and safe drug. The aim of this review is to present current progress and prospects for the use of gene therapy in the treatment of both SMA and ALS.

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Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives

Lejman

Panuciak

Nowicka

et al. 2023

IJMS

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“…In addition to conventional therapies, targeted gene therapy is a novel and attractive prospect for COQ10D7. With the development of induced pluripotent stem cells (iPSCs) and gene editing technologies, in vitro and in vivo disease models can be established more readily to advance the development of gene therapy (Karpe, et al, 2021). For example, phenotypic rescue was achieved in patient-derived iPSCs and mouse models via rectification of pathogenic variants in amyotrophic lateral sclerosis and disruption of splicing regulatory elements in spinal muscular atrophy (SMA) using gene editing (Wang, et al, 2017;Son, et al, 2019;Lin, et al, 2020).…”

Section: Treatment Of Coq10d7mentioning

confidence: 99%

Primary Coenzyme Q10 Deficiency-7 and Pathogenic COQ4 Variants: Clinical Presentation, Biochemical Analyses, and Treatment

2022

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Primary Coenzyme Q10 Deficiency-7 (COQ10D7) is a rare mitochondrial disorder caused by pathogenic COQ4 variants. In this review, we discuss the correlation of COQ4 genotypes, particularly the East Asian-specific c.370G > A variant, with the clinical presentations and therapeutic effectiveness of coenzyme Q10 supplementation from an exon-dependent perspective. Pathogenic COQ4 variants in exons 1–4 are associated with less life-threating presentations, late onset, responsiveness to CoQ10 therapy, and a relatively long lifespan. In contrast, pathogenic COQ4 variants in exons 5–7 are associated with early onset, unresponsiveness to CoQ10 therapy, and early death and are more fatal. Patients with the East Asian-specific c.370G > A variant displays intermediate disease severity with multi-systemic dysfunction, which is between that of the patients with variants in exons 1–4 and 5–7. The mechanism underlying this exon-dependent genotype-phenotype correlation may be associated with the structure and function of COQ4. Sex is shown unlikely to be associated with disease severity. While point-of-care high-throughput sequencing would be useful for the rapid diagnosis of pathogenic COQ4 variants, whereas biochemical analyses of the characteristic impairments in CoQ10 biosynthesis and mitochondrial respiratory chain activity, as well as the phenotypic rescue of the CoQ10 treatment, are necessary to confirm the pathogenicity of suspicious variants. In addition to CoQ10 derivatives, targeted drugs and gene therapy could be useful treatments for COQ10D7 depending on the in-depth functional investigations and the development of gene editing technologies. This review provides a fundamental reference for the sub-classification of COQ10D7 and aim to advance our knowledge of the pathogenesis, clinical diagnosis, and prognosis of this disease and possible interventions.

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“…Most protocols available to generate iPSC-derived MNs are typically optimized to obtain two dimensional (2D) monolayer cultures (12–17) which have allowed the study of the pathogenic molecular mechanisms associated with MNDs such as cytoskeletal abnormalities, axonal transport deficits and changes in excitability (18, 19). However, several lines of evidence suggest that the absence of three dimensional (3D) cell-to-cell and cell-to-matrix interactions may be detrimental to the maturation (20, 21), differentiation (22) and morphology (23, 24) of cells grown in vitro .…”

Section: Introductionmentioning

confidence: 99%

An optimized workflow to generate and characterize iPSC-derived motor neuron (MN) spheroids

Castellanos-Montiel

Chaineau

Franco-Flores

et al. 2022

Preprint

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Motor neuron diseases (MNDs) are characterized by the progressive degeneration of motor neurons (MNs) from the cortex, brainstem and/or the spinal cord. In an effort to understand the underlying causes of this selective degeneration, a multitude of in vitro models based on induced pluripotent stem cell (iPSC)-derived MNs have been developed. Moreover, different groups have started to use advanced 3D structures, composed of MNs and other cell types to increase the physiological relevance of such in vitro models. For instance, spheroids are simple 3D models that have the potential to be generated in large numbers that can be used across different assays. In this study, we generated MN spheroids and developed a workflow to analyze them. We confirmed the expression of different MN markers as the MN spheroids differentiate, at both the transcript and protein level, as well as their capacity to display functional activity in the form of action potentials (APs) and bursts. We also identified the presence of other cell types, namely interneurons and oligodendrocytes, which share the same neural progenitor pool with MNs. In summary, we successfully developed a MN 3D model, and we optimized a workflow that can be applied to their characterization and analysis. In the future, we will apply this model and workflow to the study of MNDs by generating MN spheroids from patient-derived iPSC lines, aiming to contribute to the development of more advance and physiological in vitro disease models.

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Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases

Cited by 10 publications

References 150 publications

Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives

Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives

Primary Coenzyme Q10 Deficiency-7 and Pathogenic COQ4 Variants: Clinical Presentation, Biochemical Analyses, and Treatment

An optimized workflow to generate and characterize iPSC-derived motor neuron (MN) spheroids

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