Nonsense Suppression as an Approach to Treat Lysosomal Storage Diseases

Leukodystrophies (LDs) predominantly affect the white matter of the central nervous system and its main component, the myelin. The majority of LDs manifests in infancy with progressive neurodegeneration. Main clinical signs are intellectual and motor function losses of already attained developmental skills. Classical LDs include lysosomal storage disorders like metachromatic leukodystrophy (MLD), peroxisomal disorders like X-linked adrenoleukodystrophy (X-ALD), disorders of mitochondrial dysfunction, and myelin protein defects like Pelizaeus-Merzbacher disease. So far, there are only single LD disorders with effective treatment options in an early stage of disease. The increasing number of patients diagnosed with LDs emphasizes the need for novel therapeutic options. Impressive advances in biotechnology have not only led to the continuous identification of new disease genes for so far unknown LDs but also led to new effective neuroprotective and disease-modifying therapeutic approaches. This review summarizes ongoing and novel innovative treatment options for LD patients and their challenges. It includes in vitro and in vivo approaches with focus on stem cell and gene therapies, intrathecal substrate or enzyme replacement, and genome editing.

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“…1). 56 Accordingly, in vitro experiments with readthrough drugs show first promising results in LSDs. 57 Nucleic Acids/Gene Editing Therapies…”

Section: Stop Codon Read-throughmentioning

confidence: 99%

Opening New Horizons in the Treatment of Childhood Onset Leukodystrophies

2019

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“…In many other cell culture and animal studies of lysosomal storage disorders, it has been demonstrated that several aminoglycoside derivatives are capable of increasing enzyme levels and even improving organ manifestations . A first clinical trial of nonsense suppression therapy in patients with Hurler disease will be initiated soon.…”

Section: Stop‐codon Read‐throughmentioning

confidence: 99%

Treatment strategies for lysosomal storage disorders

Beck

2017

Develop Med Child Neuro

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Over the past several years the number of treatments available for patients with lysosomal storage disorders has rapidly increased. Haematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction, and chaperone therapies are currently available, and gene therapies and other treatments are rapidly advancing. Despite remarkable advances, the efficacy of most of these therapies is limited, particularly because the treatments are usually initiated when organ damage has already occurred. To circumvent this limitation, screening in newborn infants for lysosomal storage disorders has been introduced in many countries. However, this screening is complicated by the broad clinical variability of the disorders and the fact that many individuals who will be detected as having an enzyme deficiency will develop symptoms very late or never in their life. This paper provides an overview of available therapies for lysosomal storage disorders and describes those treatments that are under development. What this paper adds For a few lysosomal storage disorders, new therapies are available or under development. These therapies include enzyme replacement therapy, small molecules, and gene therapy. The new therapies cannot cure patients, but can stabilize organ function or slow progression.

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“…Inhibition of NMD is therefore considered an important target to facilitate gene expression, and current strategies envisage extensive searching of chemical compounds targeting either premature translation termination, or NMD, or both. In recent years, excellent reviews have been published that cover the huge amount of information derived from the rapid progress in knowledge about (a) the fundamental steps of gene expression like translation [10,11] and NMD [10][11][12][13][14][15][16][17][18], (b) the nonsense suppression therapeutic approach [2,[10][11][12]19,20], (c) genetic diseases associated with nonsense mutations linking together the two processes [20][21][22][23], and (d) small molecules able to interfere with one, the other, or both processes [24][25][26][27], in an effort to correct in the cytoplasm errors produced in the nucleus. So far, one of the most widespread genetic diseases, β 0 -thalassemia, caused by nonsense mutations, has not been involved in the therapeutic approach based on nonsense suppression mediated by small molecules, despite it having been a long time since it was shown to be caused by nonsense mutations [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia

Borgatti

Altamura

Salvatori

et al. 2020

JCM

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Several types of thalassemia (including β039-thalassemia) are caused by nonsense mutations in genes controlling globin production, leading to premature translation termination and mRNA destabilization mediated by the nonsense mediated mRNA decay. Drugs (for instance, aminoglycosides) can be designed to suppress premature translation termination by inducing readthrough (or nonsense suppression) at the premature termination codon. These findings have introduced new hopes for the development of a pharmacologic approach to cure this genetic disease. In the present review, we first summarize the principle and current status of the chemical relief for the expression of functional proteins from genes otherwise unfruitful for the presence of nonsense mutations. Second, we compare data available on readthrough molecules for β0-thalassemia. The examples reported in the review strongly suggest that ribosomal readthrough should be considered as a therapeutic approach for the treatment of β0-thalassemia caused by nonsense mutations. Concluding, the discovery of molecules, exhibiting the property of inducing β-globin, such as readthrough compounds, is of great interest and represents a hope for several patients, whose survival will depend on the possible use of drugs rendering blood transfusion and chelation therapy unnecessary.

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Nonsense Suppression as an Approach to Treat Lysosomal Storage Diseases

Cited by 29 publications

References 167 publications

Opening New Horizons in the Treatment of Childhood Onset Leukodystrophies

Opening New Horizons in the Treatment of Childhood Onset Leukodystrophies

Treatment strategies for lysosomal storage disorders

Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia

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