Therapeutic Approaches in Lysosomal Storage Diseases

Fernández‐Pereira, Carlos; Millán-Tejado, Beatriz San; Gallardo-Gómez, María; Pérez-Márquez, Tania; Alves-Villar, Marta; Melcón-Crespo, Cristina; Fernández-Martín, Julián; Ortolano, Saida

doi:10.3390/biom11121775

Cited by 33 publications

(20 citation statements)

References 91 publications

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“…Prior to the introduction of ERT, treatment was essentially palliative and aimed to relieve symptoms. ERT studies in animal models of Fabry disease and other LSDs showed that intravenously infused lysosomal enzymes are rapidly taken up by the liver, spleen and other peripheral tissues, but do not normally reach the brain parenchyma [ 109 ]. Some of the problems associated with the use of ERT are the reduced efficacy of therapy at the CNS level, the immune response to the replacement protein, the use of lifelong therapy and the high cost of treatment [ 48 , 76 ].…”

Section: Therapies For Fdmentioning

confidence: 99%

An Overview of Molecular Mechanisms in Fabry Disease

et al. 2022

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Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation in the GLA gene on the X chromosome. The enzyme deficiency leads to a continuous deposition of neutral glycosphingolipids (globotriaosylceramide) in the lysosomes of numerous tissues and organs, including endothelial cells, smooth muscle cells, corneal epithelial cells, renal glomeruli and tubules, cardiac muscle and ganglion cells of the nervous system. This condition leads to progressive organ failure and premature death. The increasing understanding of FD, and LSD in general, has led in recent years to the introduction of enzyme replacement therapy (ERT), which aims to slow, if not halt, the progression of the metabolic disorder. In this review, we provide an overview of the main features of FD, focusing on its molecular mechanism and the role of biomarkers.

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Section: Therapies For Fdmentioning

confidence: 99%

An Overview of Molecular Mechanisms in Fabry Disease

et al. 2022

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“…Several approaches for the treatment of Fabry disease have been exploited, both preclinically and clinically, including enzyme replacement therapy (ERT), gene therapy, and chaperone therapy ( Solomon and Muro, 2017 ; Castelli et al, 2021 ; Fernández-Pereira et al, 2021 ). Despite the success of these therapeutic strategies, each approach has its limitations.…”

Section: Introductionmentioning

confidence: 99%

Fabry disease: Mechanism and therapeutics strategies

Ren

Zhang

et al. 2022

Front. Pharmacol.

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Fabry disease is a monogenic disease characterized by a deficiency or loss of the α-galactosidase A (GLA). The resulting impairment in lysosomal GLA enzymatic activity leads to the pathogenic accumulation of enzymatic substrate and, consequently, the progressive appearance of clinical symptoms in target organs, including the heart, kidney, and brain. However, the mechanisms involved in Fabry disease-mediated organ damage are largely ambiguous and poorly understood, which hinders the development of therapeutic strategies for the treatment of this disorder. Although currently available clinical approaches have shown some efficiency in the treatment of Fabry disease, they all exhibit limitations that need to be overcome. In this review, we first introduce current mechanistic knowledge of Fabry disease and discuss potential therapeutic strategies for its treatment. We then systemically summarize and discuss advances in research on therapeutic approaches, including enzyme replacement therapy (ERT), gene therapy, and chaperone therapy, as well as strategies targeting subcellular compartments, such as lysosomes, the endoplasmic reticulum, and the nucleus. Finally, the future development of potential therapeutic strategies is discussed based on the results of mechanistic studies and the limitations associated with these therapeutic approaches.

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“…Among those disorders are countless rare diseases of monogenic origin, including the lysosomal storage diseases (LSDs) that were our major focus of interest. LSDs are a particular subset of genetic diseases that can benefit greatly from even the slightest increase in protein function [ 5 ]. The vast majority of LSDs are autosomal recessive, even though three X-linked diseases are also known.…”

Section: Introductionmentioning

confidence: 99%

Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example

Santos

Gonçalves

Matos

et al. 2022

Life

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Over recent decades, the many functions of RNA have become more evident. This molecule has been recognized not only as a carrier of genetic information, but also as a specific and essential regulator of gene expression. Different RNA species have been identified and novel and exciting roles have been unveiled. Quite remarkably, this explosion of novel RNA classes has increased the possibility for new therapeutic strategies that tap into RNA biology. Most of these drugs use nucleic acid analogues and take advantage of complementary base pairing to either mimic or antagonize the function of RNAs. Among the most successful RNA-based drugs are those that act at the pre-mRNA level to modulate or correct aberrant splicing patterns, which are caused by specific pathogenic variants. This approach is particularly tempting for monogenic disorders with associated splicing defects, especially when they are highly frequent among affected patients worldwide or within a specific population. With more than 600 mutations that cause disease affecting the pre-mRNA splicing process, we consider lysosomal storage diseases (LSDs) to be perfect candidates for this type of approach. Here, we introduce the overall rationale and general mechanisms of splicing modulation approaches and highlight the currently marketed formulations, which have been developed for non-lysosomal genetic disorders. We also extensively reviewed the existing preclinical studies on the potential of this sort of therapeutic strategy to recover aberrant splicing and increase enzyme activity in our diseases of interest: the LSDs. Special attention was paid to a particular subgroup of LSDs: the mucopolysaccharidoses (MPSs). By doing this, we hoped to unveil the unique therapeutic potential of the use of this sort of approach for LSDs as a whole.

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Therapeutic Approaches in Lysosomal Storage Diseases

Cited by 33 publications

References 91 publications

An Overview of Molecular Mechanisms in Fabry Disease

An Overview of Molecular Mechanisms in Fabry Disease

Fabry disease: Mechanism and therapeutics strategies

Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example

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