Molecular Approaches for the Treatment of Pompe Disease

Bellotti, Anita Sofia; Andreoli, Luca; Ronchi, Dario; Bresolin, Nereo; Comi, Giacomo Pietro; Corti, Stefania

doi:10.1007/s12035-019-01820-5

Cited by 21 publications

(23 citation statements)

References 134 publications

(249 reference statements)

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“…The recombinant enzyme is taken up by the cells and can restore the missing enzyme activity to a varying degree. ERT has been successfully used in various diseases, including several lysosomal storage disorders, such as α-mannosidosis, Pompe disease, and classic late infantile neuronal ceroid lipofuscinosis (cLINCL), just to mention a few examples [101][102][103].…”

Section: Further Potential Therapy Optionsmentioning

confidence: 99%

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Didiášová

Banning

Brennenstuhl

et al. 2020

Cells

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Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental retardation, autism, ataxia, and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved curative therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials, and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between researchers and patients.

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Section: Further Potential Therapy Optionsmentioning

confidence: 99%

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Didiášová

Banning

Brennenstuhl

et al. 2020

Cells

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“…This enzyme catalyzes the hydrolysis the α-1,4 and 1,6-glycosidic bonds of glycogen to produce glucose in lysosomes. The incidence of PD is wide ranging from 1:14,000 (in African populations and African-Americans) to 1:238,000 in Europe [ 73 ]. There are more than 400 different GAA mutations producing PD symptoms (from HGMD).…”

Section: Second-generation Pharmacological Chaperones Against Lsdsmentioning

confidence: 99%

“…As GAA is the sole protein responsible for glycogen degradation in lysosomes, its functional deficiency causes accumulation of the glycogen in all tissues, especially in muscles and heart, giving rise to reduced motor functions and respiratory deficits. The resulting spectrum of pathological manifestations ranges from slow progressive phenotype with late onset to devastating childhood-onset [ 73 , 74 ].…”

Section: Second-generation Pharmacological Chaperones Against Lsdsmentioning

confidence: 99%

“…The recombinant h GAA produced in Chinese hamster ovary cells line was approved in 2006 (Myozyme™) and allowed the increase of patient’s survival as well as a slowdown in the disease progression. Despite these obvious benefits, the patient’s response to ERT is highly variable and the efficiency in treating the muscular involvement remains insufficient [ 73 ]. PC therapy was also explored against PD, either alone or in combination with ERT.…”

Section: Second-generation Pharmacological Chaperones Against Lsdsmentioning

confidence: 99%

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Second-Generation Pharmacological Chaperones: Beyond Inhibitors

et al. 2020

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Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.

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“…The recombinant enzyme is taken up by the cells and can restore the missing enzyme activity to a varying degree. ERT has been successfully used in various diseases, including several lysosomal storage disorders such as α-mannosidosis, Pompe disease and classic late infantile neuronal ceroid lipofuscinosis (cLINCL), just to mention a few examples [87,88,89].…”

Section: Enzyme Replacement Therapy: Special Requirements For Ssadh-dmentioning

confidence: 99%

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Didiášová¹,

Banning²,

Brennenstuhl³

et al. 2020

Preprint

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Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by the impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degree of mental retardation, autism, ataxia and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential use of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between the researchers and the patients.

show abstract

Molecular Approaches for the Treatment of Pompe Disease

Cited by 21 publications

References 134 publications

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Second-Generation Pharmacological Chaperones: Beyond Inhibitors

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

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