Gene Therapy of Sphingolipid Metabolic Disorders

Shaimardanova, Alisa A.; Solovyeva, Valeriya V.; Issa, Shaza S.; Rizvanov, Albert A.

doi:10.3390/ijms24043627

Cited by 10 publications

(6 citation statements)

References 133 publications

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“…The AAV serotype 2 was the first to be vectorized and several pseudo-types have been generated with cell- or tissue-specific tropism 25,26 . These vectors achieve stable transgene expression, and have been extensively employed in pre-clinical studies on various disease models as well as in clinical trials 27 28–45 Several AAV-mediated gene therapy clinical trials, which have been approved by both the Food and Drug Administration and the European Medicines Agency, 24 are currently in place for different LSDs, including Gaucher disease, GM1- and GM2-gangliosidoses, Krabbe disease, several mucopolysaccharidoses (I, II, IIIA, B, C, D, VII), metachromatic leukodystrophy, Pompe disease, Batten disease (neuronal ceroid lipofuscinoses; CLN1 – 8), Fabry disease, and Danon disease 20,46–50 .…”

Section: Discussionmentioning

confidence: 99%

AAV-mediated gene therapy for Sialidosis

van de Vlekkert,

Hu,

Fremuth

et al. 2023

Preprint

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Sialidosis is a glycoprotein storage disease caused by deficiency of the lysosomal sialidase NEU1, which leads to pathogenic accumulation of sialylated glycoproteins and oligosaccharides in tissues and body fluids. The disease belongs to the group of orphan disorders with no therapy currently available. Here, we have tested the therapeutic potential of AAV-mediated gene therapy for the treatment of sialidosis in a mouse model of the disease. One-month-oldNeu1−/−mice were co-injected with two scAAV2/8 vectors, expressing NEU1 and its chaperone PPCA, and sacrificed at 3 months post-injection. Treated mice were phenotypically indistinguishable from their WT controls. Histopathologically, they showed diminished or absent vacuolization in cells of visceral organs, including the kidney, as well as the choroid plexus and other areas of the brain. This was accompanied by restoration of NEU1 activity in most tissues, reversal of sialyl-oligosacchariduria, and normalization of lysosomal exocytosis in the CSF and serum of treated mice. AAV injection prevented the occurrence of generalized fibrosis, which is a prominent contributor of disease pathogenesis inNeu1−/−mice and likely in patients. Overall, this therapeutic strategy holds promise for the treatment of sialidosis and may be applicable to adult forms of human idiopathic fibrosis with low NEU1 expression.

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Section: Discussionmentioning

confidence: 99%

AAV-mediated gene therapy for Sialidosis

van de Vlekkert,

Hu,

Fremuth

et al. 2023

Preprint

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“…At Kazan Federal University, we are actively engaged in developing gene and genecell therapy drugs for the treatment of rare (orphan) hereditary diseases, including ALS, MLD, TSD, and others [3,4,8]. Additionally, we are researching the use of gene therapy drugs to stimulate neuroregeneration and provide neuroprotection through expression of various growth factors, which can potentially help patients with neurological diseases and trauma by slowing down disease progression and aiding in recovery after other treatments [9,10].…”

Section: Discussionmentioning

confidence: 99%

“…However, only a few have effective treatments available. Some common examples of rare hereditary neurological diseases include Huntington's disease, Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Metachromatic Leukodystrophy (MLD), and Tay-Sachs disease (TSD) [2][3][4]. These diseases are often progressive and can have a significant impact on the affected individual and their families, leading to reduced lifespan and substantial morbidity.…”

Section: Introductionmentioning

confidence: 99%

New Hope: Using Gene Therapy to Treat Rare Neurological Diseases

Rizvanov

2023

jour

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Gene therapy is a promising treatment approach for rare/orphan neurological diseases that have limited treatment options and no cure. This article provides a brief overview of different types of rare hereditary neurological diseases and discusses existing gene therapy drugs approved for their treatment. Despite challenges associated with the development and implementation of gene therapy, including cost, delivery, and long-term safety and efficacy, the potential benefits of gene therapy make it a compelling area of research for the treatment of rare hereditary neurological diseases.

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“…FLT190 is composed of a codonoptimized GLA transgene with a liver-specific promoter. The construct, covered by a synthetic capsid, demonstrates higher transduction efficiency in human hepatocytes compared to wild-type AAV serotypes [41].…”

Section: Gene Therapymentioning

confidence: 99%

Fabry disease: current treatment and future perspective

Yoo

2023

J Genet Med

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Fabry disease (FD), a rare X-linked lysosomal storage disorder, is caused by mutations in the α-galactosidase A gene gene encoding α-galactosidase A (α-Gal A). The functional deficiency of α-Gal A results in progressive accumulation of neutral glycosphingolipids, causing multi-organ damages including cardiac, renal, cerebrovascular systems. The current treatment is comprised of enzyme replacement therapy (ERT), oral pharmacological chaperone therapy and adjunctive supportive therapy. ERT has been introduced 20 years ago, changing the outcome of FD patients with proven effectiveness. However, FD patients have many unmet needs. ERT needs a life-long intravenous therapy, inefficient bio-distribution, and generation of anti-drug antibodies. Migalastat, a pharmacological chaperone, augmenting α-Gal A enzyme activity only in patients with mutations amenable to the therapy, is now available for clinical practice. Furthermore, these therapies should be initiated before the organ damage becomes irreversible. Development of novel drugs aim at improving the clinical effectiveness and convenience of therapy. Clinical trial of next generation ERT is underway. Polyethylene glycolylated enzyme has a longer halflife and potentially reduced antigenicity, compared with standard preparations with longer dosing interval. Moss-derived enzyme has a higher affinity for mannose receptors, and seems to have more efficient access to podocytes of kidney which is relatively resistant to reach by conventional ERT. Substrate reduction therapy is currently under clinical trial. Gene therapy has now been started in several clinical trials using in vivo and ex vivo technologies. Early results are emerging. Other strategic approaches at preclinical research level are stem cell-based therapy with genome editing and systemic mRNA therapy.

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Gene Therapy of Sphingolipid Metabolic Disorders

Cited by 10 publications

References 133 publications

AAV-mediated gene therapy for Sialidosis

AAV-mediated gene therapy for Sialidosis

New Hope: Using Gene Therapy to Treat Rare Neurological Diseases

Fabry disease: current treatment and future perspective

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