AAV-Mediated Gene Therapy for Glycosphingolipid Biosynthesis Deficiencies

Yang, Huiya; Brown, Robert H.; Wang, Dan; Strauss, Kevin A.; Gao, Guangping

doi:10.1016/j.molmed.2021.02.004

Cited by 7 publications

(5 citation statements)

References 15 publications

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“…Brain MR imaging is normal or shows a pattern of nonspecific white matter changes or atrophy in a subset of patients (Boukhris et al, 2013). Current treatment for B4GALNT1 ‐associated HSP is directed at ameliorating symptoms but an advanced understanding of the underlying molecular biology and the availability of viral vectors for gene delivery for CNS disorders carries the potential for targeted therapies, that is, gene replacement (Yang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Functional validation of novel variants in B4GALNT1 associated with early‐onset complex hereditary spastic paraplegia with impaired ganglioside synthesis

Alecu

Ohmi

Bhuiyan

et al. 2022

American J of Med Genetics Pt A

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Childhood‐onset forms of hereditary spastic paraplegia are ultra‐rare diseases and often present with complex features. Next‐generation‐sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and/or downstream pathways exists, functional studies in patient‐derived cells can aid the interpretation of molecular findings. We here illustrate the case of a 13‐year‐old female who presented with global developmental delay and later mild intellectual disability, progressive spastic diplegia, spastic‐ataxic gait, dysarthria, urinary urgency, and loss of deep tendon reflexes of the lower extremities. Exome sequencing showed a novel splice‐site variant in trans with a novel missense variant in B4GALNT1 [NM_001478.5: c.532‐1G>C/c.1556G>C (p.Arg519Pro)]. Functional studies in patient‐derived fibroblasts and cell models of GM2 synthase deficiency confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream gangliosides. Collectively these results established the diagnosis of B4GALNT1‐associated HSP (SPG26). Our approach illustrates the importance of careful phenotyping and functional characterization of novel gene variants, particularly in the setting of ultra‐rare diseases, and expands the clinical and molecular spectrum of SPG26, a disorder of complex ganglioside biosynthesis.

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“…Furthermore, inhibiting the high expression of related glycosphingolipids will have a clear palliative effect on the development of tumors and will help to block the metastatic pathway of tumors. For example, Salk found that the sialylation level of the glycosphingolipid sugar chain of cells increased with high malignancy or high metastatic potential, indicating that sialic acid glycosphingolipid may promote the metastasis and deterioration of tumor cells ( Yang et al, 2021 ). These studies have suggested a potential association between cell cycle activity and the related metabolism between LC and CIS.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of CCNB2 and Its Perspective Mechanisms in Cerebral Ischemic Stroke and All Subtypes of Lung Cancer: A Comprehensive Study

Yan

Chen

et al. 2022

Front. Integr. Neurosci.

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Cyclin B2 (CCNB2) belongs to type B cell cycle family protein, which is located on chromosome 15q22, and it binds to cyclin-dependent kinases (CDKs) to regulate their activities. In this study, 103 high-throughput datasets related to all subtypes of lung cancer (LC) and cerebral ischemic stroke (CIS) with the data of CCNB2 expression were collected. The analysis of standard mean deviation (SMD) and summary receiver operating characteristic (SROC) reflecting expression status demonstrated significant up-regulation of CCNB2 in LC and CIS (Lung adenocarcinoma: SMD = 1.40, 95%CI [0.98–1.83], SROC = 0.92, 95%CI [0.89–0.94]. Lung squamous cell carcinoma: SMD = 2.56, 95%CI [1.64–3.48]. SROC = 0.97, 95%CI [0.95–0.98]. Lung small cell carcinoma: SMD = 3.01, 95%CI [2.01–4.01]. SROC = 0.98, 95%CI [0.97–0.99]. CIS: SMD = 0.29, 95%CI [0.05–0.53], SROC = 0.68, 95%CI [0.63–0.71]). Simultaneously, protein-protein interaction (PPI) analysis indicated that CCNB2 is the hub molecule of crossed high-expressed genes in CIS and LC. Through Multiscale embedded gene co-expression network analysis (MEGENA), a gene module of CIS including 76 genes was obtained and function enrichment analysis of the CCNB2 module genes implied that CCNB2 may participate in the processes in the formation of CIS and tissue damage caused by CIS, such as “cell cycle,” “protein kinase activity,” and “glycosphingolipid biosynthesis.” Afterward, via single-cell RNA-seq analysis, CCNB2 was found up-regulated on GABAergic neurons in brain organoids as well as T cells expressing proliferative molecules in LUAD. Concurrently, the expression of CCNB2 distributed similarly to TOP2A as a module marker of cell proliferation in cell cluster. These findings can help in the field of the pathogenesis of LC-related CIS and neuron repair after CIS damage.

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“…Silencing mutant SPTLC1 and sparing the wildtype allele can potentially reduce 1-deoxySL production. Another strategy is to deliver a dual-function rAAV that expresses both amiRNA and a functional SPTLC1 cDNA, in which the amiRNA-recognized endogenous miRNA machinery degrades endogenous SPTLC1 mRNA and amiRNA-resistant SPTLC1 transcript produces wildtype SPTLC1 179,284 .Further results from preclinical studies are needed to plan a trial in humans.…”

Section: [H2] Symptomatic Therapiesmentioning

confidence: 99%

Genetic pain loss disorders

Lischka

Laššuthová

Çakar

et al. 2022

Nat Rev Dis Primers

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“…Because GM3SD is a monogenic loss-of-function disease, gene replacement therapy may be a promising approach. Recombinant adeno-associated viruses (rAAVs) have emerged as powerful gene delivery tools for the treatment of monogenic diseases, and to date have been tested in 17 clinical trials targeting CNS disorders (14,15). An ideal rAAV vector should deliver its therapeutic cargo into specific target cells to restore an appropriate spatial, quantitative, and temporal pattern of protein expression.…”

Section: Introductionmentioning

confidence: 99%

Rescue of GM3 synthase deficiency by spatially controlled, rAAV-mediated ST3GAL5 delivery

Yang¹,

Brown²,

Wang³

et al. 2023

JCI Insight

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GM3 synthase deficiency (GM3SD) is an infantile-onset epileptic encephalopathy syndrome caused by biallelic loss-of-function mutations in ST3GAL5. Loss of ST3GAL5 activity in humans results in systemic ganglioside deficiency and severe neurological impairment. No disease-modifying treatment is currently available.Certain recombinant adeno-associated viruses (rAAVs) are capable of crossing the blood-brain barrier to induce widespread, long-term gene expression in the central nervous system (CNS), and represent a promising therapeutic strategy. Here, we show that a first-generation rAAV-ST3GAL5 replacement vector employing a ubiquitous promoter restored tissue ST3GAL5 expression and normalized cerebral gangliosides in patient-derived iPSC neurons and brain tissue from St3gal5 knock-out mice, but caused fatal hepatotoxicity when administered systemically. In contrast, a second-generation vector optimized for CNS-restricted ST3GAL5 expression, administered by either intracerebroventricular or intravenous route at postnatal day 1, allowed for safe and effective rescue of lethality and behavior impairment in symptomatic GM3SD mice up to a year. These results support further clinical development of ST3GAL5 gene therapy.

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“…It occurs most prevalently in Old Order Amish communities [14] but in non-Amish patients as well [15]. Gene modification is an obvious therapeutic approach [16] but ganglioside replacement therapy in which patients are administered one or more of the missing gangliosides deemed most essential for neuronal function is also worthy of consideration. In that regard, ganglioside GM1 is receiving primary attention owing to the several functions it mediates in preservation of neuronal function and viability [17,18].…”

mentioning

confidence: 99%

Synthetic GM1 improves motor and memory dysfunctions in mice with monoallelic or biallelic disruption of GM3 synthase

Chowdhury,

Kumar,

Zepeda

et al. 2023

FEBS Open Bio

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This study attempts to answer the question of whether mice with biallelic and monoallelic disruption of the St3gal5 (GM3 synthase) gene might benefit from GM1 replacement therapy. The GM3 produced by this sialyltransferase gives rise to downstream GD3 and the ganglio‐series of gangliosides. The latter includes the a‐series (GM1 + GD1a), which has proved most essential for neuron survival and function (especially GM1, for which GD1a provides a reserve pool). These biallelic mice serve as a model for children with this relatively rare autosomal recessive condition (ST3GAL5−/−) who suffer rapid neurological decline including motor loss, intellectual disability, visual and hearing loss, failure to thrive, and other severe conditions leading to an early death by 2–5 years of age without supportive care. Here, we studied both these mice, which serve as a model for the parents and close relatives of these children who are likely to suffer long‐term disabilities due to partial deficiency of GM1, including Parkinson's disease (PD). We find that the movement and memory disorders manifested by both types of mice can be resolved with GM1 application. This suggests the potential therapeutic value of GM1 for disorders stemming from GM1 deficiency, including GM3 synthase deficiency and PD. It was noteworthy that the GM1 employed in these studies was synthetic rather than animal brain‐derived, reaffirming the therapeutic efficacy of the former.

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AAV-Mediated Gene Therapy for Glycosphingolipid Biosynthesis Deficiencies

Cited by 7 publications

References 15 publications

Functional validation of novel variants in B4GALNT1 associated with early‐onset complex hereditary spastic paraplegia with impaired ganglioside synthesis

Upregulation of CCNB2 and Its Perspective Mechanisms in Cerebral Ischemic Stroke and All Subtypes of Lung Cancer: A Comprehensive Study

Genetic pain loss disorders

Rescue of GM3 synthase deficiency by spatially controlled, rAAV-mediated ST3GAL5 delivery

Synthetic GM1 improves motor and memory dysfunctions in mice with monoallelic or biallelic disruption of GM3 synthase

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