Antisense Oligonucleotide Reverses Leukodystrophy in Canavan Disease Mice

Hull, Vanessa; Wang, Yan; Burns, Travis; Zhang, Sheng; Sternbach, Sarah; McDonough, Jennifer; Guo, Fuzheng; Pleasure, David E

doi:10.1002/ana.25674

Cited by 27 publications

(47 citation statements)

References 22 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…76 Lastly, SRT for Canavan disease (OMIM#271900), a vacuolar leukodystrophy caused by accumulation of N-acetyl-L-aspartate (NAA), has been developed that utilizes a gapmer design AON to knockdown a protein involved in NAA synthesis. 47…”

Section: Substrate-reduction Therapy Using Aons As a Potential Treamentioning

confidence: 99%

Opportunities and challenges for antisense oligonucleotide therapies

Kuijper

Bergsma

Pijnappel

et al. 2020

J of Inher Metab Disea

View full text Add to dashboard Cite

Antisense oligonucleotide (AON) therapies involve short strands of modified nucleotides that target RNA in a sequence‐specific manner, inducing targeted protein knockdown or restoration. Currently, 10 AON therapies have been approved in the United States and Europe. Nucleotides are chemically modified to protect AONs from degradation, enhance bioavailability and increase RNA affinity. Whereas single stranded AONs can efficiently be delivered systemically, delivery of double stranded AONs requires capsulation in lipid nanoparticles or binding to a conjugate as the uptake enhancing backbone is hidden in this conformation. With improved chemistry, delivery vehicles and conjugates, doses can be lowered, thereby reducing the risk and occurrence of side effects. AONs can be used to knockdown or restore levels of protein. Knockdown can be achieved by single stranded or double stranded AONs binding the RNA transcript and activating RNaseH‐mediated and RISC‐mediated degradation respectively. Transcript binding by AONs can also prevent translation, hence reducing protein levels. For protein restoration, single stranded AONs are used to modulate pre‐mRNA splicing and either include or skip an exon to restore protein production. Intervening at a genetic level, AONs provide therapeutic options for inherited metabolic diseases as well. This review provides an overview of the different AON approaches, with a focus on AONs developed for inborn errors of metabolism.

show abstract

Section: Substrate-reduction Therapy Using Aons As a Potential Treamentioning

confidence: 99%

Opportunities and challenges for antisense oligonucleotide therapies

Kuijper

Bergsma

Pijnappel

et al. 2020

J of Inher Metab Disea

View full text Add to dashboard Cite

show abstract

“…RT-qPCR was performed by using QuantiTect SYBR ® Green PCR Kit (#204145, QIAGEN) on Agilent MP3005P thermocycler. The relative mRNA level of indicated genes was normalized to that of the internal control gene Hsp90 (Hsp90ab1), using the equation 2^(Ct(cycle threshold) of Hsp90 – Ct of indicated genes) according to our previous protocol (Hull et al, 2020). The gene expression levels in control groups were normalized to 1.…”

Section: Methodsmentioning

confidence: 99%

“…The antigen/antibody complex was eluted from beads by boiling in Lane Marker Sample Buffer (#39001, Thermo Fisher) containing mercaptoethanol for SDS-PAGE and Western blotting. normalized to that of the internal control gene Hsp90 (Hsp90ab1), using the equation 2^(Ct(cycle threshold) of Hsp90 − Ct of indicated genes) according to our previous protocol (Hull et al, 2020). The gene expression levels in control groups were normalized to 1.…”

Section: Protein Co-immunoprecipitation (Co-ip)mentioning

confidence: 99%

The Wnt effector TCF7l2 promotes oligodendroglial differentiation by repressing autocrine BMP4-mediated signaling

Zhang

Wang

Zhu

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Promoting oligodendrocyte differentiation represents a promising option for remyelination therapy for treating the demyelinating disease multiple sclerosis (MS). The Wnt effector TCF7l2 was upregulated in MS lesions and had been proposed to inhibit oligodendrocyte differentiation. Recent data suggest the opposite yet underlying mechanisms remain elusive. Here we unravel a previously unappreciated function of TCF7l2 in controlling autocrine bone morphogenetic protein (BMP4)-mediated signaling. Disrupting TCF7l2 results in oligodendroglial-specific BMP4 upregulation and canonical BMP4 signaling activation in vivo. Mechanistically, TCF7l2 binds to Bmp4 gene regulatory element and directly represses its transcriptional activity. Functionally, enforced TCF7l2 expression promotes oligodendrocyte differentiation by reducing autocrine BMP4 secretion and dampening BMP4 signaling. Importantly, compound genetic disruption demonstrates that oligodendroglial-specific BMP4 deletion rescues arrested oligodendrocyte differentiation elicited by TCF7l2 disruption in vivo. Collectively, our study reveals a novel connection between TCF7l2 and BMP4 in oligodendroglial lineage and provides new insights into augmenting TCF7l2 for promoting remyelination in demyelinating disorders such as MS.

show abstract

“…Other forms of therapies like antisense oligonucleotides, targeted drug therapy, enzyme replacement therapy and stem cell‐based therapy need further evidence before they are proved efficacious in the clinic. Table 6 summarizes the currently recommended therapeutic measures and Table S6 lists the emerging treatment modalities for common and selected disorders 4,62‐95 …”

Section: Treatmentmentioning

confidence: 99%

Genetic disorders with central nervous system white matter abnormalities: An update

et al. 2020

View full text Add to dashboard Cite

Several genetic disorders have variable degree of central nervous system white matter abnormalities. We retrieved and reviewed 422 genetic conditions with prominent and consistent involvement of white matter from the literature. We herein describe the current definitions, classification systems, clinical spectrum, neuroimaging findings, genomics, and molecular mechanisms of these conditions. Though diagnosis for most of these disorders relies mainly on genomic tests, specifically exome sequencing, we collate several clinical and neuroimaging findings still relevant in diagnosis of clinically recognizable disorders. We also review the current understanding of pathophysiology and therapeutics of these disorders.

show abstract

Antisense Oligonucleotide Reverses Leukodystrophy in Canavan Disease Mice

Cited by 27 publications

References 22 publications

Opportunities and challenges for antisense oligonucleotide therapies

Opportunities and challenges for antisense oligonucleotide therapies

The Wnt effector TCF7l2 promotes oligodendroglial differentiation by repressing autocrine BMP4-mediated signaling

Genetic disorders with central nervous system white matter abnormalities: An update

Contact Info

Product

Resources

About