Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules

Reddy, Kaalak; Jenquin, Jana R.; Cleary, John D.; Berglund, J. Andrew

doi:10.3390/ijms20164017

Cited by 17 publications

(19 citation statements)

References 112 publications

(196 reference statements)

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“…In HSA LR mice, furamidine increased MNBL1 functional expression by inhibiting transcription of CTG exp DNA and by disrupting the MNBL-CUG exp complex [ 93 ]. Compared to pentamidine, furamidine presented the lowest number of off-target gene expression changes [ 94 ]. In combination with erythromycin, furamidine enhanced the effects on MNBL-CUG exp complex disruption, reducing nuclear foci presence in patient-derived DM1 cells, without specific toxic effects [ 95 ].…”

Section: Targets and How To Reach Them: Dna And Rnamentioning

confidence: 99%

Nanomedicine for Gene Delivery and Drug Repurposing in the Treatment of Muscular Dystrophies

et al. 2021

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Muscular Dystrophies (MDs) are a group of rare inherited genetic muscular pathologies encompassing a variety of clinical phenotypes, gene mutations and mechanisms of disease. MDs undergo progressive skeletal muscle degeneration causing severe health problems that lead to poor life quality, disability and premature death. There are no available therapies to counteract the causes of these diseases and conventional treatments are administered only to mitigate symptoms. Recent understanding on the pathogenetic mechanisms allowed the development of novel therapeutic strategies based on gene therapy, genome editing CRISPR/Cas9 and drug repurposing approaches. Despite the therapeutic potential of these treatments, once the actives are administered, their instability, susceptibility to degradation and toxicity limit their applications. In this frame, the design of delivery strategies based on nanomedicines holds great promise for MD treatments. This review focuses on nanomedicine approaches able to encapsulate therapeutic agents such as small chemical molecules and oligonucleotides to target the most common MDs such as Duchenne Muscular Dystrophy and the Myotonic Dystrophies. The challenge related to in vitro and in vivo testing of nanosystems in appropriate animal models is also addressed. Finally, the most promising nanomedicine-based strategies are highlighted and a critical view in future developments of nanomedicine for neuromuscular diseases is provided.

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Section: Targets and How To Reach Them: Dna And Rnamentioning

confidence: 99%

Nanomedicine for Gene Delivery and Drug Repurposing in the Treatment of Muscular Dystrophies

et al. 2021

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“…Preclinical therapeutic strategies for DM1 (currently there are no approved treatments for it) use antisense oligonucleotides or small molecules [7][8][9] to degrade DMPK transcripts or to interfere with CUG expansions. Gene therapy based on CRISPR-Cas9 or on RNA interference and delivered systemically by recombinant adeno-associated viruses (AAVs) is also being explored 10,11 .…”

Section: Denis Furlingmentioning

confidence: 99%

Cas9 targeting of toxic foci of RNA repeats

Furling

2021

Nat Biomed Eng

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“…Remarkably, in the last decade, some drugs for specific muscular disorders have been developed, including small molecules and antisense oligonucleotides. 7 – 11 However, these treatments must demonstrate efficacy and safety in the clinical phases before being widely used in patients. The development of a new drug takes years, even decades, from preclinical studies to reach the market and it is a very costly process.…”

Section: Introductionmentioning

confidence: 99%

Bioengineered in vitro skeletal muscles as new tools for muscular dystrophies preclinical studies

et al. 2021

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Muscular dystrophies are a group of highly disabling disorders that share degenerative muscle weakness and wasting as common symptoms. To date, there is not an effective cure for these diseases. In the last years, bioengineered tissues have emerged as powerful tools for preclinical studies. In this review, we summarize the recent technological advances in skeletal muscle tissue engineering. We identify several ground-breaking techniques to fabricate in vitro bioartificial muscles. Accumulating evidence shows that scaffold-based tissue engineering provides topographical cues that enhance the viability and maturation of skeletal muscle. Functional bioartificial muscles have been developed using human myoblasts. These tissues accurately responded to electrical and biological stimulation. Moreover, advanced drug screening tools can be fabricated integrating these tissues in electrical stimulation platforms. However, more work introducing patient-derived cells and integrating these tissues in microdevices is needed to promote the clinical translation of bioengineered skeletal muscle as preclinical tools for muscular dystrophies.

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Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules

Cited by 17 publications

References 112 publications

Nanomedicine for Gene Delivery and Drug Repurposing in the Treatment of Muscular Dystrophies

Nanomedicine for Gene Delivery and Drug Repurposing in the Treatment of Muscular Dystrophies

Cas9 targeting of toxic foci of RNA repeats

Bioengineered in vitro skeletal muscles as new tools for muscular dystrophies preclinical studies

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