A new chemically defined lipid nanoparticle could overcome the limitation of adeno-associated virus (AAV) vectors in delivering genome editing therapies to skeletal muscles and may hold promise for the treatment of neuromuscular conditions such as Duchenne muscular dystrophy (DMD).

Even though a number of antisense oligonucleotide treatments are available to treat DMD caused by different mutations, their effect is transient due to the fact that they target pre-mRNA.

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The CRISPR/Cas9 genome editing technology holds great promise in that it has the potential to directly target the DNA, therefore having long-lasting effects. 

AAV vectors have been used by many researchers to introduce the CRISP/Cas 9 system to muscle tissue. However, there are some problems associated with this approach. For example,  the long expression of AAV increases the risk of off-target effects. Moreover, multiple injections are necessary to be able to treat a large tissue such as muscle, but this is not possible with AAV vectors due to their capsid protein, which is easily targeted by the immune system and neutralizing antibodies attacking the gene therapy after the second injection.

Lipid nanoparticles are currently being investigated as nonviral RNA delivery vehicles with low immunogenicity for a number of diseases. 

In the present study, a team of researchers from Japan reported a chemically defined lipid nanoparticle system able to deliver the CRISPR/Cas9 system to skeletal muscles by repeated injections. 

Even though the expression of the system was transient, the researchers said it could induce stable genomic exon skipping and restore the expression of dystrophin protein in a mouse model of DMD.

The team that used the limb perfusion method to introduce the lipid nanoparticles to the body of the animals said the approach enabled the targeting of multiple muscle groups.

“The repeated administration and low immunogenicity of our LNP system are promising features for a delivery vehicle of CRISPR-Cas9 to treat skeletal muscle disorders,” they wrote.

Reference

Kenjo E, Hozumi H, Makita Y, et al. Low immunogenicity of LNP allows repeated administrations of CRISPR-Cas9 mRNA into skeletal muscle in mice. Nat Commun. 12;7101(2021). doi:10.1038/s41467-021-26714-w

gene editing Neurologists