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Research Review No. 101.
New techniques to look out for.
The Studies:
The authors of the studies to be discussed in this review are working at
the cutting edge of molecular biology and are linking these studies to finding a
cure for Duchenne Muscular Dystrophy (DMD). The authors of the first paper to
be reviewed from U.S.A. use the recently developed technique of CRISPRmediated Genome Editing in an attempt to restore Dystrophin expression and
function in mdx mice (1). CRISPR stands for clustered regularly-interspaced
short palindromic repeats. This technique has enormous potential applications,
which including altering the germline of humans, animals and other organisms,
and modifying the genes of food crops. In their studies, which are clearly
presented and illustrated, they demonstrate that CRIPSR-mediated genome
editing actually efficiently excised a 23-kb genomic region on the X-chromosome
which included the mutated exon 23 in the mdx mouse model of DMD, and
restored dystrophin expression as well as the dystrophin-glycoprotein complex at
the sarcolemma of the skeletal muscles in live mdx mice. The prospect of this
technique being applied to patients with DMD provides the exciting prospect of a
‘cure’ for DMD being developed. The authors conclude their summary of these
studies by stating: “This study provides proof evidence for permanent gene
correction in DMD.”
The second paper to be discussed (2) is a brief review that considers that
the use of both the CRISPR technique combined with the development of the
viral vector techniques designed to transport the gene editing to the site, where it
is needed. They close their review with the hopeful comments: “The
simultaneous exploration of these different therapeutic strategies in parallel is
therefore warranted and offers the best hope for those patients and their families,
who are blighted by these devastating muscle disorders.”
Another brief review (3) stresses the importance of the correct diagnosis
of DMD, noting not just the large mutations in the dystrophin gene but also any
small ones. The authors remind us that the dystrophin gene is the largest known
human gene and that 1/3 of mutations are new. These facts underlie the situation
that there are an enormous variety of mutations being described. The authors
conclude their review with these words: ” Raising awareness with family
physicians and other healthcare professionals who see young children could
improve this further. Finally, given that new genetic therapies are emerging, one
could consider offering neonatal screening for DMD.”
Finally in the last study to be reviewed (4) also from U.S.A., we return to
the topic of gene-editing. They describe the various methods of gene-editing that
are being developed not just for DMD but for many other conditions as well,
including viral and bacterial infections, blood disorders, liver problems, skin, eye
and respiratory disorders, as well as DMD.
They conclude that: “The rapid progress in the field is likely to continue to
lead to new technologies that will expand the scope of genome-editing.
Alternative genome-editing technologies, such as targetable site-specific
recombinases that do not rely on the creation of double-strand breaks, alternative
CRISPR systems with unique properties, and DNA-guided nuclease systems will
continue to change what is possible with these tools.” However, they introduce a
note of caution in their final words, with which I fully concur: “In summary,
genome editing has changed the definition of gene and cell therapy and has
been a key factor in the recent resurgence of this field, but there is still significant
fundamental and translational work to realize the full promise of these
technologies for widely treating human disease.”
1. Xu, L., Park, K.H., Zhao, L.X., Xu, J., El Refaey, M., Gao, Y.D., Zhu, H.,
Ma, J.J. & Han, R.Z. (2016) CRISPR-mediated Genome Editing Restores
Dystrophin Expression and Function in mdx Mice. Molecular Therapy.
2. Vanden Driessche, T. & Marinee K., Chuah, M.K. (2016) CRISPR/Cas9
Flexes Its Muscles: In Vivo Somatic Gene Editing for Muscular Dystrophy.
Molecular Therapy. 24(3):414-416.
3. Aartsma-Rus, A., Ginjaar, I.B. & Bushby, K. (2016) The importance of
genetic diagnosis for Duchenne muscular dystrophy. Journal of Medical
Genetics. 53(3):145-151.
4. Maeder, M.L. & Gersbach, C.A. (2016) Genome-editing Technologies for
Gene and Cell Therapy. Molecular Therapy. 24(3):430-446.
Karl A. Bettelheim