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Today, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than 1 million visitors each month. The field of early embryology has grown to include the identification of the stem cell as not only critical to organogenesis in the embryo, but equally critical to organ function and repair in the adult human. The identification and understanding of genetic malfunction, inflammatory responses, and the progression in chronic disease, begins with a grounding in primary cellular and systemic functions manifested in the study of the early embryo.

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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Dec 9, 2014

Untreated DMD skeletal cells do not express dystrophin (green) due to deletion of exon 44.
But after any of three correction strategies, differentiation resulted in normal dystrophin.
Image Credit: Dr. Akitsu Hotta, Kyoto University




"Designer" genes correct Muscular Dystrophy

Researchers use one patient's induced pluripotent stem (iPS) cells and laboratory created "gene cutters" to correct genetic mutation causing Duchenne muscular dystrophy (DMD).

Researchers at the Center for iPS Cell Research and Application (CiRA), Kyoto University published their results in Stem Cell Reports.

The team demonstrated that nucleases (enzymes that cut bonds between nucleic acids 1) can be used to edit the genetic information within one patient's own iPS cells created from the patient's skin cells. These cells were then differentiated into skeletal muscle cells, in which the mutation responsible for DMD was either recovered or disappeared.

DMD is a severe muscular degenerative
disease caused by a mutation in the
dystrophin gene. Dystrophin, a rod-
shaped protein, is a vital part of a
protein complex knitting cytoskeletal
muscle fibers to the surrounding extra-
cellular matrix via the cell membrane.
DMD afflicts 1 in 3500 boys and leads
to death by early adulthood. Currently,
very little is available in terms of
treatment for patients outside of
palliative, or comforting care.

One treatment gaining interest is genomic editing using the enzymes TALEN and CRISPR. These enzymes allow scientists to cut up genes at specific locations and then modify gene remnants into sequences of their own design. However, genomic editing is not perfect. Gene sequences that are similar — varying by a few base pairs from the actual target sequence —  are often mistakenly edited, making the treatment unreliable for clinical use because of the potential for gene mutations.

For this reason, induced pluripotent stem cells (iPS cells) are ideal as models for genomic editing. They provide researchers with an abundance of a patient's own cells with which to test the programmable nucleases and find the optimal conditions to minimize errors in gene modifications.

CiRA scientists generated iPS cells from a DMD patient's skin cells. They then used several different TALEN and CRISPR enzymes to cut up and modify the genes within those cells. The cells were then manipulated to differentiate into skeletal muscle cells where dystrophin is concentrated.

In every test, the dystrophin protein was either recovered or fully corrected by the edited genes.

One key to the success of this new method was the development of a computer protocol to minimize the risk of errors in gene editing.

The team built a database of all possible recombinations of gene sequences using the patient's own muscle iPS cells previously derived from his skin cells. Researchers found the DMD patient in this study had a deletion in a specific region of his dystrophin gene called exon 44.

This research provides proof-of-principle for using iPS cell technology to treat DMD in combination with the TALEN or CRISPR enzymes. The research team now aims to expand this protocol to other diseases. First author Lisa Li explains, "We show that TALEN and CRISPR can be used to correct the mutation in the DMD gene. Now I want to apply the nucleases to correct mutations for other genetic-based diseases".

•A unique k-mer database was used to identify unique targetable regions in human genome
•A dystrophin frameshift was corrected using TALENs or CRISPR-sgRNAs in iPSCs
•Genomic integrity tests identified minimum off-target mutagenesis by the nucleases
•Dystrophin protein was detected by myogenic differentiation in the corrected iPSCs

Duchenne muscular dystrophy (DMD) is a severe muscle-degenerative disease caused by a mutation in the dystrophin gene. Genetic correction of patient-derived induced pluripotent stem cells (iPSCs) by TALENs or CRISPR-Cas9 holds promise for DMD gene therapy; however, the safety of such nuclease treatment must be determined. Using a unique k-mer database, we systematically identified a unique target region that reduces off-target sites. To restore the dystrophin protein, we performed three correction methods (exon skipping, frameshifting, and exon knockin) in DMD-patient-derived iPSCs, and found that exon knockin was the most effective approach. We further investigated the genomic integrity by karyotyping, copy number variation array, and exome sequencing to identify clones with a minimal mutation load. Finally, we differentiated the corrected iPSCs toward skeletal muscle cells and successfully detected the expression of full-length dystrophin protein. These results provide an important framework for developing iPSC-based gene therapy for genetic disorders using programmable nucleases.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

Authors: Hongmei Lisa Li, Naoko Fujimoto, Noriko Sasakawa, Saya Shirai, Tokiko Ohkame, tetsushi Sakuma, Michihiro tanaka, Naoki Amano, Akira Watanabe, Hidetoshi Sakurai, Takashi Yamamoto, Shinya Yamanaka, and Akitsu Hotta

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