Genome editing for MPS I and MPS II using Zinc Finger Nucleases

Sangamo Therapeutics has announced plans to conduct clinical trials of genome editing using zinc finger nucleases (ZFN’s) for MPS I and MPS II in 2017. More details of the planned trials can be found on the website here.

Neither trial has started recruiting at the time of this post. Both trials will use the same technology (zinc finger nucleases, ZFN’s) to insert the transgenes for MPS I and MPS II respectively into the genome of hepatocytes (liver cells) using the albumin gene to control expression.


The liver is in many ways an ideal organ of choice for gene therapy, serving as a permanent “factory” for secreted proteins, including lysosomal enzymes, for delivery to other organs.

Two sets of agents have to be delivered to the body. The first is the ZFN’s to cut or cleave the DNA in the hepatocytes. The following video describes how they work in a way that is very easy to understand. It is about 12 minutes long and well worth watching. I should point out that there is one small mistake; please read Fok1 instead of Fokl (ie the number 1 not the letter l). However this really does not detract appreciably from the video.

Both strands of DNA are cleaved, so this break is called a double-stranded break. Once the DNA is cleaved, the required transgene (ie the genetic material that needs to be transferred) is inserted. So the second agent to be delivered is the transgene for MPS I or MPS II. In order to deliver the transgene to the liver, a vector is required. In the Sangamo trials, an adeno-associated virus (AAV) will be used. AAV’s have many properties that make them desirable for liver-directed gene therapy.

For a more detailed discussion of these topics please read these two articles.

Adeno-Associated Virus Gene Therapy for Liver Disease

The Liver as a Target Organ for Gene Therapy: State of the Art, Challenges, and Future Perspectives

Once the transgene is inserted, it is incorporated into the DNA by a process known as homologous recombination. 

Albumin is a protein that is produced in the liver and the albumin gene is very strongly expressed in hepatocytes. This “platform” forms the basis for the development of the methodology on which the trials are based, and which was developed by teams at the Childrens Hospital and Howard Hughes Institute in Philadelphia, and Sangamo Biosciences and published in this article.

In vivo genome editing of the albumin locus as a platform for protein replacement therapy.

The genetically engineered DNA will now start manufacturing the required protein, in this case the deficient enzyme. It is hoped that this will provide a permanent source of enzyme.

Both trials are restricted to adult patients with the attenuated forms of the disease. For the MPS I trial, this means patients with Hurler-Scheie, Scheie or Hurler post-HSCT. For the MPS II trial, it will be patients with the attenuated form of MPS II. This usually means patients who do not have central nervous system involvement (this is a personal observation).


Author: Ashok Vellodi

I have had a lifelong interest in lysosomal storage disorders. Having recently retired I now have time to pursue my passion for teaching and training of young doctors and scientists, and hopefully instil in them the passion for their patients that is so integral to working in this field.

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