It's All in the "Genes"

Andrew L. Pecora, MD
Published: Monday, Sep 23, 2013
Andrew L. Pecora, MD

Andrew L. Pecora, MD

Editor-in-Chief of Oncology & Biotech News

Chief Innovations Officer, Professor, and Vice President of Cancer Services

John Theurer Cancer Center at Hackensack University Medical Center

President, Regional Cancer Care Associates, LLC

I remember trying to explain to my son when he was in the fifth grade how the genetic code contained in all of our cells is translated, resulting in the various tissues we all possess for daily life. It started off well, but soon fell apart when he asked, “If all it takes to make an organ is for cells to read select portions of that cell’s DNA, why not type in new DNA in broken cells to make them better?” Not bad for a 10-year-old, but we know from experience that it’s not that easy.

For starters, we do not consist of one cell, unless, of course, you go back to our conception. In fact, by the time the diseases that we are trying to fix manifest, we consist of trillions of cells that are not necessarily organized in a way that allows the transfer of new genetic material to the relevant cells to fix the problem. Even if this issue is overcome, once delivered, the new DNA causes new problems by making the cells it entered immunogenic, and, if not immunogenic, premalignant or unable to perpetuate to daughter cells to maintain the intended effect.

Over the past three decades, significant effort has gone into the delivery, immunogenicity, and in vivo scaling of applied gene therapy. There was a recent breakthrough, of sorts, involving two studies published in the journal Science.1,2 The studies by Biffi et al and Aiuti et al each used a lentivirus to treat children with rare genetic defects. After early success in children with X-linked severe combined immunodeficiency, gene therapy trials have somewhat languished until these two reports.

The new trials addressed Wiskott-Aldrich syndrome (WAS) and metachromatic leukodystrophy. Both diseases are a consequence of underproduction of requisite proteins. The studies were started in 2010 with isolation of hematopoietic stem cells (CD34+) from affected children and insertion of ARSA and WASP genes ex vivo followed by systemic infusion of transfected cells.

Now, 3 years later, the first reports are encouraging. In addition to not causing immunogenicity, the insertion sites of these genes were random, avoiding concentrated insertion points that predispose to malignancy, and the transfected cells replicated, thus maintaining the intended effect. Of the three children treated in each group, all improved and had functioning protein present that persisted during the 3-year trial follow-up.

This type of encouraging new research makes one think of future applications. Start with a disease like CML, which is a stem-cell disease. One wonders if future gene therapy trials will aim to shut off the aberrant tyrosine kinase in affected cells without the need for continued oral medication with tyrosine kinase inhibitors. Other approaches might include the introduction of suicide genes that confer lethal sensitivity to common agents that are not toxic to non-transfected cells. The work by Biffi et al and Aiuti et al is truly the tip of the iceberg and though my son is now 25 years old, it may not be long before I can finally answer his fifth-grade question.

  1. Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158.
  2. Aiuti A, Biasco L, Scaramuzza S, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341(6148):1233151.

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