Gene Therapy: Comeback? Cost-Prohibitive?

The Center for Genetics and Society and many others have long argued that it’s important to draw a sharp policy line between heritable genetic modification and genetic alterations aimed at treating an existing patient – gene therapy. That does not, however, mean that gene therapy is problem-free. With the CRISPR boom of the last three years, a number of biotech companies have been planning human clinical trials for a range of gene therapy applications, which raise important questions of their own.

At a recent UC Irvine conference on The Challenge of Informed Consent in Times of Controversy, Columbia University law professor and Nation columnist Patricia Williams described the hype now surrounding CRISPR “gene editing” developments, whether applied to heritable or non-heritable genetic changes:

What’s happening now is also a rat race, to beat out others in the charge to the patent office; a lunge to own all parts of the genome, to close down the public commons in the bioterritory of the genome.  Hence, much of this has a temporal urgency to its framing that exploits our anxiety about mortality itself. Hurry up or you’ll die of a really ugly disease. And do it so that ‘we’ win the race, for everything is a race, a race against time, a race to file patents, a race to market, to better babies … there is never enough glory or gain, there is always the moving goalpost. And this is a cause for worry in the framing of a broad spectrum of technologies.

Amid the excitement about the new generation of genetic engineering tools and protocols that Williams evokes, and the fast-paced reporting on research developments and scientists’ speculations, important distinctions are too often being muddied and serious concerns are too often overlooked.

Three recent developments in the gene therapy world, for example, were sometimes reported in ways that not only conflated somatic and germline applications, but also failed to distinguish in vivo treatments (inserting specifically programmed CRISPR complexes inside the body, in which case precision is paramount) from ex vivo approaches (editing cells in a lab, and then inserting the successfully edited cells into a patient’s body). On the other hand, the developments did lead reporters to raise concerns about the huge costs associated with the field of gene therapy, and the many obstacles still left to overcome.

Baby Layla and Cellectis

The first was widespread commentary starting November 5 on a press release from Great Ormond Street Hospital in London and biotech company Cellectis in France about an infant named Layla who had received gene-edited cells that had rid her body of otherwise unresponsive leukemia. The genetic repair method used for this somatic gene therapy was a lesser-known molecular nuclease known as TALENs. It involved not an ex vivo or in vivo engineering of the infant’s cells (that is, “personalized medicine” based on the patient’s DNA), but edited donor immune cells that were already on hand when the prospect of Layla’s experimental clinical case emerged. 

Layla’s doctors were excited but circumspect in the press release, with one saying:

We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children.

Yet as Ricki Lewis pointed out some days later in an article in PLOS Biology, Will Layla Save Gene Editing?: 

Three months may seem way too soon to report even startling results on a single cancer patient. ‘Cancer-free’ is usually evoked only 5 years after successful treatment, and I wouldn’t even use it then…The timing of the announcement may be important when we look back on the birth of gene and genome editing.

Lewis speculated that given the hype surrounding CRISPR, Layla’s story (even though it involves gene therapy enabled by a different gene editing tool) may have “its greatest impact” on the upcoming “International Summit on Human Gene Editing to be held in Washington D.C. December 1-3” which concerns germline modification. She added that following the news release, “Cellectis’s stock rose, 11% after the news broke and another 3% the next day.”

Editas Medicine CRISPR human clinical trials in 2017?

A second gene editing development that broke on the same day was Editas Medicine CEO Katrine Bosley’s announcement at a tech conference that the biotech company would begin human clinical trials of CRISPR somatic gene therapy by 2017 to treat a form of the rare genetic blindness, Leber’s congential amaurosis (LCA)—what could amount to the first use of CRISPR for human medical treatment. The UK Telegraph misleadingly reported Editas’ plans with the headline First genetically modified humans could exist within two years. While gene therapy technically produces “genetically modified humans,” the term is typically used to refer to (hypothetical) humans created after the genetic modification of embryos or gametes. The confusion can’t be blamed on the headline writer, since the article also overbroadly states that CRISPR (regardless of application) is “controversial because it fundamentally changes a person’s genetic code which can then be passed down to offspring.” Contrary to the Telegraph’s reporting, however, Editas’ proposed CRISPR gene therapy trial would not target the genes that are passed on to future generations.

In addition, the article and its headline also mislead by implying that the Editas clinical trial would be the first instance of gene therapy. This suggestion erases a wrought history of gene therapy trials in the last decades that were largely unsuccessful, and that harmed or killed patients, most notably Jesse Gelsinger in 1999.

Spark Therapeutics gene therapy partially restores vision?

A third development, reported a few days later (November 11) in The Washington Post, described a different gene therapy for LCA blindness. This clinical trial, sponsored by Spark Therapeutics, partially restored the vision of Allison Corona, who began experimental clinical treatment three years ago. Reporters Carolyn Y. Johnson and Brady Dennis did a good job both of putting this story in the context of previous gene therapy clinical trials gone wrong, and of confronting a clearly controversial aspect of the current approaches: “soaring drug prices.” The estimated cost of Spark’s LCA gene therapy? $500,000 per eye. The reporters also cited a 2014 study in Nature Biotechnology that “found that a gene therapy could conceivably be priced as a one-time payment of $4 million to $6 million.”

In reporting on Editas’s plans (and helpfully distinguishing them from what Spark is doing), MIT Technology Review writer Antonio Regalado also noted that “the eventual cost of such a treatment could be extraordinarily high, given the small number of people who would need it.” Of the roughly 3,000 people in the United States with LCA, Editas’s gene therapy is targeting a gene impacting some 20%, or 600 people. 

Gene therapy's troubled comeback

As clinical trials using the latest genetic engineering tools for gene therapy are announced, there will be many questions to consider. Among them: How should we distinguish the safety and technical risks associated with in vivo and ex vivo applications? Will CRISPR or other molecular nucleases remain in a clinical patient, continuing to snip DNA and causing potentially dangerous off-target effects for years to come? How will we as a society resolve the huge six- and seven-figure costs associated with a medical treatment that stands to benefit so few in a world plagued by health disparities? And how can we make sure patients are protected if biotech companies rush their gene editing products to market, whether to influence international summits, to boost their stock prices, or just to overshadow a competitor’s recent press?

Previously on Biopolitical Times:

• What Will 120 Million CRISPR Dollars Buy?
• "Moonshot Medicine": Putative Precision vs. Messy Genomes
• Mistakes Were Made (by Geneticist James Wilson)

Image via Flickr/NIH