Envisioning Gene Transfer: Report on Congenital Blindness Studies

This week, the New England Journal of Medicine published two preliminary trial reports using gene transfer against a rare form of congenital blindness– Leber's Congenital Amaurosis type 2.  Since Jean Bennett and coworkers at the University of Pennsylvania reported in 2001 successfully correcting visual deficiencies in dogs afflicted with a nearly identical genetic condition, the field of gene transfer has been atwitter with anticipation of these results.

In the next few posts, I will comment on the studies, the science, the ethics, and the reporting of the LCA studies. (photo credit: chrisphoto, optomap retina scan, 2005)

More Grey Matter: Parkinson's Disease Gene Transfer

Ceregene published long awaited results of its phase 1 gene transfer study of a Parkinson's disease treatment in the May issue of Lancet Neurology. The open-label study involved two dose levels. After one year of observation, the authors report no major adverse events relating to the study product, CERE-120 (importantly, no neutralizing antibodies against the transgene product were observed).

The authors also report some hints of efficacy. For example, various motor functions appear improved over the course of the study. As the authors point out, however, the study was uncontrolled, and the road to effective neuroprotection strategies in Parkinson's disease is littered with casualties. And there are many reasons to greet these results with caution. First, imaging performed in concert with the study is not consistent with a therapeutic effect. Second, a major concern with studies like this is whether they produce symptomatic treatment, or whether they actually stem neurodegeneration. Disentangling the two presents an extraordinary scientific and biostatistical problem. Third, a relationship between dose and response does not seem to have been observed.

Still, the case for proceeding to phase 2 studies- to this observer at least- looks credible (photo credit: brunsdon 2007)

Teddy's Frowning

This blog primarily covers the ethics of translational clinical trials. Products tested in such studies, should they progress towards licensure, will eventually fall under the oversight of drug regulatory agencies like the FDA. How prepared will the FDA be to protect the public once these highly complex interventions are introduced to clinical practice? And when they are tested in early phase trials, how much should IRBs be reassured by the fact that sponsors can show a letter of "no objection"?

The FDA has long been considered the world's "gold standard" for the evaluation of drug safety and efficacy. But here is a list of NYTimes headlines over the last 6 months that suggest that standards at the agency have fallen.

Panel's Bipartisan View: FDA is Underfinanced (April 16, 2008). Headline says it all

Drug Makers Near Old Goal: A Legal Shield (April 6, 2008). Reporting that, if the FDA screws up its review, courts are increasingly reluctant to allow injured parties to sue drug and device manufacturers.

Tainted Drugs Put Focus on the FDA (March 17, 2008).  FDA violated its own safety rules in not inspecting overseas drug manufacturing facilities.

Justices Shield Medical Devices from Lawsuits (February 21, 2008).  Reporting that the Supreme Court found that device manufacturers have immunity from tort litigation if the FDA approves them– even though FDA standards on device approval are notoriously weak.

FDA Seeks to Broaden Range of Use for Drugs (February 16, 2008).  Reporting on proposed FDA guidelines that, more or less, would allow drug makers to promote applications of their drugs that have not yet been reviewed or approved by the FDA.

FDA in Crisis: It Needs More Money and Talent (February 3, 2008).  Editorial.

Advisors Say FDA's Flaws Put Lives at Risk (December 1, 2007).  Reporting that an FDA Science Board report stated that "FDA's inability to keep up with scientific advances means that American lives are at risk."

FDA Tests on Devices Scrutinized (October 23, 2007).  Reporting on a letter from Congressman Waxman to the FDA questioning the rigor of their review of a Medtronic implantable defibrillator. (photocredit: sluggerwv 2008, though probably lifted from someone else)

Is Embryonic Stem Cell Research Fully Developed?

As reported by Monya Baker in the April 10 issue of Nature (and Alicia Mundy in Wall Street Journal, April 11), FDA is convening a public hearing on the safety of therapies derived from embryonic stem cells as I write this blog entry. (Note: for info on the meeting, visit http://www.fda.gov/OHRMS/  DOCKETS/98fr/E7-24629.htm)

As yet, (reputable) researchers have not yet administered embryo-derived tissues to human beings. For several years, however, Geron has talked about a trial involving volunteers with spinal chord injury. The Nature report says that Geron intends to submit their IND this summer.

I (and others) have previously warned about too hasty a move into human clinical trials.  There are several concerns: 1- will embryo-derived tissues develop into cancers? 2- how will we assay this risk preclinically?  3-how will human volunteers be monitored? 4-embryo derived tissues are heterogeneous. What kinds of purity standards should be expected?  Each of these questions is incredibly complex, dividing into numerous sub-questions.

Let's hope that researchers avoid some of the mistakes made in the field of gene transfer– and that the FDA plays a more proactive role in establishing appropriate guidelines. One troubling difference between this field and gene transfer is that initial studies of the latter took place in public settings.  Expect that embryonic stem cell tissue transplantation studies will largely take place beyond the gaze of the public. (photo credit: uiruriamu 2007)

Unique Forms of Discontinuity

What is "special" about the ethics of gene transfer trials? To many, the answer is "nothing." Indeed, many gene transfer researchers resent what they perceive as an unusually high bar for initiating human studies of gene transfer.

The March 2008 issue of Molecular Therapy contains an excellent article by ethicist Nancy King and gene transfer researcher Odile Cohen-Haguenauer that attempts to answer this question. They argue that gene transfer is subject to high degrees of uncertainty, and that a trial's knowledge environment can change rapidly. Though the authors shy from branding gene transfer as "unique" or "distinctive," they also seem to suggest that scientific uncertainty, and a number of other considerations, call out for a different model for thinking about translational research ethics.

I couldn't agree more. (photo credit: his noodly appendage 2005, Alberto Boccioni 1913)

Seeing Red

In the next issue of the journal Haemophilia, two researchers, Katherine Ponder and Alok Srivistava, take me to task for an article I recently published on the ethics of hemophilia gene transfer trials.  My article discusses the little noticed phenomenon of researchers at elite medical centers in the U.S. recruiting trial subjects in Brazil and India for Phase 1 studies.

Ponder and Srivastava make two basic arguments in defense of the practice: 1- they represent a good therapeutic option for persons living in low and middle-income countries (LMICs) who can't afford standard of care of high-income countries, and 2- we needn't worry about exploitation at all, because such studies might produce medical applications that can be used in LMICs.

Could be.  But the latter argument strikes me as logical and doubtful as any generic ethical claim, such as "We needn't worry about safety in gene transfer trials, because gene transfer can be safe."  At any rate, look for a full response to their letter in an upcoming issue of Haemophilia. (photo credit: wallyg 2008– Rothko No.25/28).

For Whom the Cell Tolls?

A month ago or so, I wrote about a new gene-based strategy against disease: RNAi.  Recall that in 2006, Andrew Fire and Craig Mello won Nobel Prizes in Medicine for the discovery of RNAi.

The idea of using RNAi in therapeutic applications would be to administer these small genetic sequences to "knock down" the activity of certain, aberrant genes. Because they function on the basis of genetic complementation, RNAi therapies should be highly specific. Such specificity is key for limiting side effects, which are often caused when drugs stray to the wrong target.

As with almost all novel technologies (and, in particular, genetic ones), researchers will not have an EZ-Pass in attempting to translate RNAi to the clinic. In a recent issue of Nature (and a corresponding news story by Andrew Pollack in the NYTimes on April 2), researchers reported that any sequence consisting of 21 or so nucleotides could trigger a physiological effect (angiogenesis inhibition) in mice through a generic mechanism, the "Toll-like Receptor 3" pathway. The study is particularly troubling, because it suggests that RNAi (or, at least certain types of RNAi) might be prone to worrisome side-effects.

According to Pollack, at least five such drugs are presently being tested in human beings. (photo credit: pbo31, 2005)