ASGCT in Washington DC

Another year, another annual meeting of the American Society of Gene Therapy- now rechristened American Society of Gene AND CELL Therapy. The meeting ends today, and I am way behind in posts. There have been, to my knowledge, no startling new revelations about high impact trials or disastrous adverse events. The studies of Leber's Congenital Amaurosis- a rare genetic disorder causing blindness- continue to dazzle, with several groups presenting results showing consistent safety and functional recovery- especially in younger patients. The ADA-SCID data continue to show very encouraging results without any indication of the safety problems encountered using similar vectors. Same goes for the adrenoleukodystrophy study- now three children have received a lentivirus-based cell intervention. Again- no evidence that delivered cells are expanding in a way that would raise concerns about a malignancy, and the disease course for children appears to be significantly improved. Off, now, to catch a session on a new product for another genetic disease- LPL deficiency- which (by the title of the session) has been submitted for regulatory licensure. To be continued, with some ethical commentary... (photo credit: afagan 2007)

ASGT in San Diego

This year's annual meeting of the American Society of Gene Therapy is in San Diego.  I've been to several interesting talks thus far, and plan to post entries on a few. For now, here's an overview of some major (or some not so major) clinical developments in gene transfer that are being reported at this meeting.

1- Last year, I predicted that the first gene transfer applications were nearing licensure.  Not so fast.  Because of concurrent sessions, I was unable to attend the entire talk given by Robert Shaw of the British biotech company Ark Therapeutics.  Ark has developed a gene transfer approach, Cerepro, that uses adenovirus to treat malignant glioma (which is one of the most aggressive types of cancer).  Ark recently applied to the European drug regulatory authority, EMEA, for registration of Cerepro.  Why not FDA? Dunno (though the speaker stated that the review standards are more or less the same).  The data behind the product are less than earth shaking.  According to information available over the web [proviso- these data are from August 2008], the pivotal phase 3 study of Cerepro showed only a 42-day increase in survival for patients in the active drug arm.  And the product caused "increases" in hemiparesis, aphasia, and fever.

2- Another somewhat discouraging indication of the challenges in reaching licensure for gene transfer products was a session titled "late stage industry clinical trials."  To me, late stage means phase 3.  But three talks centered on phase 1/2 studies, and none presented phase 3 results.  The first talk was given by Ceregene on their Parkinson's disease product Cerepro. The product did not show any significant advantage over sham for their primary endpoint.  

3- Last year, the "buzz" at ASGT was the preliminary results from three studies testing AAV vectors for a form of congenital blindness, LCA. I also discussed the somewhat ethically controversial decision to move this study into children.  I will look forward to attending Jean Bennett's talk on Friday; her abstract reports that her LCA study has enrolled "9 children and young adults" ranging from age 8 to 26 years.  The abstract claims improvement in "subjective and objective" measures of vision.  To be continued... (photo credit: slack12, 2008)

Soft Cells and C-Sections

The American Society of Gene Therapy is renaming itself: "American Society of Gene and Cell Therapy" (membership has yet to finalize the name change."  The European Society of Gene Therapy has already done so: "European Society of Gene and Cell Therapy."

Why is gene transfer going cellular? The publicly stated reasons are two fold. First is a recognition that gene transfer has always involved "cell transfer." For instance, ADA-SCID and X-SCID protocols-- for that matter, all ex vivo protocols– involve modifying cells outside the body, and returning them to the volunteer.

A second reason is to have a more "inclusive" society, and an "expanded membership base." I suspect this partly reflects a concern that cell-types might affiliate with groups like ISCT (International Society of Cell Therapy), which has a "gene therapy" committee, or perhaps also ISSCR (International Society of Stem Cell Research).

Of course, this raises the question of what ASGCT means by "CT." Does the society intend "American Society of Gene AND Cell Therapy," or is it "OR Cell Therapy (which would include protocols that do not involve genetic modification). I can't help but wonder what the realignment will mean for gene transfer. Since its founding, "gene transfer" has represented a kind of "invisible college" - an international network of collaborations and co-citations with a common set of concerns. Does renaming represent the demise of the gene transfer invisible college, as "genes" are absorbed under the more powerful social category of "cells?"  Or does it represent a promising extension of the network? Is this simply a reflection that in the first decade of the 21st century, "cells" are, in terms of scientific capital, what "genes" were to the 1990s? (photo credit: I like 2008)

Also at ASGT: Collins Steps Down

Francis Collins spoke for the first time after announcing his resignation after fifteen years as director of the National Human Genome Research Institute. Collins presided over the completion of the human genome project, as well as a series of other genome sequence and other "big-science" programs like the HapMap.

Attendance at Collins' talk seemed surprisingly spotty. His speech did not particularly highlight gene transfer research; the subject was stacked like cord wood along with other genome project achievements like pharmacogenetics and drug target identification. Perhaps tellingly in terms of where he sees the biggest impact of genomics, Collins said he intends to write a book on personalized genomics.

Collins did, nevertheless, offer a tip of the hat to the Leber's Congenital Amaurosis study, saying he was "exhilarated" by it. To be continued...(photo credit: dawn m. armfield 2007)

Also Noted: Almost Licensed

Also noticeable at this year's ASGT meeting was what seemed to be a larger volume of phase 2 and 3 studies. One session was devoted to "late stage" clinical trials. I did not attend this– it conflicted with sessions on immunology and cancer gene transfer. Still, one observer told me, informally, that the first gene transfer product could very well be registered for commercial use in the U.S. within the next year.

Any truth to this?  The U.S. database of gene transfer trials lists 6 phase 3 gene transfer studies in the last two years; this represents 40% of all phase 3 gene transfer studies ever registered with the NIH. Three of these studies involve cancer; the other three are for various cardiovascular treatments.  I took a look at the abstract and press materials for the session I missed on late stage studies. In one case, the product only showed significant efficacy in women. In another, efficacy was significant only in populations with particular genetic profiles. But one needs to be very cautious interpreting efficacy claims that depend on subgroup analysis.

The third study was referenced above- it involved use of AAV for treatment of a rare genetic disease, LPL deficiency.  An interesting twist here: the researchers first developed the intervention in the Netherlands. They exhausted the entire Dutch population of LPL deficient patients for their first trial, which did not successfully correct the deficiency. The next trial was pursued in Quebec with a fresh patient pool. According to various conversations I had, this trial showed a lot of promise. Press materials for the company sponsor, Amsterdam Molecular Therapeutics, state "upon completion of the study the results will be part of the filing dossier for the marketing approval of Glybera(R)."

A number of other orphan disease studies, like ADA-SCID-show a lot of promise. What is badly needed now is  careful analysis of the ethical and policy challenges of gene transfer in the post-licensure era. My postings on biological generics give some hint of what I believe will emerge as a major challenge in this field: cost and access. (photo credit: home invasion tour 2007)

Also Hot: Diplomatic Immunity for Vectors

Also hot at the ASGT annual meeting: immunomodulation and gene transfer. The immune system has proven the bane of successful gene transfer (truth be told, there are other banes-like delivery). It confounds results. It causes toxicity. It stymies efficacy. It's unpredictable. It behaves one way in some tissues-the blood- and another way in other tissues- the gut.

Talk after talk was devoted to ways of better managing immune responses in gene transfer studies. This consisted of recruiting: cancer gene transfer researcher Steven Albelda spoke about ways to reduce inhibition of immune response within tumors so that immune-based strategies can work against cancer. Antonio Chiocca discussed how the immune system thwarts cancer virotherapy (that is, use of viruses that selectively infect and destroy tumor cells) and how, in his estimate, translating this approach will require dampening the immune response of patients.  Along a similar vein, researchers in Quebec and Netherlands showed encouraging results using short-term immunosuppression in a protocol using AAV vectors against a rare genetic disease, lipoprotein lipase deficiency. (photo credit: Miss Starr, Neutrophil migrating across bone marrow, 2007)

What's HOT: ASGT Annual Meeting

I've just returned from the annual American Society of Gene Therapy Meeting.  In the next several posts, I share my impressions on the state of the field in 2008.

What's Hot? Retinal gene transfer. The buzzzzzz of the meeting was the recent promising results for the Leber's Congenital Amaurosis study (discussed in previous posts). In one session, U of Florida researcher William Hauswirth shared results of a third LCA study using AAV.  His talk described results using functional MRI showing that visual centers in the brain are activated in LCA dogs following application of his vector. As for the results of the U Florida study, 3 volunteers received vector so far. No visual recovery was observed per se, though they saw large increases in light sensitivity. Hauswirth attributed the modest visual recovery results to the fact that only one section of the retina received vector.

In talking with many researchers not involved with this study, it's clear that the field sees this as the most exciting development of the year, and is putting its money on this horse to ride the field out of adversity. (photo credit: Chubby Bat 2007)