Notes: * AV = adenovirus; AAV = adeno-associated virus; SYN = synthetic (lipid; polymer)


As well, there have been several conceptual shifts in the last decade: Like researchers developing other sorts of therapies, there's a realization that these treatments don't always have to represent cures. Often, an improvement in the quality of a patient's life is a noble end. And, the timelines for product development turn out to be no different than for any other sort of drug: Given that development can take 15 years from start to finish, gene therapy's right on track. In fact, genes themselves are just another type of drug -- and gene therapy is a way to deliver them.

Importantly, some potential treatments have shown extremely promising results in clinical trials. For instance, Onyx Pharmaceuticals Inc.'s anti-cancer product ONYX-015 (which is now in Phase III trials) was able to reduce the tumor size by at least 50 percent in 11 of 30 patients with head and neck cancer in a Phase II study. Cell Genesys Inc.'s GVAX lung cancer vaccine elicited a major response rate in 18 percent of the patients enrolled in a Phase I/II trial. And two of the severely ill patients receiving Transkaryotic Therapies Inc.'s ex vivo gene therapy for hemophilia A in a Phase I trial had no spontaneous bleeding episodes for at least 10 months after the treatment. Clinical results are starting to emanate from many other trials, as well, clearly evidenced by the number of presentations at last month's ASGT meeting. (The tables in this article list a representative [and small] sample of the many gene therapy trials being conducted by biotech companies.) But no trial has yet to match the stunning success of Alain Fischer's SCID trial -- which many are heralding as a downright cure.



In this landmark trial -- the current bookend on the gene therapy shelf -- French researchers treated five baby boys, all less than one year old, who were born with X-linked SCID, a very rare form of the disease. The researchers infected progenitor cells isolated from the boys' bone marrow with a retrovirus containing the gamma-c gene, which encodes part of a cell-surface receptor found on T cells and natural killer (NK) cells. This receptor is important in binding cytokines, Fischer explained. "Its function is to induce cell proliferation."

"We initiated the trial about two years ago, and five patients were treated in the first trial. There were no adverse effects," Fischer said in remarks at a press conference held during the ASGT meeting. Not only that, but in four of five patients, "we were able to reconstitute a normal immune system." And, 26 months later, they're still OK. "So far, so good," Fischer said. But, he cautioned, "This is not necessarily a cure. It's still possible that we'll see a silencing of gene expression." Moreover, since it's unknown exactly which precursor cells received the gene -- nor their state of maturation at the time -- it's premature to claim that the therapy will last forever. Still, since T cells have a life span of 10 to 20 years, according to Fischer, the benefit may well last that long. The French group started a second trial on two patients in May 2001. "Our goal is to treat more patients."

Even if the treatment turns out not to be a cure, the results have already proved one very important point: They demonstrated for the first time that it is, indeed, possible to correct a disease by means of gene therapy.


Representative Gene Therapy Trials

Notes: * AV = adenovirus; AAV = adeno-associated virus; SYN = synthetic (lipid; polymer)



That wasn't the case in the first SCID trial -- which earned its place in history precisely because it was the first time that a therapeutic gene therapy procedure was performed in humans. In September 1990, two little girls suffering from adenosine deaminase (ADA) deficiency -- one of the genetic causes of SCID and potentially fatal -- received regular infusions of their own T cells transfected with a retroviral vector carrying the human gene responsible for producing ADA. The procedure, performed by French Anderson, Michael Blaese and Kenneth Culver, was repeated every month or two over the next year or two. Gene transfer was more efficient in one child than it was in the other, but 10 years later (and presumably today, as well), the two girls appeared to be healthy and have functional immune systems. However, clinical evaluation of those early trials is still hampered by the fact that the patients also received regular replacement of the enzyme via the drug PEG-ADA -- and they still do.



Interestingly, both SCID trials used retroviral vectors to transfect the patients' own cells ex vivo. There are some differences between the two, but generally speaking "The technology is not that different now than it was 10 years ago," explained Barrie Carter, executive VP and CSO at Targeted Genetics Corp. "The fundamental technology in 1990 was essentially usable as it was." Thus, even 10 years ago, gene therapists were on the right track: When retroviral vectors were correctly applied, they worked fine as gene delivery mechanisms.

But, as researchers subsequently discovered, retroviral vectors don't work in every case. And neither do the other delivery vehicles, which today include adenoviruses, adeno-associated viruses and synthetic carriers (usually lipid-based). The raging debates about which delivery vector was the right one to use have gradually dissipated as researchers came to realize that there is no one answer. Instead, they now appreciate the fact that gene therapy has to be customized: "You have to understand the disease target, which [delivery] system is useful and which is appropriate," Carter said.



Representative Gene Therapy Trials