BioWorld International Correspondent

SAN FRANCISCO - The expectations of gene therapy have exceeded reality so far, but that situation could be reversed with a growing number of clinical trials generating robust safety and - increasingly - efficacy data, while in parallel companies are preparing for commercial-scale manufacture.

"In the last decade gene therapy has moved from an academic pursuit into established product development," Barrie Carter, executive vice president and chief scientific officer of Targeted Genetics Corp., of Seattle, told delegates at the BIO 2004 convention at a session titled "The State of Gene Therapy Today."

As yet no gene therapy product has been approved. But there are diverse products in the clinic, representing large market opportunities. They are delivering a number of genes and nucleic acids for disease correction and modification, and gene regulation.

"Gene therapy has got to the stage where [the companies involved] are thinking about reimbursement," Carter said.

Gene therapy would offer significant advantages over biologics and other drugs, including sustained expression, the ability to target locally or systemically, the potential for less frequent dosing, a good cost profile and applicability to a variety of diseases.

"Gene therapy is being driven in an appropriate direction, and it will result in approved products," Carter said.

Targeted Genetics' products are based on adeno-associated viral vectors that have been in the clinic for seven years and can be manufactured on a large scale. The lead product, tgAAVCF, delivers a functional copy of the cystic fibrosis transmembrane regulator gene to the lung epithelium via an aerosol. A Phase IIa study completed last year gave the first indication that gene delivery could have a functional effect, and a Phase IIb trial involving 100 cystic fibrosis sufferers now is in progress.

"The primary endpoint is mean change in lung function," Carter said. "In other words, we are progressing to the point where we are looking at efficacy as the primary endpoint. We have gotten past the safety issues."

Ian Maclachland, chief scientific officer of Protiva Biotherapeutics in Seattle, noted that in recent years the definition of gene therapy has been expanded to include delivery of nucleic acids such as siRNA, thus presenting the opportunity to silence disease-associated proteins. "We can therefore downregulate otherwise nondruggable targets," Maclachland said.

To date there has been a lack of viable in vivo system to deliver siRNAs, as they are labile and not effectively taken up by cells.

Protiva is developing stable plasmid lipid particles (SNALPs) that encapsulate siRNA and can deliver it directly to disease sites, where it promotes expression of the desired protein, leading to a local therapeutic effect.

In Phase I trials, SNALPs had a half-life of 21 hours in the blood. Protiva has succeeded in using SNALP-enveloped siRNA to downregulate expression of target proteins in animal models, and now is recruiting patients to a Phase I/II trial in melanoma.

Another company, Ceregene Inc., of San Diego, is using gene therapy to deliver nervous system growth factors designed to keep degenerating neurons alive, thus dealing with the underlying causes of degenerative diseases, including Alzheimer's and Parkinson's.

There already is proof of concept to show the genes Ceregene is aiming to deliver with adenoviral vectors can slow disease progression. Six patients in the first trial of the approach in Alzheimer's disease had a 50 percent reduction in their mean rate of decline compared to the pretreatment rate.

"We are using local delivery to deliver well-characterized proteins that have been shown to delay neuron degeneration and delay disease progression," said Jeffrey Ostrove, president and chief operating officer of Ceregene.

"We are quite excited about gene therapy in the 21st century. There are a lot of tremendous data sets coming through," he said.

Even armed with proof of clinical efficacy, as a new class of medicine gene therapy products will face additional hurdles in achieving registration and commercialization. Robert Tenerowicz, vice president of process development and clinical supplies at GenVec Inc., of Gaithersburg, Md., told delegates that in parallel with clinical development, GenVec has been working on commercial-scale manufacturing for its product TNFerade. That uses an adenovirus to deliver the gene for tumor necrosis factor-alpha by direct injection into tumors.

GenVec has been planning for commercial-scale production of TNFerade since 1998. One underlying assumption was to deal with safety issues by adopting similar approaches to those used for manufacturing biologics. GenVec will meet with the FDA later this year to discuss the registration strategy for TNFerade.

"All the potential perceived risks in gene therapy, we believe, are no different from any other biologic. It all depends on the clinical data, and we are going to make sure we are ready to commercialize [when the clinical proof is there]," Tenerowicz said.

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