SAN FRANCISCO – The 2012 European approval of Uniqure BV's Glybera has sparked a renewal of interest in gene therapy, a field that was marred by a serious setback in 1999 that proved fatal for a patient.

Since then, the sector appears to have overcome some of its safety hurdles and even has attracted venture capital interest – more than $600 million over the last two years – following a decade-long drought.

However, ethical concerns and regulatory and delivery challenges remain, as discussed by panelists during the 13th BIO Investor Forum's therapeutic session Wednesday, the conference's final day, at the Palace Hotel. Company heads of Editas Medicine Inc., Avalanche Biotechnologies Inc. and Tocagen Inc. discussed various strategies and perspectives in a workshop, titled "Gene Therapy Ascending? Today's Advancements Over Past Hurdles."

The death of Jesse Gelsinger in 1999 "certainly cast a pall on the area for a long time," said Katrine Bosley, CEO of Cambridge, Mass.-based Editas Medicine, a gene-editing company launched a year ago. Gene therapy suffered the serious setback when the 18-year-old enrolled in a University of Pennsylvania study died from a major immune response of ornithine transcarbamylase deficiency. (See BioWorld Today, Dec. 10, 1999.)

Harry Gruber, chairman, CEO and president of Tocagen, pointed out that Gelsinger had liver failure, didn't sign his consent and should never have been in the trial. While the death resulted in a negative investor perception of gene therapy, the field "persisted in spite of Wall Street's lack of funding in over a decade," Gruber said.

San Diego-based Tocagen, for example, has worked on targeting brain cancer using a simple retrovirus as its platform to develop gene transfer products that deliver therapeutic genes to cancer cells. Editas focuses on CRISPR/Cas9 (clustered, regularly interspaced short palindromic repeats; CRISPERassociated protein 9), which acts by a mechanism in which the Cas9 protein binds to specific RNA molecules that guide the complex to the exact genome location where repair is required.

Research has succeeded in overcoming some ethical issues through careful, low-dose animal studies, and many patients are more than willing to try a new therapy when there are no other options. Most are not concerned with the modality of treatment – be it regenerative health, gene therapy or small molecule – but are focused on whether the treatment works, said Thomas Chalberg, founder and CEO of Menlo Park, Calif.-based Avalanche.

His company's product, AVA-101, comprises the AAV2 vector that contains a gene encoding sFLT-1, a naturally occurring anti-VEGF protein. When administered to the eye, the protein inhibits the formation of new blood vessels and reduces vascular permeability. Phase I data showed it was well tolerated with no significant safety concerns. Phase IIa data in macular degeneration are expected in mid-2015.

Chalbert said wet age-related macular degeneration left untreated results in blindness 12 to 24 months following diagnosis and requires four to five injections per year of current treatments, whereas Avalanche's therapy offers a one-time treatment. The opportunity for such a treatment is "completely green from a competitive perspective," he said.

While gene therapy may show promise over current treatments, and the safety kinks are being worked out through thorough research, high regulatory and delivery hurdles remain.

"Manufacturing, by itself, is a major issue," Gruber stressed. He said he believes intravenous gene therapy delivery will represent a new class of biologics and entail an expensive production process along the lines of monoclonal antibodies, which stood in the same position 20 years ago. Companies cannot build their factories to supply their drugs until after approval. "These are going to be big costs, but I think the payoff is going to be there."

While regulators appear as an ally of the space, they are designed to protect the public. Panelists said they are working to determine answers as to what a preclinical toxicology package will look like and whether their companies are pursuing clinically validated targets with clinically validated endpoints.

FDA guidelines require 15-year follow-up for any gene therapy, with the agency strongly concerned about environmental spread. It is an interesting situation, Gruber said, when treating a disease like brain cancer. "Physicians tell the patients they have to be followed for 15 years and they only have six months to live," he said.

While Avalanche's product is non-genome modifying with no risk of spread to the germ line, other gene therapies present true dilemmas to those concerned not only with safety and spread, but with altering a genome to the point that treatment with subsequent, more efficacious therapies no longer becomes an option.

"It is permanent for the most part," Gruber said. "It's like Lasik surgery for the eye. Do you do it or do you wait for the next Lasik to come out?"

Payers' adoption of gene therapies also represents an unknown for companies working in the space. A long-term transformative treatment could be extremely expensive, more than $1 million in the case of Glybera (alipogene tiparvovec) for orphan disease lipoprotein lipase deficiency, but "if you take someone who has hemophilia and they no longer have hemophilia, a million dollars is cheap," Gruber said.

While drug companies have long touted the advantages of taking pills every day, continuing their revenue stream, they have sometimes displayed anti-gene therapy attitudes, Gruber said, but they are starting to consider the potential promise of the therapies.

"Insurance companies are going to see it is cheaper to have curative diseases than to take pills forever," he said.