[For updated information on gene therapy, please see our articles on this blog dated November 16, 2015 and November 23, 2015.]

The idea of gene therapy has been around since at least the early 1970s. In 1972, an article by Theodore Friedmann and Richard Roblin advanced the concept of treating genetic diseases by replacing defective endogenous DNA with exogenous “good” DNA. However, these authors concluded that it was premature to begin gene therapy studies in humans because of lack of basic knowledge of genetic regulation and of genetic diseases, and for ethical reasons. They did, however, propose that studies in cell cultures and in animal models aimed at development of gene therapies be undertaken. Such studies–as well as abortive gene therapy studies in humans–had already begun as of 1972.

In the 1970s and 1980s, researchers applied such technologies as recombinant DNA and development of viral vectors for transfer of genes to cells and animals to the study and development of gene therapies. In the 1990s, several research groups conducted FDA-approved human studies of gene therapies, based on this technological development and increased knowledge of genetic diseases. However, several notable failures put a damper on development of gene therapies.

The most notorious case was the 1999 death of 18-year-old Jesse Gelsinger, who had ornithine transcarbamylase deficiency. In a clinical trial at the University of Pennsylvania, he was injected with an adenoviral vector carrying a corrected gene to test the safety of use of this procedure. He suffered a massive immune response triggered by the use of the viral vector, and died four days later. As a result of this incident, the FDA suspended several gene therapy clinical trials pending review of ethical and scientific/medical practices.

This incident, as well as the failure of other clinical studies put a severe damper on the gene therapy field, especially attempts at commercialization of gene therapies and of building biotech companies specializing in this field. Nevertheless, between 2003 and 2012, researchers have been quietly developing more advanced gene therapy technologies and conducting clinical studies, with some success. Entrepreneurs have also been building gene therapy specialty companies to commercialize this research.

Now comes the July 20, 2012 ruling by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) that recommends marketing of a gene therapy known as Glybera (alipogene tiparvovec) as a treatment for the ultra-rare genetic disease lipoprotein lipase deficiency (LPLD) under exceptional circumstances. LPLD affects no more than two people per million in the general population. People with LPLD cannot break down fat, and must manage their disease with a restricted diet. However, dietary management is difficult, and a high proportion of patients suffer life-threatening pancreatitis.

Glybera is being developed by a small Dutch biotech called uniQure biopharma. Glybera consists of an adeno-associated virus (AAV) vector that carries the gene for LPL. Therapy consist of multiple intramuscular injections of the product, resulting in the delivery of functional LPL genes to muscle cells.

The European Commission (EC) generally follows the recommendations of the CHMP. At the time of the CHMP ruling, uniQure expected initial approval from the EC within 3 months of that decision. Articles published in Nature and Nature Biotechnology in the late September/early October 2012 period anticipate EC approval in a mater of days or a week or two.

If it is approved in the European Union (EU) as expected, that approval will require that Glybera be offered through dedicated centers of excellence with expertise in treating LPLD, and by specially trained doctors to ensure ongoing safety of the therapy. uniQure is now preparing to apply for approval in the U.S., Canada, and other markets.

uniQure is also using its AAVvector platform as the basis of a series of gene therapies for other rare diseases, including porphyria and Sanfilippo B, as well as what it calls “disruptive innovation” products for such diseases with established treatments as Parkinson’s disease and Hemophilia B.

Does the expected approval of Glybera herald the beginning of a new era of gene therapy?

Jörn Aldag, the CEO of uniQure, believes that “just like antibodies, gene therapy will one day be a mainstay in clinical practice.” Although uniQure is concentrating its development efforts in the area of rare diseases, Mr Aldag believes that “the potential of gene therapy stretches far beyond rare diseases.” He cites a December 2011 publication in the New England Journal of Medicine, which describes a study in which 6 patients with hemophilia B were treated (via peripheral-vein infusion) with an AAV vector carrying a proprietary (codon-optimized) human factor IX (FIX) transgene. This treatment resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects, all of which were easily treatable. Hemophilia B, the second most common form of hemophilia, is nowhere as rare as the ultra-rare disease LPLD. Some of the patients treated with this gene therapy were able to discontinue prophylactic treatment with FIX. uniQure’s program in gene therapy for Parkinson’s disease exemplifies the companies efforts to move beyond the rare disease area.

However, others are not so sure that the approval of Glybera will usher in a new era of gene therapy, at least not in the near future. In particular, Fulvio Mavilio, Ph.D., Scientific Director of Genethon (Evry, France) (a non-profit center for development of gene therapies), does not believe that a large number of patients will be treated with gene therapies in the near future.

Dr. Mavilio cites the “relatively rich pipeline of gene therapy candidates already in human trials,” which  “suggests there may be a surge in the number of gene therapies approved over the next few years.” However, most of the gene therapy clinical candidates are for ultra-rare single Mendelian genetic deficiencies, with similar frequencies in the population to LPLD. The hemophilias (hemophilia A, 1 in every 5,000 male babies diagnosed per year in the US; hemophilia B, 1 in every 30,000 male babies per year) are the most common diseases to be addressed by gene therapies now in clinical development, according to Dr. Mavilio’s article. Moreover, Dr. Mavilio–as well as others–expects safety issues to thwart or slow the development of at least some gene therapies, which will also face competition from existing enzyme replacement therapies similar to those developed by Genzyme.

No gene therapy has yet been approved in the U.S. However, the FDA has established a system that facilitates faster reporting of adverse events in human gene transfer trials and that tracks such trials that are taking place. And uniQure has been planning to work with the FDA to seek U.S. approval of Glybera.

Gene therapy as a “premature technology”

Gene therapy fits the model of a “premature technology”. A field of biomedical science is said to be scientifically or technologically premature when despite the great science and exciting potential of the field, any practicable therapeutic applications are in the distant future, due to difficult hurdles in applying the technology. Moving a premature technology up the development curve requires the development of enabling technologies that can allow researchers and product developers to overcome the hurdles.

The classic case of a premature technology that has moved up the development curve and become successful is the field of therapeutic monoclonal antibodies (MAbs). We discussed the history of MAbs in detail in our September 28, 2009 blog article. The first ever MAb to enter the market, Johnson & Johnson’s Orthoclone OKT3 was approved in 1986 for use in transplant rejection. However, this drug can only be used once in a patient due to its immunogenicity. There were not any further approvals of MAb drugs until 1994. The numerous MAbs that have entered the market since then were made possible by the development of enabling technologies that overcame the immunogenicity problem. Several of these products are highly successful, and there is a rich pipeline of MAb therapeutics now in development.

Commentators on recent developments in gene therapies, including the ones we cited earlier, compare Glybera to Orthoclone OKT3. Given the limited number of patients for whom Glybera is appropriate, and especially given the exceptional circumstances under which Glybera may be prescribed and used, they are likely to be right.

bluebird bio

Among the many companies that are developing gene therapies, one has been singled our for special attention lately. That is bluebird bio (Cambridge, MA). On September 19, 2012, bluebird bio was named to FierceBiotech’s 2012 “Fierce 15”. By naming bluebird bio to the Fierce 15, FierceBiotech is designating the company as “one of the most promising private biotechnology companies in the industry”. “The Fierce 15 celebrates the spirit of being ‘fierce’ – championing innovation and creativity, even in the face of intense competition.” bluebird bio was formerly known as Genetix Pharmaceuticals.

bluebird bio has developed a novel gene therapy platform, in which a wild-type version of a patient’s disease-causing gene, carried in a lentiviral vector, is inserted into autologous CD34+ bone marrow-derived stem cells. These transformed autologous stem cells are then transfused into the patient. This eliminates potential complications associated with donor cell transplantation, or with systemic administration of gene therapy vectors.

bluebird bio’s platform thus represents both a gene therapy technology and an adoptive cellular transfer (ACT) technology. We have discussed ACT technologies (in this case, for immunotherapy for cancer) in a previous article on this blog. Since some of these technologies involve genetically-engineered autologous T cells, they may also be thought of as representing both ACT and a kind of gene therapy. (However, the “gene therapy” in these cases is not directed toward repairing a genetic disease, as  in classic gene therapy.)

For a list of links to bluebird bio publications using this and other gene therapy technologies, see the publications page of the company’s website.

bluebird bio is preparing a pivotal Phase 2/Phase 3 study of its lead treatment, for childhood cerebral adrenoleukodystrophy (ALD). The company is also in Phase 1/2 trials for its beta-thalassemia therapy, and in Phase 1 for its sickle cell disease program.

ALD is a rare, inherited neurological disorder that affects one in every 21,000 boys worldwide. It can cause damage to neural myelin sheaths in the brain, and progressive dysfunction of the adrenal glands. ALD is the disease that was featured in the 1992 movie Lorenzo’s Oil. Beta-thalassemias affect one in every 100,000 people throughout the world, with the greatest prevalence in the Mediterranean basin and in South Asia. Sickle cell disease mainly affects sub-Saharan Africans and their decedents, as well as residents of other areas with a high prevalence of malaria. Its prevalence in the U.S. is around 1 in 5,000, in France one in 2,415, and in the U.K. 1 in 2,000.

Thus the diseases that constitute the current focus of bluebird bio are much more common than is LPLD, the target of Glybera. The prevalence of the diseases that are the current targets of bluebird bio resemble the prevalence of “rare diseases” targeted by current Genzyme therapies–Gaucher’s disease (1 in 40,000 in the U.S.), and lysosomal storage disorders (individual diseases, an incidence of less than 1:100,000; total lysosomal storage diseases, an incidence of about 1 in 5,000 to 1 in 10,000).

bluebird bio’s business thus lies in the intersection between gene therapy and the “rare diseases” that are the main targets of an increasing number of biotechs and Big Pharmas.

bluebird bio is backed by several venture capital firms, notably TVM Capital, Third Rock Ventures, and Forbion Capital Partners, as well as by Genzyme (which is now part of Sanofi) and Shire. According to the Fierce 15 press release, bluebird bio is also “exploring a potential set of partnerships”.

Conclusions

In the long history of gene therapy, the expected approval in Europe of Glybera represents a key milestone–if indeed the EC approves the therapy as expected. However, given the very limited number of patients for whom Glybera is appropriate, and the exceptional circumstances under which Glybera may be prescribed and used, this milestone may be analogous to the approval of Orthoclone OKT3. Thus there may be a lag between the approval of the first gene therapy and the beginning of a more steady stream of gene therapy approvals.

However, bluebird bio’s cellular approach may enable it to circumvent many of the pitfalls of gene therapy. Other gene therapy companies may also possess enabling technologies that can help drive the gene therapy field up the technology development curve.

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