Gene therapy used to be a far-off idea in the medical world, but with the trailblazing approval of the world’s first gene therapy product, Glybera, a normal life may no longer be a dream for patients with genetic illnesses. In 1972, gene therapy pioneers Dr. Theodore Friedmann and Dr. Richard Roblin made the bold prediction that altering defective DNA could someday treat human diseases.
‘In our view, gene therapy may ameliorate some human genetic diseases in the future. For this reason, we believe that research directed at the development of techniques for gene therapy should continue,’ they wrote in their paper, ‘Gene therapy for human genetic disease?’
For a Netherlands-based medical company, this ‘future’ has finally come.
UniQure, a pioneer in developing gene therapy treatments, has dispelled concerns about the safety, efficacy and reproducibility of the technique with its groundbreaking treatment Glybera, the first gene therapy product approved in the world.
Glybera or alipogene tiparvovec is an AAV serotype 1-based gene therapy vector that is composed of a CMV immediate early promoter driving expression of a lipoprotein lipase cDNA, mutated at the last amino acid (S447X); a Woodchuck Post-transcriptional Regulatory Element; and a bovine growth factor poly A nucleic acid sequence flanked by AAV2 inverted terminal repeats.
Simply put, Glybera consists of an engineered copy of the human LPL gene packaged with a constitutive promoter in a non-replicating AAV1 vector, which has a particular affinity for muscle cells, uniQure explains. The composition of Glybera was designed by uniQure, but several third-party inventors discovered certain individual components of the product.
Treating LPL deficiency
According to uniQure, Glybera was developed to help patients suffering from a very rare disease: lipoprotein lipase deficiency or LPLD. This particular gene mutation results in hyper-chylomicronemia, or dramatic and potentially life-threatening increases in the level of large fat-carrying particles (chylomicrons) in the blood after eating. Glybera restores and even improves the LPL enzyme activity needed toprocess fat-carrying chylomicron particles formed in the intestine after a meal. This is possible because Glybera uses a naturally occurring variant of the LPL gene that has ‘higher enzyme activity than the normal version of the gene that encodes the protein.’
Before Glybera was given the green light in Europe, there had been no approved therapy for the treatment of LPLD. Patients suffering from the disease were advised to adhere to a rigid diet restricting fat to less than 20% of their daily calorie intake.
Despite their supreme efforts, however, patients found it very hard to comply with this severe diet regimen, which often proved to be ineffective in reducing chylomicronemia. LPLD patients remained at increased risk for severe pains and pancreatitis, which can be fatal in some cases. With gene therapy, LPLD patients are given hope that they can finally live normal lives.
According to uniQure, this type of treatment entails the one-time administration of a drug that can replace a patient’s malfunctioning gene with a functioning one, either significantly improving the gene or potentially ‘curing’ the disease.
Glybera was granted regulatory approval by the European Medicines Agency on 2 November 2012.
Fixing faulty genes
While only 300 patients in the European Union suffer from LPLD, the significance of this invention extends to other conditions caused by gene mutation. With the success of Glybera, healthcare regulators now have proof that gene therapy can help patients suffering from other ailments as rare and as difficult to treat as LPLD, such as haemophilia.
‘A lifelong treatment for a disease like haemophilia B would have a huge impact on both patients and the worldwide healthcare system,’ uniQure says. Like other genetic disorders, haemophilia involves a malfunctioning gene that inhibits a patient’s ability to produce the protein that allows blood to clot. If a drug could ‘fix’ that faulty gene, uniQure surmises, haemophilia patients would no longer need constant and long-term infusions of the replacement protein. They would no longer be at risk of severe blood loss from something as simple as losing a tooth.
If a drug could ‘fix’ that faulty gene, haemophilia patients would no longer need constant and long-term infusions of the replacement protein.
Therapies that hope to address haemophilia and other diseases such as Sanfilippo B Syndrome, Parkinson’s Disease, and congestive heart failure are currently under development. uniQure has signed a potential US$2-billion partnership with global pharmaceutical company Bristol-Myers Squibb to develop novel gene therapies that will help heart failure patients.
Collaborations in Canada
The story of uniQure began almost three decades ago in a laboratory at the University of British Columbia (UBC) in Vancouver, Canada. UBC’s Dr. Michael Hayden and Dr. John J.P. Kastelein, a Dutch physician from the Academic Medical Center (AMC) of the University of Amsterdam in The Netherlands, had then begun collaborating to diagnose and treat metabolic lipid disorders.
After meeting a young patient with LPLD, Hayden and Kastelein conducted investigations that eventually revealed that gene defect was the cause of the debilitating disease. The physicians then decided to think of new therapeutic options for LPL-deficient patients that were based on the LPL gene itself. Their efforts, together with the work of then postdoctoral research fellow Dr. Colin J.D. Ross and the rest of their team, led to the development of Glybera.
Along with outstanding research, Glybera’s successful roll-out can be traced to a well-oiled technology transfer process.
In 1997, the University of Amsterdam’s AMC realised that it was not maximising the value of its research and scientists. The AMC Board then decided to implement a program that would stimulate researchers with promising and innovative products to start a spin-off company. AMC hired an experienced technology transfer professional to evaluate and report on interesting projects with commercialization potential. In 1998, Kastelein’s LPLD gene therapy project was developed into a spin-off company named Amsterdam Molecular Therapeutics (AMT).
From lab to market
According to Dr. Willem van Oort, who in 2003 helped establish and joined AMC’s first technology transfer office (TTO), AMC had acknowledged that the gene therapy project focused on a technique that was ‘largely unknown’ at the time.’ ‘For that reason, the Board preferred to remain the dominant shareholder, and initially did not invite venture capital,’ explains Van Oort, who provided expertise on the establishment of AMT, and the ensuing licensing agreement between AMC and the spin-off company.
An umbrella agreement was made between AMC and AMT: AMC expressed willingness to invest in and fund AMT’s programs during its initial years of operation, in exchange for 100% of the shares, while the researchers obtained option rights to eventually buy minority certificates.
The agreement also included the exclusive licensing of the patent applications, in addition to certain licensing rights for the company on future patent application on subsequent innovations in the same field made by the AMC researchers.
AMC and AMT also conducted discussions with the University of British Columbia, which owned a dominant patent on the product with pharmaceutical company Aventis. A licensing contract was
successfully arranged between the parties under the guidance of the technology transfer expert.
While AMC maintained control of the company in the beginning, it eventually invited venture capitalists to invest in AMT when the development of the LPL gene therapy product began to show promise. This investment allowed AMT, which later became uniQure, to develop Glybera.
‘The majority of new products, certainly in the area of medicine, are based on new insights obtained in scientific projects,’ explains Joris Heus, Director and Business Development Manager of the AMC’s Office of the Innovation Exchange Amsterdam, a collaboration of the TTOs in the region.
The results of such projects are screened by TTOs in knowledge institutes for commercial applicability, and subsequently offered and licensed to existing companies or new spin-off companies, as uniQure once was. ‘This way, new technologies find their way to the market, to the benefit of patients and society in general,’ Heus says.
With Glybera’s launch in 2015, uniQure has undoubtedly broken new ground in medicine. ‘UniQure has made the concept of gene therapy a reality and will continue to develop new gene therapies to help patients suffering from disease,” the pioneering medical company says.
In the spotlight
The human gene
A gene is an essential unit of hereditary information. Genes, which are made up of DNA, carry the information that determines the traits, characteristics, function, and physical development of living organisms. An individual has around 20000 genes present in 23 chromosomes.
Each person has two copies of each gene, one inherited from each parent. Most genes are the same in all humans, but a small number of genes slightly differ between people. Forms of the same
gene with small differences in their sequence of DNA bases are called alleles. The combined effect of alleles results in the physical differences in appearance among people, such as the colour of their eyes or the shape of their nose.
Dysfunctional gene behaviour is commonly referred to as a mutation. According to the World Health Organization, these mutations are responsible for causing illnesses. If the gene mutations exist in the egg or sperm cell, children can inherit the defective gene from their parents.