Genzyme pens deal for Parkinson's gene therapy
Parkinson's drug, as a rival gene therapy for the same disease
shows promise in initial clinical trials.
The US company is one of the world's largest biotechs and has committed well over $150m (€112m) to the development of Ceregene's Cere-120, a gene therapy aimed at repairing dying neurons which cause the symptoms of Parkinson's disease. Parkinson's is a common neurodegenerative disorder characterised by the loss of neurons in the midbrain that produce dopamine. This loss of dopamine leads to decreased stimulation of the brain's motor cortex, leading to increasingly reduced movement, and the patient is eventually consigned to a wheelchair, unable to talk. It is the second most common neurodegenerative disorder in the US, affecting around one million people. Although Genzyme is perhaps best-known for developing drugs to treat lysosomal storage disorders, it is no stranger to gene-based Parkinson's therapies either: its own treatment is currently in a Phase I/II trial. That drug is designed to restore the therapeutic effectiveness of levodopa (L-dopa) by enhancing the brain's ability to convert it into dopamine, through the adeno-associated virus (AAV) delivery of the gene for dopa decarboxylase (also called human aromatic L-amino acid decarboxylase, hAADC-2). Cere-120 works on a different basis, however. It is based upon the gene for neurturin, a natural protein known to repair damaged and dying dopamine-secreting neurons. Neurturin is a member of the same protein family as glial cell-derived neurotrophic factor (GDNF) and are thought to be beneficial to keeping these neurons alive and kicking. The drug is composed of AAV vector carrying the therapeutic gene and is delivered by stereotactic injection to the affected area of the brain. Ceregene claims this provides stable, long-lasting expression of neurturin in a highly targeted fashion. Under the terms of the agreement, Genzyme will pay Ceregene a $25m up-front payment in exchange for certain partnership-related expenses. Ceregene will also be entitled to development-related milestone payments of up to $125m and 50 per cent reimbursement of Phase III development costs. In return for this cash outlay, Genzyme will gain marketing rights to Cere-120 outside the US and Canada; these markets will be retained by Ceregene. If approved, Genzyme will then pay Ceregene tiered royalties based on sales in those markets. Rival drug in 'ground-breaking' trial Meanwhile, Neurologix has just announced the results of the Phase I study of its own Parkinson's disease gene therapy. The genes were transferred directly into the patients' own brain cells, but only on one side so that the other side of the brain could be used as a control. Again, an AAV vector was used to deliver the therapy, but this time carrying an inhibitory gene called glutamic acid decarboxylase (GAD) to an area of the brain normally over-active in Parkinson's patients. This activity is primarily thanks to a lack of gamma-aminobutyric acid (GABA), but increasing GAD levels causes more GABA to be produced and calms that area of the brain. "This ground-breaking study represents not only an encouraging first step in the development of a promising new approach to Parkinson's disease therapy, but also provides a platform to translate a variety of new gene therapy agents into human clinical trials for many devastating brain disorders," said Dr Paul Greengard, chairman of the Neurologix scientific advisory board and recipient of the 2000 Nobel Prize for Physiology or Medicine for his work related to how brain cells communicate. The researchers reported "very encouraging" trial results, with treated patients showing significant improvement in both the "on" and "off" states of their illness, beginning at three months following surgery and continuing through the end of the study. These improvements occurred predominantly on the side of the body corresponding to the side of the brain receiving treatment. Also, the absence an effect until three months is also encouraging as it suggests that the improvement was unlikely to be due to the surgical lesioning of the targeted brain region - surgical approaches typically give rise to immediate, short-lasting benefit around the time of surgery, while AAV-mediated gene therapy typically takes several weeks to achieve its maximum effect. "The significant and sustained improvements in clinical symptoms following treatment of only one side of the brain are impressive," he continued.
