More bad news for neurotrophic factors—the appealing theory that growth factors (e.g. glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and neurturin (NRTN)) might rescue weakened neurons and halt PD. First, there was Amgen’s failed direct GDNF infusion trials. Then, in February British company Phytopharm plc announced that Cogane, an oral medicine designed to stimulate production of GDNF and BDNF, showed no efficacy in a phase II trial on early stage PD patients. Now Ceregene, Inc. have reported that its CERE-120 Phase 2b clinical trial of neurturin delivered by gene therapy, has failed. Ceregene’s previous attempt at AAV-neurturin gene therapy back in 2008 also was a bust.
Ceregene’s latest study enrolled 51 patients with moderately advanced Parkinson's disease. Half got CERE-120 and half placebo surgery. After 15-24 months follow up there was no difference between the groups on the primary endpoint––UPDRS when off medication. Rush University’s Christopher Goetz, called it “disappointing.” C. Warren Olanow, praised the study as " extremely well-conceived and designed,” adding, “these results illustrate how difficult it is to establish clinical efficacy with entirely novel therapeutic approaches in complicated neurological diseases.“ Is this the end of the road for growth factors? Not quite. Canadian biotech company Medgenesis plans a GDNF gene therapy trial using a Convection Enhanced Delivery (CED) platform, which promises to deliver much larger doses to the right target.
Alpha-synuclein: toxic escape artist
Once neurons have been invaded by rogue alpha-synuclein molecules, the cell’s garbage disposal troops go into action. One arm of this system—the autophagy-lysosome pathway is designed to trap unwanted invaders in lysosomes and digest them. But, virologist Edward Campbell et al has shown (in cell culture) that alpha-synuclein can break out of the lysosome. Employing a trick used by some viruses, the alpha-synuclein bursts out of its sub cellular prison, ready to spread prion-like to other neurons. The rupture also releases reactive oxygen species that stress and kill the host neuron.
Freeman D, Cedillos R, Choyke S, Lukic Z, McGuire K, et al. (2013) Alpha-Synuclein Induces Lysosomal Rupture and Cathepsin Dependent Reactive Oxygen Species Following Endocytosis. PLoS ONE 8(4): e62143. doi:10.1371/journal.pone.0062143
Power Failure in Heart and Brain
One of the many unexplained mysteries of Parkinson’s is that patients have a 50% increased risk of dying from heart failure. Yun Chen and Gerald Dorn think they know why: heart and brain share a quality control problem with mitochondria, the cell’s power supply. Neurons and heart cells (in fact, all cells) come with their own mitochondria—some cells have thousands of them. They’re vital and they’re vulnerable. Numerous factors—environmental toxins, oxidative stress, inflammation, alpha-synuclein aggregates, genetic mutations etc––can damage these power centers, making a good mitochondrion go bad, and changing it from an energy maker into an energy taker. Cells need to act quickly instructing biological garbage trucks called lysosomes to eat up the bad mitochondria. Working in mice and fruit flies, Chen and Dorn think they have decoded the mitochondria quality control chain, explaining what can go amiss in heart and brain. The chain involves three proteins: two, PINK, and PARKIN, were well known. The authors claim that the third––the missing link in the chain––is a protein called mitofusin 2. Mutations in PINK and PARKIN by disrupting this chain might be expected to have deleterious consequences. And, of course, they do---they are well known to cause recessive early onset forms of PD. Dorn, a cardiologist, suggests that mutations in PINK, PARKIN and mitofusin, might cause similar mitochondrial quality control disruption in heart cells as well thus explaining some forms of heart failure.
Chen Y, Dorn GW. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science. April 26, 2013.
DBS Re-trains Body
Proper balance involves the integration of vestibular, visual and proprioceptive sensory data—an ability that is impaired in PD patients. Shukla et al report that DBS improved (in fact, normalized) sensory integration and proprioceptive ability in PD patients over a six-month period. The study measured short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI) in addition to proprioception (distance and spatial errors) in 11 DBS patients and 10 controls. The team theorizes that DBS causes long-term plastic changes in the basal ganglia thalamocortical circuit. Previous studies have found similar improvements. But in longer term follow up studies of DBS over five years or more some patients reveal serious balance problems, indicating that the progressing disease can overwhelm whatever benefit the DBS is providing.
Shukla AW, Moro E, Gunraj C, Lozano A, Hodaie M, Lang A, Chen R. Long-term subthalamic nucleus stimulation improves sensorimotor integration and proprioception. J Neurol Neurosurg Psychiatry. 2013 Apr 24.