Parkinson’s disease is a progressive and incurable brain disorder. Currently available therapies only alleviate symptoms rather than deter the development of the disease itself. As a novel drug candidate, CDNF has the potential to stop the progression of Parkinson’s disease by protecting neurons from degeneration and restoring the functions of already damaged neurons.
CDNF is currently in a Phase 1-2 randomized, placebo-controlled, double-blind, multicenter clinical study in three university hospitals in Sweden and Finland for the treatment of Parkinson’s disease.
CDNF is a protein naturally present in humans. It was discovered by Professor Mart Saarma at the University of Helsinki and published in the leading scientific journal Nature in 2007. Following this, Herantis patented CDNF worldwide and launched a drug development program based on this discovery. The research and development efforts have confirmed that CDNF is a promising neuroprotective and neurorestorative drug candidate, which functions via several mechanisms relevant to Parkinson’s disease. It can protect neurons from degeneration and restore the function of already degenerating neurons. This suggests that CDNF has the potential to stop the progression of Parkinson’s disease, which would make a significant therapeutic impact on the lives of patients. If successful, CDNF therapy would enable Parkinson’s patients to maintain their quality of life.
CDNF has a multi-modal mechanism by which it improves neuronal survival in Parkinson’s disease and other neurodegenerative diseases.
- CDNF promotes neuronal survival and functionality by reducing endoplasmic reticulum (ER) stress
CDNF is internalized by stressed neurons and reduces endoplasmic reticulum (ER) stress, a common feature in neurodegenerative diseases. Reduced ER stress levels support recovery of neuronal functionality via multiple mechanisms, such as improved calcium homeostasis, mitochondrial function, and protein translation and secretion.
- CDNF promotes neuronal survival by activating Protein kinase B (Akt)
Akt is a protein kinase that is centrally involved in neuronal survival signaling. CDNF stimulates Akt activity in neurons.
- Inhibiting formation and toxicity of alpha-synuclein aggregates
Aggregated alpha-synuclein is the main component of Lewy bodies which are abnormal protein inclusions found in the brains of Parkinson’s disease patients. Alpha-synuclein is an aggregation-prone protein and various abnormal forms of alpha-synuclein can be toxic to neurons. CDNF protects neurons by reducing the formation and toxicity of alpha-synuclein aggregates.
- Decreasing neuroinflammation
CDNF reduces production and secretion of pro-inflammatory cytokines, such as TNF-alpha, interleukin-1beta and interleukin-6, by glial cells, thereby reducing chronic neuroinflammation in the brain, which is an important pathological mechanism in most neurodegenerative diseases.
- Improving functionality of stressed and degenerating neurons
CDNF has long-term effects in the brain which are related to the regulation of gene transcription and the maintenance of functionality of dopamine neurons.
CDNF Clinical Development Status
CDNF is currently in a Phase 1-2 randomized, placebo-controlled, double-blind, multicenter clinical study in three university hospitals in Sweden and Finland for the treatment of Parkinson’s disease. The patient recruitment has been completed with 17 randomized patients.
As a protein, CDNF cannot pass the blood-brain barrier, the organ protecting our brains from toxins that may appear in the circulating blood stream. Therefore, in the Phase 1-2 clinical study, CDNF is administered using a drug delivery device that directly targets the putamen, a specific area in the brain that is affected in Parkinson’s disease. Implanting the clinically tested device requires a neurosurgical procedure comparable to the placement of a Deep Brain Stimulation device, a common procedure in advanced-stage Parkinson’s patients. The drug delivery device used in the Phase 1-2 clinical study is manufactured by Renishaw Plc.
The clinical trial, also called TreatER, is partially financed by the European Union. More details on the study are available here: www.treater.eu.
About Parkinson’s Disease
Parkinson’s disease is an incurable, progressive brain disorder estimated to affect over seven million patients worldwide. It is caused by the degeneration of dopamine-producing neurons in the brain. The underlying reasons that trigger degeneration of dopamine neurons In Parkinson’s disease remain poorly understood. However, the symptoms are a consequence of reduced brain levels of dopamine, a neurotransmitter, in the brain. The typical symptoms include tremor, slowness of movement, muscle stiffness and impaired balance. As the disease progresses symptoms get worse, and also various non-motor symptoms, including sleep problems, depression, speech changes, and severe constipation, may occur.
Available treatments for Parkinson’s disease do not cure the disease or even slow down its progression because the pathological processes resulting in degeneration and death of dopamine neurons are not affected. Current standard-of-care treatments are drugs, such as L-dopa, that increase dopamine levels in the brain. The efficacy of the L-dopa is typically gradually lost with disease progression as an increasing amount of the dopamine-producing neurons have degenerated. One currently available treatment for advanced-stage Parkinson’s disease patients is Deep Brain Stimulation, which together with the required neurosurgery, can cost over EUR 75,000.
Parkinson’s disease is associated with a significant societal economic burden in addition to the immense human suffering. The majority of costs are not linked to treatments but, for instance, lost productive years and supported living arrangements for disabled patients. In 2010 the societal costs of Parkinson’s disease in Europe alone totaled approximately EUR 14 billion. A study in the USA suggested that a treatment, which could stop the progression of Parkinson’s disease would save society about EUR 400,000 per patient. This is Herantis’ goal with CDNF.
CDNF has shown preclinical activity also in other neurodegenerative diseases
CDNF affects cellular mechanisms that are involved in pathophysiology of a variety of central nervous system diseases. Particularly, endoplasmic reticulum stress, unfolded protein response and neuroinflammation are involved in many chronic neurodegenerative diseases. Preclinical data suggests that CDNF has therapeutic potential in diverse neurodegenerative disease in addition to Parkinson’s disease. It is possible that CDNF could be used as a basis of developing novel disease-modifying treatments for e.g. Alzheimer’s disease and amyotrophic lateral sclerosis (ALS).