Novel BBB penetrating peptide for the treatment of Parkinson’s disease
Cure Parkinson's
University of Helsinki
The prevalence of neurodegenerative diseases, such as Parkinson’s disease (PD), is growing rapidly due to an aging population. Current treatments for PD only relieve symptoms and cannot stop the progression of the disease, thus there is an urgent need for new therapies. Neurotrophic factors (NTFs) are secretory proteins that regulate the growth, survival, regeneration and plasticity of neurons. They have been explored as novel drugs for the treatment of Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and PD but their efficacy in clinical trials has been variable. Cerebral dopamine neurotrophic factor (CDNF), discovered in our lab, is an ER located protein that works completely differently from known NTFs, but protects and restores the function of dopamine (DA) neurons in rodent and rhesus monkey toxin models of PD more effectively than other NTFs. CDNF is currently in phase 1/2 clinical trials on PD patients in three medical centers. Despite the promising results in animal models of PD, NTF and CDNF-based treatments share a fundamental drawback: they require direct delivery to the brain through invasive surgery, since they cannot pass through the blood-brain barrier (BBB) and do not treat non-motor symptoms. Prof Saarma's group's recent discovery, however, may overcome this difficulty: they showed that a novel CDNF variant, the 61 amino acids (aa) long C-CDNF, enters DA neurons efficiently in culture. Furthermore, these data show that C-CDNF can cross through the BBB as measured by four different methods and has a neurorestorative effect in both 6-OHDA and MPTP toxin models of PD when administered subcutaneously. Although C-CDNF data are promising, they believe it is not yet the optimal CDNF-derived molecule for clinical trials. C-CDNF is 61 amino acids (aa) long and harbors three alpha-helical regions. The preliminary data suggest that deletion of helix 1 or helix 3 and the sequence after the helix 3 from C-CDNF does not affect the biological activity in vitro. Systemic administration of the shortest 33 aa long C-CDNF peptide (CDNF33) is even more effective in rat 6-OHDA model of PD and passes through the BBB more readily than the longer 61 aa long C-CDNF peptide (not shown). Thus, the goal of this project is to generate the smallest active C-CDNF polypeptides, using deletion and site-directed mutagenesis, and to optimize BBB penetration properties, stability, and activity to design the optimal C-CDNF polypeptide. Structural analysis will be followed by in vitro and in vivo testing in 6-OHDA and in alfa-synuclein (aSyn) aggregation models of PD in order to identify the best drug candidate for the disease. The innovative aspect of this proposal is a new groundbreaking concept of peripheral delivery of BBB-penetrating CDNF-derived polypeptides with trophic factor properties and their potential to simultaneously treat both the non-motor and motor symptoms of PD. The effect of C-CDNF variant on non-motor symptoms will also be tested and its mode of action studied.
5.1 Pharmaceuticals