Parkinson's Disease

Assembly of a-synuclein into pentamers, currently held to be the initiating step of Parkinson's disease. Image: The Michael J. Fox Foundation

Background

Parkinson’s disease is a progressing and devastating illness caused by a loss of dopamine-producing neurons in the brain. Currently, there is no therapy with lasting efficacy.

Overexpression of alpha-synuclein has been identified as a major cause of the development of Parkinson’s disease (PD) in humans. As little as a 1.5 or 2-fold upregulation of alpha-synuclein can cause familial PD (Singleton et al Science. 2003 (PMID 14593171), Chartier-Harlin et al Lancet. 2004 PMID 15451224).

Lewy bodies, consisting mainly of aggregated alpha-synuclein, are a histological hallmark of the disease. However, it is unclear whether these large alpha-synuclein aggregates are responsible for the pathology or whether small alpha alpha-synuclein oligomers may also be toxic and cause disease (Conway et al Proc Natl Acad Sci U S A. 2000 PMID: 10639120).

Therapies based on antibodies against alpha-synuclein should therefore preferably employ antibodies of broad specificity able to recognize soluble, oligomeric as well as aggregated alpha-synuclein.

Research Aims

To develop a vaccine against Parkinson’s, we will use virus-like particles (VLPs) displaying alpha -synuclein or fragments derived from it on their surface. The use of VLPs has a number of advantages. These include:

1) VLPs and antigens attached to their surface induce reproducibly high antibody levels in humans (Philos Trans R Soc Lond B Biol Sci. 366:2815). 

2) No adjuvants are necessary for the induction of potent antibody responses (Nat Rev Drug Discov. 3:81). 

3) Target-derived peptides can be displayed on VLPs resulting in the induction of strong antibody responses in the absence of measurable peptide-specific T cell responses (Nat Rev Immunol. 10:787-96). 

4) There is significant experience with induction of self-specific antibodies using VLPs and no adverse event has been reported nor have there been undue target-specific T cell responses observed (Annu Rev Pharmacol Toxicol. 49:303-26.).

Use of VLP-based vaccines therefore has documented ability to induce strong and clinically relevant levels of self-specific antibodies in preclinical models and clinical studies. This is different from most other platforms where strong adjuvants not compatible with use in humans are employed for preclinical experiments resulting in failure to translate these observations from animals to clinical efficacy in humans.

Clinical trials

If the preclinical experiments can be concluded successfully, we will proceed to Phase I/II clinical trials in Parkinson’s patients