Study Rationale: The aggregation of a structurally abnormal form of the protein alpha-synuclein appears to be responsible for the initiation and progression of Parkinson’s disease (PD). In previous studies, we found that the use of targeted nanobodies—essentially small antibodies—that bind to alpha-synuclein can prevent its switch to the structurally abnormal form, reducing aggregation and alleviating the impaired movement seen in preclinical models of PD. In this study, we propose to perform the experiments needed to bring this technology to a clinical trial.
Hypothesis: We hypothesize that, using gene therapy, we can deliver our therapeutic nanobody to the brain and that this treatment will protect and restore the normal function of dopamine-producing neurons. We further hypothesize that nanobodies clear alpha-synuclein via the proteasome, a structure that destroys damaged proteins.
Study Design: In the first part of the study, we will use a variety of inhibitors to determine the mechanisms by which the therapeutic nanobody supports the disposal of abnormal alpha-synuclein. In particular, we will inhibit proteasomes and lysosomes, two systems cells use to degrade damaged and worn-out components. Next, we will inject different doses of the therapeutic nanobody into the brain and examine its penetration and distribution. Finally, we will use multiple techniques to assess whether protection of dopamine-producing neurons by nanobodies restores normal function of these neural circuits.
Impact on Diagnosis/Treatment of Parkinson’s disease: Abnormal folding of alpha-synuclein is responsible for the motor and nonmotor symptoms of PD, including changes to cognition. If our program is successful, the use of nanobodies can prevent this misfolding from ever reaching the brain structures that mediate these symptoms, thus preventing their development.
Next Steps for Development: Should the nanobody program be successful, we will perform tests of safety, tolerability, and toxicology, with the ultimate goal of filing an IND for a clinical trial.