Objective: We evaluated the efficacy of JNX3001 in an aSyn-based macaque model with plasma exposures associated with efficacy in rodents.

Background: Alpha-synuclein (aSyn) deposition is a pathological feature of PD. Reductions in aSyn, by enhancing autophagy, is an attractive disease modifying approach in PD. We, and others, have demonstrated that JNX3001 enhances autophagy and is efficacious in rodent models of PD. We recently demonstrated that JNX3001 was efficacious in an AAV aSyn rodent model of PD.

Methods: Pharmacokinetic Study. 3 female macaques were administered JNX3001 (2.67g/kg, p.o.) once daily for 7 days and plasma collected on days 1 and 7. In a subsequent step, macaques were administered JNX3001 for 2 days and brain and CSF samples collected 1 h post-administration. Trehalose levels were analysed by LC-MS/MS. Efficacy Study. Female cynomolgus macaques (~9 y, ~3.5kg) received AAV1/2 A53T aSyn or empty vector into the SN. Once daily treatment with JNX3001 (2.67 g/kg, p.o.) or vehicle commenced the day after surgery and continued to day of necropsy (day 142). Brain samples were collected for postmortem measures; striatal DA by HPLC, striatal DA transporter by autoradiography and DA neuron numbers by stereology.

Results: Pharmacokinetic Study. Administration of JNX3001 (2.67 g/kg, p.o.) produced plasma and brain trehalose levels comparable to those associated with efficacy in the rat. Efficacy Study. Five months of exposure to AAV1/2-produced A53T aSyn resulted in significant reductions in striatal dopamine (by 50%; HPLC), striatal DAT (by 45%; autoradiography) and dopamine neurons of the SN (by 38%; stereology). Once daily oral dosing with JNX3001 (2.67 g/kg, p.o.) commenced one day after AAV1/2 delivery and resulted in significant protection on striatal measures of DA function, including DA (deficit reduced to 31%) and DA transporter levels (deficit reduced to 17%), while SN DA neuron numbers were not protected.

Conclusions: AAV1/2 delivery of A53T aSyn results in significant deficits on measures of nigrostriatal dopaminergic function in which to evaluate efficacy of potential disease modifying treatments. Once daily treatment with JNX3001 is able to produce plasma and brain JNX3001 levels comparable to those associated with efficacy in a rodent model of PD. Once daily administration of JNX3001 for 5 months is well tolerated and results in significant protection on striatal measures of DA function. These data support the continued development of JNX3001 as a disease modifying therapy for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/oral-treatment-with-jnx3001-protects-dopaminergic-function-in-a-non-human-primate-model-of-parkinsons-disease-alpha-synucleinopathy/