Adenosine Augmentation, A Novel Therapeutic Strategy for Neurodegenerative Diseases

Invention Description
Aiming at the enhancement of adenosine tone in the brain, JMF3464 and its analogues were designed for the treatment of neurodegenerative diseases such as Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Spinocerebellar Ataxia Type 3 (SCA3), and Alzheimer’s Disease (AD). JMF3464 and its analogues are novel adenosine analogue that elevate extracellular adenosine level in the brain by blocking an adenosine transporter (the equilibrative nucleoside transporter 1 (ENT1)). Chronic oral administration of JMF3464 improved motor functions and survival of a mouse model of HD (R6/2). In addition, treatment of two mouse models (PS1/APP, THY-Tau22) of Alzheimer’s disease (AD) also ameliorated major symptoms of AD (including spatial memory deficiency and poor synaptic plasticity). JMF3464 and its analogues are first-in-class drugs for the treatment of neurodegenerative diseases.

Competitive Advantages
HD is an autosomal dominant neurodegenerative disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene, which subsequently leads to the accumulation of mutant HTT aggregates in the brain and many peripheral tissues. It is a rare disease with a prevalence of 4-8 per 100000 in the world. Only two symptom-alleviating therapies (Xenazine ® , Austedo ® ) are currently available with limited therapeutic efficacy. No disease-modifying therapy is available. JMF3464 and its analogues are orally active, BBB-permeable inhibitors of ENT1. Pharmacokinetic (PK) analyses demonstrated that JMF3464 has an excellent oral bioavailability (F=65%) and a good compound exposure in the target tissue (i.e., brain). No hERG- or CMC- related issue was observed. Sub-kilogram-scale production of JMF3464 can be successfully achieved.

Intellectual Property
Patent applications were filed in 16 countries including USA, China, European, and Taiwan.

Key Publications
1. Kao Y-H, Lin M-S, Chen C-M, Wu Y-R, Chen H-M, Lai H-L, Chern Y*, and Lin C-J*. 2017. Targeting ENT1 and adenosine tone for the treatment of Huntington’s disease. Human Molecular Genetics, 26, 467-478.
2. Lai C-Y, Liu Y-J, Lai H-L, Chen H-M, Kuo H-C, Liao Y-P, Chern Y. 2018. The D2 dopamine receptor interferes with the protective effect of the A2A adenosine receptor on TDP-43 mislocalization in experimental models of motor neuron degeneration. Frontiers in Neuroscience: 12: 187-199.
3. Lee C-C, Chang C-P, Lin C-J, Lai H-L, Kao Y-H, Cheng S-J, Chen H-M, Liao Y-P, Faivre E, Buée L, Blum D, Fang J-M, Chern Y. 2018. Adenosine augmentation evoked by an ENT1 inhibitor improves memory impairment and neuronal plasticity in the APP/PS1 mouse model of Alzheimer’s disease. Molecular Neurobiology, 55:8936-8952.

Business Opportunity
Licensing, Co-development

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