BMCC-2022-C03

Neural Rejuvenation, a Novel Therapeutic Strategy for Neurodegenerative Diseases

BMCC

J4 is a novel compound that provides a first-in-class approach to address the fundamental issue of insufficient energy supply in neurons during aging-associated dementia and Alzheimer’s disease.

未定中標題
BMCC Targeted indication

Alzheimer’s disease and neurodegenerative diseases

BMCC Status

Pre-clinical studies

BMCC Key features
  • First-in-class
  • Orally active, BBB-permeable, and decent bioavailability (F=65%)
  • No drug-drug interaction
  • Potent efficacious
  • No obvious toxicity
  • No CMC issues
  • IP well protected
BMCC Market

We have developed an orally active, small molecule (J4) that can be used to treat neurodegenerative diseases including Alzheimer’s disease (AD) by targeting the dysregulated adenosine homeostasis in the brain. To date, AD is the most common progressive neurological disease in the aging population. In June 2021, the FDA has approved Aducanumab (Brand name: Aduhelm), an amyloid beta-directed antibody, as a new medicine for AD. However, Aduhelm is only suitable for patients with mild dementia and that its efficacy remains controversial. J4 targets at a new machinery (adenosine homeostasis) that rejuvenizes neurons by enhancing the level of ATP. J4 is a novel treatment option for patients with MCI and AD.

MODE OF ACTION

J4 is a competitive inhibitor of ENT1 that modulates adenosine homeostasis.

Adenosine is a neuronal modulator, an energy sensor, and a basic building block of DNA and RNA that controls various physiological functions. J4 treatment fine-tunes the adenosine level in the brain and ameliorates neuronal energy failure in AD.

EXPERIMENTAL RESULTS

in vitro efficacy

The Ki (50 nM) and IC50 (0.068 μM) of J4 were determined by 1) Binding of 3H-NBTI in the cortex of guinea pigs (Ki), and 2) Uptake of 3H-adenosine uptake by PC12 cells (both models express endogenous ENT1), respectively.

in vivo efficacy

Oral treatment of J4 effectively ameliorates the cognitive dysfunctions and reduces the accumulation of Ab plaques and hyperphosphorylated Tau in the brain of two different AD mouse models (i.e., APPswe/PS1dE9 and THY-Tau22) after the symptom onset. Additionally, oral treatment of J4 also effectively normalizes the energy abnormality in the hippocampus of THY- Tau22 mice.

 

 

  1. Improved memory and cognitive function (Morris Water Maze)
  2. Reduced abnormal accumulation of misfolded proteins and increased mitochondrial distribution

 

Safety pharmacology and general toxicology
  • J4 has a low potential to induce cardiac arrhythmia side effects (non-GLP hERG assay). 
  • J4 has no genotoxic effects in standard assays (Ames and chromosome aberration assays) (GLP).
  • Dose range finding studies in rats and dogs were conducted (non-GLP).
Pharmaceutical development
  • 6-kg production of J4 has been successfully achieved (non-GMP).
  • Long-term and accelerated stability studies of J4 are ongoing.

INTELLECTUAL PROPERTY

Patents on the treatment of neurodegenerative diseases by J4 have been granted in multiple countries.
Taiwan Patent: 發明第 I650328 號 (2019/02/11 - 2034/11/10) 、發明第 I668007 號 (2019/08/11 - 2034/11/10)
China Patent No.: ZL 201480058727.3 (2018/12/14 - 2034/10/22)
EP Patent No.: EP 306056B1 (2018/09/05 - 2034/10/22)
USA Patent No.: US 10,301,348 B2 (2019/05/28 - 2035/11/27)
Australia Patent No.: 2014340114 (2019/01/31 - 2034/10/22)
Japan Patent No.: 特許第 6534997 號(2019/06/07 - 2034/10/22)
Russia Patent No.: 2695358 (2019/07/23 - 2034/10/22)

SELECTED PUBLICATIONS

1. Lee et al., 2018. Mol Neurobiol.55(12):8936- 8952. doi: 10.1007/s12035-018-1030-z.
2. Chang et al., 2021. Acta Neuropathol Commun. 9(1), 112-129. doi: 10.1186/s40478- 021-01213-7.

BUSINESS OPPORTUNITY

License and/or Collaboration and Sponsored Research

CONTACT

service@biip-dcc.org

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