PIPELINE | CV-06
iCP-Parkin, Parkinson’s Disease
A Superior Disease-Modifying Neuroprotective Agent Against Parkinson’s Disease (PD)
Parkinson’s disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons, leading to clinical symptoms such as exercise relaxation, tremor, and postural instability. The pathological hallmark of PD is the abnormal accumulation of α-synuclein, resulting in the formation of Lewy body in the dopaminergic neurons. These striking clinical features have focused efforts to understand the mechanisms responsible for neuronal death and reasons why dopaminergic neurons are differentially affected.
In these neurogenerative microenvironment, Parkin protein, which functions as an E3 ubiquitin ligase, appears to rescue dying neurons from toxic and abnormal accumulations of cellular components despite the complexity of PD etiology.
To deliver therapeutic neuroprotective molecules into a target neuron without any brain surgery or direct injection, it should be capable of penetrating across Blood-Brain Barrier (BBB), a rigid cell-base layer of brain protecting from the circulating system. The BBB is a compact microvasculature formed by endothelial cells in strong association with astrocytes and pericytes, which is a huge challenge for the development of biotherapeutics for central nervous system disorders due to its insufficient BBB-penetration.
By utilizing our TSDT platform, an improved cell-permeable Parkin (iCP-Parkin) is our first-in-class PD drug candidate, which has superior BBB-penetration/neuronal delivery and recover the damaged neurons. Like endogenous Parkin as an E3 ubiquitin ligase, iCP-Parkin can have cytoprotective action by recovering dysfunctional mitochondria through mitophagy and mitochondrial biogenesis. iCP-Parkin can reduce the accumulation of pathological α-Synuclein, thereby suppressing PD phenotypes. Currently, typical PD treatment such as L-Dopa employs symptom-relieving drugs replenishing the loss of Dopamine in brain, temporarily recovering patient’s abnormal motor function. Although the symptom maybe eased, it is not addressing loss of dopaminergic neurons.
Therefore, the disease will get worse as time passes and side effects will be occurred. In contrast, iCP-Parkin has neuroprotection capability against PD-induced cellular stress, having a great potential as a disease-modifying therapy for PD biotherapeutics.
In AAV-α-Synuclein-induced PD mouse models, conducted in Severance Hospital and Cellivery, the behavior deficit was recovered with the treatment of iCP-Parkin, and the accumulation of pathological α-Synuclein was removed in the SN, with the recovery of tyrosine hydroxylase (TH) level (Figure 1). Our research on the action mechanism & efficacy of iCP-Parkin in PD was published in Science Advances (IF: 13.116, 2020), suggesting a potential therapy to treat PD even after the onset of motor symptoms. Also, Cellivery as a first-time grant recipient in South Korea, established iCP-Parkin research in support of Michael J. Fox Foundation (MJFF) for Parkinson’s Research (MJFF Program: No.14241. 2017. 07 ~ 2019. 03). Currently, we are conducting preclinical R&D of iCP-Parkin with various global CROs and CMOs to move forward to clinical phase.
Figure 1. iCP-Parkin restores dopaminergic neurons (red) in Parkinson’s disease animal model
PIPELINE | CV-06
iCP-Parkin, Alzheimer’s Diseas
Therapeutic Potential Of iCP-Parkin Can Be Extended To Various Neurodegenerative Diseases Including Alzheimer’s Disease (AD) By Utilizing Superior BBB Permeability
Alzheimer's Disease (AD) is the most common neurodegenerative disease mostly associated with progressive memory loss and cognitive dysfunction. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) in the brain, causing neurotoxicity. Typical AD therapeutic approach employs symptom-relieving drugs replenishing the cholinesterase inhibitor in brain. However, these agents cannot only prevent AD progress but also its life-long treatment induces several side effects. Due to this unmet medical needs, therapeutic trials and pharmaceutical efforts to address these clinical features, are focused on dealing with the mechanisms how pathological proteins (Aβ & NFT) are responsible for neuronal death.
Improved cell-permeable Parkin (iCP-Parkin) is a Therapeuticmolecule Systemic Delivery Technology (TSDT) applied cell-/tissue-permeable Parkin recombinant protein. iCP-Parkin can penetrate through the blood-brain barrier (BBB) to repair damaged neurons in the brain caused from AD.
The neuroprotective mechanisms of iCP-Parkin as an E3 ubiquitin ligase are involved in suppressing accumulation of pathological protein aggregations as well as damaged cellular organelles, suggesting the indication expansion for various neurodegenerative diseases. Therefore, with new insights for current pathological protein aggregation targeted strategies and the emergence of novel therapeutic strategies, iCP-Parkin appears to rescue dying neurons from toxic and abnormal accumulations of cellular components despite the complexity of AD etiology. It is demonstrated that iCP-Parkin effectively removes pathological protein aggregation and rescues cognitive dysfunction in Aβ-induced animal model. In fibril Aβ-induced AD mouse models, conducted in Cellivery, the cognitive behavior deficit was recovered with the treatment of iCP-Parkin, and the accumulation of pathological Aβ Plaques were removed in the hippocampus (Figure 1).
Currently, with process development of iCP-Parkin protein manufacturing for clinical evelopment, we are demonstrating therapeutic efficacy of iCP-Parkin in various AD models complex range of AD phenotypes & etiology including pathological Aβ Plaques and Tau Tangles.
Figure 1. iCP-Parkin removes pathological Aβ plaque in Alzheimer's disease dementia model