ICB International, Inc

ICBI is leveraging its BBB-permeable technology to develop diagnostics and therapeutics for Alzheimer's and Parkinson's. Below is a brief description of these projects.

Alzheimer's Disease (AD) 

AD is the single most prevalent cause of degenerative dementia. Worldwide, more than 35 million people are suffering from the disease. AD affects roughly10% of the population over the age of 65 and approximately 40% of population over the age of 85. Alzheimer’s disease leads to loss of memory, cognitive function, and ultimately, loss of one's independence, taking a heavy personal and financial toll on patients and loved ones. The U.S. alone has 5.3 million patients, whose care costs $184 billion/year. Death usually occurs in approximately 9-10 years after diagnosis. Current drugs only improve symptoms, but do little to modify the disease. Unfortunately, most of the drugs stop working after sometime leaving the patient helpless and succumb to the disease.

Etiology

Alzheimer’s disease is a multifactorial ailment with both genetic and non-genetic links to it. Postmortem analysis of human AD brains has identified the hallmark lesions of AD: 1) Senile plaques composed of extracellular deposits of amyloid-beta peptide;  and 2) neurofibrillary tangles formed by the accumulation of abnormal phosphorylated Tau in brain regions that serve memory and cognition. In addition to these hallmarks, prominent activation of inflammatory processes and the innate immune response are observed.

The amyloid cascade hypothesis has been the original hypothesis, which postulates that the deposition of the amyloid-beta peptide in form of insoluble amyloid-plaque in the brain is crucial to the etiology of AD. Although most cases of AD are sporadic, mutations in genes such as amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are linked to early-onset (< 60 years old) AD, and accounts for less than 5% of AD cases. ApoE4 has been genetically linked to late-onset (> 60 years old) familial and sporadic AD, accounting for more than 95% of AD cases. Over the years, however, the amyloid cascade hypothesis has been modified because, at a pathological level, the scale of those deposits appears not to be strongly related to amount of cognitive decline [Tomiyama T, Brain Nerve, 62, 691 (2010); Shankar GM, et al, Mol Neurodegeneration, 4, 48 (2009); Dietrich HH, et al, Mol Neurodegeneration, 5, 15 (2010); Broersen K, et al, Alzheimer’s Res and Therapy, 2, 12 (2010)]. If insoluble beta-amyloid plaque does not correlate to the cognitive decline (dementia), do soluble forms of amyloid-beta do any better? The answer is yes. A study of 19 AD patients with dementia confirms that they do [McDonlad JM, et al, Brain, 133, 1328 (2010)]. Thus, lately there has been a shift in emphasis from plaques and tangles to smaller, soluble forms of amyloid-beta peptide.  

1. Diagnostics for Alzheimer's Disease (AD) 

ICBI has already shown that its proprietary technology is capable of detecting  disease-causing soluble and insoluble amyloid-plaques in the brain of Alzheimer’s-like transgenic mice. Therefore, ICBI has positioned itself to developing a clinically useful neuroimaging test for diagnosing AD. Consequently, our main focus now is to devlop a neuroimaging test for the early detection of Alzheimer’s disease to save human lives. One of the key requirements is to establish a GMP facility for scaling up key components of our assay, which will facilitate the development of a diagnostic test within two years from now.

A key and notable difference between ICBI’s technology and the technology of others is that our technology detects AD disease-causing soluble plaques, whereas other technologies primarily bind to insoluble plaques, a plaque species that poorly correlates with cognitive decline in AD patients. ICBI’s technology should be superior to rival neuroimaging tests for the detection of soluble, cognitive-damaging plaques.  

2. Therapeutics for Alzheimer's Disease (AD) 

The foundation for ICBI's development for therapeutics for AD has already been laid out with the validation of our BBB-permeable molecules in a mouse model. Our therapeutic approach involves the targeting of several pathological proteins implicated in AD, including amyloid-beta. It is well known that a therapeutic agent targeting amyloid-beta need not necessarily cross the BBB for the reason that amyloid-binding agents, such as conventionally used murine antibodies, bind to amyloid in the peripheral blood stream, disrupt the plaque equilibrium between brain and blood, and cause an efflux resulting in the attenuation of the plaque burden in the brain [Drug Discovery Today, 11, 931 (2006)]. Studies suggest that a BBB-permeable agent such as ICBI’s molecule -- capable of binding to both soluble and insoluble plaques in the peripheral blood and in the brain -- would be far more therapeutically efficacious than anti-amyloid agents that merely bind to amyloid plaques in the blood, cross the BBB very poorly, or blind selectively to just one species of amyloid plaque in the brain. With this hypothesis in mind, ICBI has transitioned from early stage discovery to a development stage company to develop diagnostic (discussed above) and therapeutic products for AD.

We believe that the complexity of Alzheimer's disease, however, requires a combination of drugs in order to treat successfully the majority of AD patients . With that in mind, ICBI has undertaken the development of drugs to target additional pathological proteins. We expect to have 3-4 pharmaceutically effective inhibitors for the other target key proteins in 5-6 months.

Parkinson's Disease (PD)

Parkinson’s disease (“PD”) is the second most common neurodegenerative disorder affecting 2% of the population above the age of 60 years. PD is characterized by movement disabilities,  including resting tumor, muscle tone rigidity and bradykinesa. Estimated 10 million people are inflicted by PD worldwide, with about 1.3 million American suffering from the disease whose care is costing about $25 billion annually to the U.S. Currently, there are no diagnostic tests and treatment available for the disease. Modern treatments are effective at managing the early motor symptoms of the disease, mainly through the use of levodopa and dopamine agonists. As the disease progresses, a point eventually arrives at which the drugs become ineffective at treating the symptoms and at the same time produce a complication called dyskinesia, marked by involuntary writhing movements.

Etiology

PD etiology is mysterious. There is no single causative agent identified with direct link to PD, except a pesticide like MPTP, which most of the patients have not been exposed.  What is known is that PD is caused by the progressive degeneration of the dopamine producing neurons in the substantia nigra and is accompanied by the appearance of intraneuronal inclusions enriched in alpha-synuclein, the Lewy bodies (LBs).  Dopamine is an essential neurotransmitter responsible for electrical signal between nerve cells for controlling smooth, coordinated muscle movement. The reduced level of dopamine causes the neurons to fire out of control and causes a loss of controlled smooth muscle activity. However, the underlying mechanism that leads to degeneration of dopaminergic neurons is not fully understood.

The loss of dopamine production is believed to be caused by an abnormal accumulation of LBs, which are oligomeric and fibril forms of the protein α–synuclein. This insoluble protein accumulates inside neurons resulting in neuronal degeneration, cell death and disruption in dopamine production. Lewy bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum, with individuals at this stage being asymptomatic. As the disease progresses, Lewy bodies later develop in the substantia nigra, areas of the midbrain and basal forebrain, and in a last step the neocortex.

The major breakthrough in PD came in 2004 with the addition of LRRK2 (Leucine-rich repeat kinase 2) to the list of PD causing genes. Mutations in the LRRK2 have been identified as a genetic cause of familial and the more common sporadic form of PD. Out of the 20 LRRK2 mutations identified, the most prevalent mutation, LRRK2 (G2019S), located within the kinase domain of LRRK2, is present in more than 85% of PD patients carrying LRRK2 mutations, with R1441C/G (within the GTPase domain) the next most prevalent, at approximately 10%. In addition, the G2019S was observed in 4% of all familial PD cases, 0.5 -2.0% of sporadic PD cases, suggesting the link of the mutation to the etiology of PD.  Tremor in PD is more frequently observed in individuals with LRRK2 (G2019S) mutation. Remarkably, it accounts for PD in 29% of Ashkenazi Jews and 37% of North African Arabs. Although there is conflicting data on other mutations such as R1441C, Y1699C, and I2020T, LRRK2G2019S mutation has consistently shown to be more neurodegenerating than the WT. Also, LRRK2 G2019S is primarily associated with brainstem Lewy body pathology, reminiscent of typical, late-onset idiopathic PD. The risk of PD with an LRRK2 G2019S mutation increases with age; it is 28%at age 59 years, 51% at age 69 years, and 74% at age 79 years. 

3. Development of a Non-invasive Diagnostic test for Parkinson's Disease  

Early diagnosis of any disease is a key to saving lives. Unfortunately, when it comes to Parkinson’s disease, there aren’t any premortem diagnostic tests. The standard imaging techniques such as MRI and CT scans are not helpful except to exclude some other causes of neurological dysfunction. First time ever, ICBI’s BBB permeable technology offers a real  possibility of developing a non-invasive neuroimaging test for detecting soluble and insoluble intraneuronal inclusions (aka: Lewy bodies) by detecting the proteins that form these aggregates. The test, comprising an intravenous injection of a tagged molecule, will first be optimized in an animal model before testing in humans. Given the appropriate resources, ICBI could have a prototype test ready, with all the pharmacokinetics studies done, within 18 months. Almost a year after, Phase-3 clinical validation probably can be started in human patients.

4. Development of a Non-invasive Therapeutic test for Parkinson's Disease  

After a careful review of the literature, ICBI has selected several key pathogenic proteins, which have been linked to the etiology of the Parkinson’s disease.  We have already begun to develop modulators for one of the protein targets. The development of modulators for the remaining targets will commence in the very near future. These BBB permeable modulators of the pathogens are expected to seek their pathogens with precision, bind and neutralize the pathogens with a possible disease halting and modifying effect. According to some of the reported studies, modulators of LRRK2 kinase activity has been shown to attenuate neurodegeneration and Parkinsonism in-vivo models [Human Molecular genetics, 20, 3933 (2011)]. Our drug modulators are expected to show superior performance to the conventional small molecules drugs, which usually work only for a short period, and with considerable toxicity. Some anti-Parkinson drugs such as “Rasagiline”, an irreversible inhibitor of the enzyme monoamine oxidase (MAO), promote regeneration of dopaminergic neurons of the susbtantia nigra [Neurochem Res., 32, 1694 (2007)]. Until we produce our drug candidates and evaluate them in transgenic mice models, we won’t if these modulators have properties to regenerate dopaminergic neurons. However, we have a back-up strategy to promote the regeneration of dominergic neurons by delivering neurotrophic factors such as NGF, BDNF and GDNF to the brain.