Overview

We are developing a drug therapy to regenerate functional neurons without cell transplantation for neurodegenerative diseases, including Alzheimer’s disease. Our first milestone is filing Investigational New Drug applications to FDA and PMDA in 18 months since the US and Japanese are 45.5% of the worldwide dementia drug market. It requires $3 million to achieve this milestone. This innovative technology to increase endogenous stem cells without relying on cell transplantations will be the future of regeneration therapy.

Technology

Alzheimer’s disease is a chronic debilitating neurodegenerative disease, essentially “kills” a person long before they are physically dead. It affects millions of people worldwide, is robbing them of memory, humanity, and dignity. With the number of diagnoses on the rise, if we do not find an effective therapy for AD soon, society will lose the ability to support the growing population affected by this disease.
Currently, commercially available drugs for AD are symptomatic therapies. Many pharmaceutical companies tried to develop a cure for AD by focusing on immunotherapy and other treatments to eliminate amyloid-beta (Aβ) depositions. However, to date, all their efforts to prevent plaque formation in the AD brain have failed to benefit the patients.
It has been quite a while since we have shown neural stem cell (NSCs) transplantation improved cognition of aged animals. However, it is challenging to get NSCs for transplantation since they are in the deep part of the brain. We developed a technology to produce pluripotent stem cells from adult mesenchymal stem cells, which allows us to use autologous stem cells for transplantation. Still, it has an issue controlling cell fate and developing tumors. Thus, it seems to take more time for cell transplantation-based neuroregenerative therapy to contribute to medicine than expected.
We found a pyropyrimidine derivative that passes through the blood-brain barrier to increase endogenous NSCs significantly. Although atypical antidepressants (SSRIs) have been known to increase neural stem cells, it is up to only 20%. However, our medicine increased NSCs by up to 600% in vivo, eliminating the need for cell transplantation.  We also found that the pathological concentration level of amyloid precursor protein (APP) in the AD brain caused glial differentiation of NSCs by activating inflammatory cytokine signaling. We developed combination therapy to modify the AD brain’s inflammatory conditions and increase endogenous NSCs. This treatment proved to increase neurogenesis under AD pathology and reverse the cognitive impairment in model animals.
Our goal is AD therapy, though we would like to develop our technology as an orphan disease therapy to benefit from incentives, including a partial tax credit for clinical trial expenditures, waived user fees, and eligibility for 7 years of marketing exclusivity. Down syndrome (DS) patients have a trisomy of the 21st chromosome, where the APP gene is localized, meaning the patients express excess APP compared to the control subject. Most of the subjects with DS develop early onset of AD. We found that APP induced glial differentiation in NSCs, preventing neurogenesis independent of Aβ production. We have also showed that DS patients’   NSCs behave the same as NSCs overexpressing APP. In some sense, DS subjects are human AD models with overexpression of APP. Thus, we will target developing our technology as an orphan drug for acute regression associated with DS first and then moving to AD therapy.
Further basic pre-clinical efficacy studies, such as in vitro study using iPS cells from DS patients and in vivo study using DS genetic animal models at the University of Central Florida. Pre-clinical safety tests will be conducted by a 3rd party, such as Charles River Laboratories, to deliver independent toxicity and PK/PD studies that the FDA will acknowledge as a credible analysis of the compound. For the Phase 1 clinical study, we will collaborate with UCF, the College of Medicine in the US, and Tohoku University, the school of medicine in Japan, to get human safety and PK/PD results in American and Japanese populations for IND approval by FDA and PMDA. After getting a proof of concept in humans in Phase 2a clinical study, we will seek a pharmaceutical company to license the technology.

Patents

• A method of biasing implanted human neural stem cells away from differentiation into glial cells by (+)phenserine to modulate the concentration of soluble βapp in tissue or CSF（US 9,095,573）
• Use of Modified Pyrimidine Compounds to Promote Stem Cell Migration and Proliferation (US 7,687,505, US 8,273,756、US 9,084,789、1/14/2003, 7/21/2015）
• Drug Treatment to Increase Stem Cell Population (CA2473503、EP1471918,603 50 413.2, 1471918FR, JP4623967B, 5414626JPD）
• Combination therapy to improve brain function or promote neurogenesis for treating neurodegenerative conditions (US 62/346,166, PCT/US17/36220)
• Pending
• Combination therapy for neurogenesis (Pending) Filed on 8/27/2020
• Other related patents
• Compositions for Treating or Delaying the Onset of Hair Loss (US 8,791,128, PCT/US09/57134, CA2,736,018, EP2326330, 602009028877.6, 2326330FR, 2324023UK, 5555922JP)
• Vigor Enhancement Via Administration of Pyrimidine Derivatives (CA2,670,341, PCT/US07/85765, EP2324023, 602007047544.9, 2324023FR, 2324023UK, HK1158204B)

Establishment

January 24, 2020

Location

Kobe International Conference Center S606,6-9-1 Minatojima　Nakamachi, Chuo-ward,Kobe-city, Hyogo 650-0046, Japan

Industry

Biotech, Drug discovery,

Indication

Small molecular compound to increase endogenous stem cells

Funding Round

Seed Early

Raising

$3million