Many studies have been conducted to find an effective drug for Alzheimer's disease (AD) treatment. However, no effective drug applicable for clinical use has been developed. Recently, the FDA approved Lecanemab, an antibody drug that acts as an aggregation inhibitor against Amyloid-beta (Aβ), for AD treatment. However, there are still no fundamental drugs for AD. In this study, we present a strategy for AD treatment that removes Aβ by cleavage reaction using one of the Catalytides, JAL-TA9 (YKGSGFRMI). A single dose of JAL-TA9 administered into the CA1 region of the hippocampus and the intraventricular space improved the deficits in short-term memory of APP-knock-in mice. It also improved the memory of Aβ25-35-induced model mice, as evaluated by the Y-maze and objective recognition tests. These data strongly suggest that JAL-TA9 could be effective in treating AD. However, these administration methods are difficult to apply clinically due to their high invasiveness. Thus, we tested the improvement effects of dementia by administering JAL-TA9 nasally. It is very interesting and exciting that the dementia of Aβ25-35 induced AD model mice was improved by four applications once every three days. These results strongly suggest that JAL-TA9 is the best candidate for AD treatment because it is effective even in the late stage of AD.

01 Nov 2024·Folia Pharmacologica Japonica

Delivery of JAL-TA9 to the brain by nasal application

Article

Author: Hatakawa, Yusuke

We have reported on two Catalytides (Catalytic peptides), JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMI). Both peptides belong to the Tob/BTG family proteins and cleave Aβ42. Although Catalytides must be delivered to the brain parenchyma to treat Alzheimer's disease, the blood-brain barrier (BBB) limits their entry into the brain from the systemic circulation. Thus, we evaluated the direct route of ANA-TA9 from the nasal cavity to the brain to bypass the BBB. In this study, we present our findings on JAL-TA9. Animal studies using rats and mice clarified that the plasma clearance of JAL-TA9 was more rapid than its in vitro degradation in plasma, whole blood, and cerebrospinal fluid (CSF). After nasal administration of JAL-TA9, brain concentrations were significantly higher than after intraperitoneal administration, despite much lower plasma concentration. This observation strongly suggests direct delivery of JAL-TA9 to the brain from the nasal cavity. Similar findings were observed for its transport to CSF after nasal and intravenous administration. The concentration of JAL-TA9 in the olfactory bulb peaked at 5 ‍min, while those in the frontal brain peaked at 30 ‍min and in the occipital brain at 60 ‍min. In conclusion, JAL-TA9 was efficiently delivered to the brain by nasal application compared to other routes.

01 Nov 2024·Folia Pharmacologica Japonica

The discovery of JAL-TA9 which cleaves amyloid-β with proteolytic activity

Article

Author: Nakamura, Rina

Amyloid-β (Aβ) 42, one of the causes of Alzheimer's disease (AD), is produced by the cleavage of amyloid precursor protein (APP) by β- or γ-secretases. Since Aβ42 oligomers exhibit strong neurotoxicity, Aβ42 is predicted to be a potentially efficient target for drug therapies. Recently, we screened peptides that activate MMP7 using our peptide library and found that the synthetic peptide JAL-TA9 (YKGSGFRMI), which is derived from the BoxA region of Tob1 protein, showed proteolytic activity. It is generally accepted that an enzyme should be a large molecular protein consisting of more than thousands of amino acids. Thus, this is the first finding that a small synthetic peptide has protease activity, and we termed Catalytide as the general name of peptides with protease activity. In this study, we demonstrate the cleavage activity of JAL-TA9 not only against the authentic soluble form of Aβ42 but also against the solid type of Aβ42 in the central region. In addition, we demonstrated the cleavage activity using brain slices of AD patients. JAL-TA9 decreased the amount of accumulated Aβ42 in the brain of Alzheimer's patients. Taken together, JAL-TA9 is an attractive seed for the development of peptide drugs with a new strategy for Alzheimer's disease.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Preclinical	JP	O-Force Co., Ltd	-
Alzheimer Disease	Preclinical	JP	Setsunan University	-
Alzheimer Disease	Preclinical	JP	Kochi University of Technology	-
Prion Diseases	Discovery	JP	O-Force Co., Ltd	-

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