Drugs ～Intractable disease～
Development of inhibitors of protein phosphatases involved inneurodegenerative diseases and investigation of their effects in animal models
PrincipalInvestigator

The department of Biological Control, RIMD, Osaka University
Specially Appointed Assistant Professor Shizuka ISHITANI

Project Outline
Polyglutamine disease is an inherited neurodegenera�vedisorder including SBMA (Spinal and Bulbar MuscularAtrophy), Sca (Spinocerebellar ataxia), and Hun�ngton's
disease. In polyglutamine diseases, the number of repeats ofthe CAG sequence encoding glutamine is abnormallyincreased in the genes responsible for each disease, resul�ng
in the expression of proteins with abnormally longpolyglutamine sequences, which accumulate in neurons along
aging and lead to degenera�on. All types of polyglutamine
disease cause severe disability, and independent living
becomes impossible within 10 years a�er onset. However,current treatment of polyglutamine disease generally consistsof symptoma�c therapies such as improvement of motor andneurologicalsymptoms
withan�psycho�cdrugs,
improvement of ataxic symptoms with drugs that ac�vate thenervous system, exercise therapy, lifestyle guidance, andtreatment of complica�ons. On the other hand, thedevelopment
ofeﬀec�ve
therapies
targe�ng
neurodegenera�on itself has not progressed and remains as
an urgent issue. In recent years, the mechanism by which
abnormal polyglutamine proteins lead to neurodegenera�on
has been par�ally clariﬁed, and the development oftherapeu�c methods based on these ﬁndings is graduallyprogressing both in Japan and overseas. Evalua�on of someof these methods have already been ini�ated, but suﬃcienttherapeu�c eﬀects have not been conﬁrmed at this �me.

In this project, we will focus on protein kinase X, which
phosphorylates abnormal polyglutamine proteins andpromotes its cytotoxicity, and create a drug that preventsneurodegenera�on through inhibi�on of its ac�vity. Because
kinase X "directly" regulates abnormal polyglutamine
proteins, our approach is expected to broaden the range oftherapeu�c strategies.
Through our extensive screening and structural
modiﬁca�on, we have succeeded in crea�ng a potent andselec�ve X inhibitor. The X inhibitor inhibited the substratephosphoryla�on ac�vity of X protein and inhibited theaccumula�on of abnormal polyglutamine proteins in the cell.
This indicates that the X inhibitor has the poten�al to be afundamental therapeu�c agent for polyglutamine disease.
We are currently tes�ng the therapeu�c eﬃcacy of the X
inhibitor in mouse models of polyglutamine diseases andfurther modifying its structure to improve its proper�es as adrug. We hope that this project will lead to the developmentof deﬁni�ve therapies for polyglutamine disease.

Target disease: Polyglutamine disease
Patent informa�on: Under planning
Characteris�cs of the Technology: Development of a cura�ve medicine for polyglutamine diseases
Marketability and challenges in development: Polyglutamine disease is a gene�c disorder, for which only
symptoma�c treatment currently exists. Therefore, it is expected to develop a cura�ve medicine that prevents theonset of the disease or suppresses the progression of symptoms.
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