Establishment of fundamental treatment for human genetic hearing loss

2018 Fiscal Year Final Research Report

• Project/Area Number: 15H04989
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: Kumamoto University
• Principal Investigator: Minoda Ryosei 熊本大学, 医学部附属病院, 非常勤診療医師 (30284772)
• Research Collaborator: MURAKAMI Daizo ; KUMAI Yoshihiko ; ISE Momoko
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 遺伝子治療 / 胎生期治療 / Slc26a4遺伝子 / Tet systemベクター

Outline of Final Research Achievements

Firstly, we constructed the plasmid vector which included Slc26a4 gene targeted short hairpin RNA with tet system. Then, that plasmid vector was injected and transferred into otocyst at embryonic day 11.5 according to our previous reported methods.
Doxycycline was administrated via ingestion between embryonic day 16 to postnatal day 6. As control, no Doxycycline group were used. Auditory assessment showed that hearing loss was detected in the treated mice, but not in the non-treated mice at postnatal day 30. Our results suggested that Slc26a4 gene expression between embryonic day 16 to postnatal day 6 was crucial for hearing. In the future, we investigate the Slc26a4 gene expression timing which is necessary for hearing.

Free Research Field

胎生期遺伝子治療

Academic Significance and Societal Importance of the Research Achievements

遺伝子補充治療においては本来の遺伝子発現の時期と部位への厳密な一致は必要ないことが示唆される。このことを明らかにするために今回申請者は、これまで確立してきたマウス耳胞への遺伝子導入技術とテトラサイクリン系抗生剤の投与にて遺伝子発現の調整が可能なTet systemを組み合わせることにより、時期特異的な内耳遺伝子発現誘導マウスモデルを作製し研究を行った。本研究は、ヒト遺伝性難聴の主たる原因遺伝子であるSlc26a4をターゲットとして、機能欠失型変異による難聴に対する正常遺伝子補充治療の有効性とその限界を時間的・空間的視点から明らかにする一助となった。