Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin,Science Advances

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Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin
Science Advances ( IF 11.7 ) Pub Date : 2021-01-08 , DOI: 10.1126/sciadv.abb1703
Pike-See Cheah _{1,

2} , Shilpa Prabhakar ₁ , David Yellen ₁ , Roberta L Beauchamp ₃ , Xuan Zhang ₁ , Shingo Kasamatsu _{4,

5} , Roderick T Bronson ₆ , Elizabeth A Thiele _{7,

8} , David J Kwiatkowski ₉ , Anat Stemmer-Rachamimov ₁₀ , Bence György _{11,

12,

13} , King-Hwa Ling _{14,

15} , Masao Kaneki _{4,

5} , Bakhos A Tannous ₁ , Vijaya Ramesh ₃ , Casey A Maguire ₁ , Xandra O Breakefield ₁

Affiliation

Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Shriners Hospitals for Children, Boston, MA, USA.
Rodent Histopathology Core Facility, Harvard Medical School, Boston, MA, USA.
Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
The Pediatric Epilepsy Program, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.
Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland.
Department of Ophthalmology, University of Basel, Basel, Switzerland.
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.

Tuberous sclerosis complex (TSC) results from loss of a tumor suppressor gene - TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins formed a complex to inhibit mTORC1-mediated cell growth and proliferation. Loss of either protein leads to overgrowth lesions in many vital organs. Gene therapy was evaluated in a mouse model of TSC2 using an adeno-associated virus (AAV) vector carrying the complementary for a “condensed” form of human tuberin (cTuberin). Functionality of cTuberin was verified in culture. A mouse model of TSC2 was generated by AAV-Cre recombinase disruption of Tsc2-floxed alleles at birth, leading to a shortened lifespan (mean 58 days) and brain pathology consistent with TSC. When these mice were injected intravenously on day 21 with AAV9-cTuberin, the mean survival was extended to 462 days with reduction in brain pathology. This demonstrates the potential of treating life-threatening TSC2 lesions with a single intravenous injection of AAV9-cTuberin.

中文翻译：

通过递送编码浓缩形式的马铃薯蛋白的 AAV9 对小鼠模型中的 2 型结节性硬化症进行基因治疗

结节性硬化症 (TSC) 是由肿瘤抑制基因TSC 1 或TSC 2（分别编码错构蛋白和马铃薯蛋白）缺失引起的。这些蛋白质形成复合物来抑制 mTORC1 介导的细胞生长和增殖。任何一种蛋白质的丢失都会导致许多重要器官的过度生长病变。使用携带“浓缩”形式人马铃薯蛋白 (cTuberin) 互补物的腺相关病毒 (AAV) 载体在 TSC2 小鼠模型中评估基因治疗。 cTuberin 的功能在培养物中得到验证。 TSC2小鼠模型是通过 AAV-Cre 重组酶破坏出生时Tsc2 -floxed 等位基因而产生的，导致寿命缩短（平均 58 天），并且脑病理学与 TSC 一致。当这些小鼠在第 21 天静脉注射 AAV9-cTuberin 时，平均生存期延长至 462 天，并且脑部病理学减少。这证明了单次静脉注射 AAV9-cTuberin 治疗危及生命的 TSC2 病变的潜力。

更新日期：2021-01-10

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