Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

AbstractMutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1−/− mice to treat both the hearing and vestibular symptoms. Results showed early treatment prevented collapse of the Reissner’s membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells. In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months. In the low-dosage group, a subgroup of mice (13/20) showed improvements only in the vestibular functions. Results supported that highly efficient transduction is one of the key factors for achieving the efficacy and maintaining the long-term therapeutic effect. Secondary outcomes of treatment included improved birth and litter survival rates. Our results demonstrated that gene therapy via the canalostomy approach, which has been considered to be one of the more feasible delivery methods for human inner ear gene therapy, preserved auditory and vestibular functions in a dose-dependent manner in a mouse model of JLNS2.

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Synapsin-caveolin-1 gene therapy preserves neuronal and synaptic morphology and prevents neurodegeneration in a mouse model of Alzheimer’s disease

Molecular Therapy — Methods & Clinical Development ◽

10.1016/j.omtm.2021.03.021 ◽

2021 ◽

Author(s):

Shanshan Wang ◽

Joseph S. Leem ◽

Sonia Podvin ◽

Vivian Hook ◽

Natalia Kleschevnikov ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gene Therapy ◽

Mouse Model ◽

Caveolin 1 ◽

Model Of Alzheimer’S Disease

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XIAP gene therapy effects on retinal ganglion cell structure and function in a mouse model of glaucoma

Gene Therapy ◽

10.1038/s41434-021-00281-7 ◽

2021 ◽

Author(s):

Shagana Visuvanathan ◽

Adam N. Baker ◽

Pamela S. Lagali ◽

Stuart G. Coupland ◽

Garfield Miller ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Cell Structure ◽

Structure And Function ◽

Retinal Ganglion ◽

And Function

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GLT1 gene delivery based on bone marrow-derived cells ameliorates motor function and survival in a mouse model of ALS

Scientific Reports ◽

10.1038/s41598-021-92285-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Natsuko Ohashi ◽

Tomoya Terashima ◽

Miwako Katagi ◽

Yuki Nakae ◽

Junko Okano ◽

...

Keyword(s):

Spinal Cord ◽

Gene Therapy ◽

Bone Marrow ◽

Mouse Model ◽

Lentiviral Vector ◽

White Blood Cells ◽

Glutamate Toxicity ◽

Pathological Lesion ◽

Arginase 1 ◽

Therapy Strategy

AbstractAmyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease. CD68-positive bone marrow (BM)-derived cells (BMDCs) accumulate in the pathological lesion in the SOD1(G93A) ALS mouse model after BM transplantation (BMT). Therefore, we investigated whether BMDCs can be applied as gene carriers for cell-based gene therapy by employing the accumulation of BMDCs. In ALS mice, YFP reporter signals were observed in 12–14% of white blood cells (WBCs) and in the spinal cord via transplantation of BM after lentiviral vector (LV) infection. After confirmation of gene transduction by LV with the CD68 promoter in 4–7% of WBCs and in the spinal cord of ALS mice, BM cells were infected with LVs expressing glutamate transporter (GLT) 1 that protects neurons from glutamate toxicity, driven by the CD68 promoter, which were transplanted into ALS mice. The treated mice showed improvement of motor behaviors and prolonged survival. Additionally, interleukin (IL)-1β was significantly suppressed, and IL-4, arginase 1, and FIZZ were significantly increased in the mice. These results suggested that GLT1 expression by BMDCs improved the spinal cord environment. Therefore, our gene therapy strategy may be applied to treat neurodegenerative diseases such as ALS in which BMDCs accumulate in the pathological lesion by BMT.

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