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Novel rAAV vector mediated intrathecal HGF delivery has an impact on neuroimmune modulation in the ALS motor cortex with TDP-43 pathology

Gene Therapy volume 30, pages 560–574 (2023)Cite this article

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Abstract

Recombinant adeno-associated virus (rAAV)-based gene therapies offer an immense opportunity for rare diseases, such as amyotrophic lateral sclerosis (ALS), which is defined by the loss of the upper and the lower motor neurons. Here, we describe generation, characterization, and utilization of a novel vector system, which enables expression of the active form of hepatocyte growth factor (HGF) under EF-1α promoter with bovine growth hormone (bGH) poly(A) sequence and is effective with intrathecal injections. HGF’s role in promoting motor neuron survival had been vastly reported. Therefore, we investigated whether intrathecal delivery of HGF would have an impact on one of the most common pathologies of ALS: the TDP-43 pathology. Increased astrogliosis, microgliosis and progressive upper motor neuron loss are important consequences of ALS in the motor cortex with TDP-43 pathology. We find that cortex can be modulated via intrathecal injection, and that expression of HGF reduces astrogliosis, microgliosis in the motor cortex, and help restore ongoing UMN degeneration. Our findings not only introduce a novel viral vector for the treatment of ALS, but also demonstrate modulation of motor cortex by intrathecal viral delivery, and that HGF treatment is effective in reducing astrogliosis and microgliosis in the motor cortex of ALS with TDP-43 pathology.

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Fig. 1: Construction of HGF-X7 variants.
Fig. 2: Comparison of elements constituting the expression cassette in vitro and in vivo.
Fig. 3: Effect of each promoter on the production yield of rAAV, and comparison of rAAV1 and rAAV9 in vivo.
Fig. 4: Experimental design to study the effects of HGF treatment via intrathecal rAAV delivery in the prpTDP-43A315T-UeGFP mice, which are the well-characterized TDP-43 pathology model of ALS cortex in which diseased UMNs are genetically labeled with eGFP expression.
Fig. 5: Intrathecal injection of rAAV9 HGF reduces microgliosis in the motor cortex of prpTDP-43A315T-UeGFP mice.
Fig. 6: Intrathecal injection of rAAV9 HGF reduces astrogliosis in the motor cortex of prpTDP-43A315T-UeGFP mice.
Fig. 7: Intrathecal injection of rAAV9 HGF reduces cytoplasmic accumulation of ubiquitinated proteins and the extent of UMN degeneration in the motor cortex of prpTDP-43A315T-UeGFP mice.
Fig. 8: Intrathecal injection of rAAV9 HGF reduces percentage of UMN with vacuolated apical dendrites in prpTDP-43A315T-UeGFP mice.

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Data generated or analyzed during this study can be found within the published article.

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Acknowledgements

Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. This work was supported by grants from NUCATS Translational Innovation Grant (PHO), Spastic Paraplegia Foundation grant (PHO), and in part by Helixmith Co., Ltd. Company collaboration grant (PHO).

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Author notes

  1. Boram Nho, Sunyoung Kim & Junghun Lee

    Present address: Helixmith Co., Ltd., R&D Center, 21, Magokjungang 8-ro 7-gil, Gangseo-gu, Seoul, 07794, Republic of Korea

  2. These authors contributed equally: Barış Genç, Boram Nho.

Authors and Affiliations

  1. Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Chicago, IL, 60611, USA

    Barış Genç, Benjamin Helmold, Öge Gözütok & Hande Özdinler

  2. School of Biological Sciences, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea

    Boram Nho, Nayeon Lee, Sunyoung Kim & Junghun Lee

  3. Helixmith Co., Ltd., R&D Center, 21, Magokjungang 8-ro 7-gil, Gangseo-gu, Seoul, 07794, Republic of Korea

    Hana Seung, Huiwon Park, Seunghyun Kim, Jinil Park, Sanghyun Ye, Haneul Lee & Seung-Shin Yu

  4. Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, IL, 60208, USA

    Hande Özdinler

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  1. Barış Genç
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Contributions

BN, BG, HS, ÖG, HP, BH, SK, JP, SY, HL, NL, S-SY, and PHO performed experiments. BN, BG, HS, ÖG, HP, BH, SK, JP, SY, HL, NL, S-SY, SK, JL, and PHO analyzed data, and BN, BG, JL, and PHO contributed to the writing of this manuscript.

Corresponding authors

Correspondence to Junghun Lee or Hande Özdinler.

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Competing interests

BN, HS, HP, SK, JP, SY, HL, NL, S-SY, SK, and JL are employees and/or shareholders of Helixmith Co., Ltd. Barış Genç, Öge Gözütok, Benjamin Helmold, and Hande Özdinler declare that they have no competing interests.

Ethical approval

All experimental and injection protocols were approved by the Institutional Animal Care and Use Committee (IACUC) at Helixmith Co. Ltd, Seoul National University and at Northwestern University.

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Genç, B., Nho, B., Seung, H. et al. Novel rAAV vector mediated intrathecal HGF delivery has an impact on neuroimmune modulation in the ALS motor cortex with TDP-43 pathology. Gene Ther 30, 560–574 (2023). https://doi.org/10.1038/s41434-023-00383-4

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