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Gene Therapy for Neurodegenerative Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 25616

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Special Issue Editors

Prof. Dr. Javier Díaz-Nido

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Guest Editor

Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain
Interests: neurodegeneration; neurodegenerative diseases; ataxias; cerebellum; neurotrophic factors; neuroprotection; gene therapy

Dr. S. Herranz-Martin

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Guest Editor

Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain
Interests: Gene therapy; cell therapy; AAV; Ataxias; mitochondria; Neurodegenerative diseases; neuroprotection

Prof. Dr. Ahad Rahim

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Guest Editor

School of Pharmacy, University College London, London, UK
Interests: AAV; gene therapy; cell therapy; neurodegeneration; inherited metabolic diseases; lysosomal storage diseases

Special Issue Information

Dear Colleagues,

According to the Foof and Drug Administration (FDA) “gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use”. Within the past few decades, gene therapy has emerged as a very valuable tool to restore defective genes causing human disorders. This technology is especially attractive for the treatment of monogenic diseases. Many neurodegenerative conditions, especially rare disorders, are in fact, monogenic, making them, therefore, ideal for their treatment using gene therapy approaches. Different viral vectors, such as Adeno-associated virus (AAV), lentivirus (LV), retroviruses (RV), adenoviruses (Ad) or herpes simplex virus (HSV), among others, or non-viral vectors, have been widely used to carry the therapeutic gene into the host cell, showing promising results in hundreds of preclinical and clinical studies published. Indeed, some AAV-based gene therapy products, such as Zolgensma®, have been already approved by the FDA for the treatment of Spinal Muscular Atrophy (SMA), a fatal neurodegenerative disease affecting children. However, there still remain many important challenges for the development of effective gene therapies for neurological disorders. In a year in which pandemic has made that many laboratories have focused their efforts in the fight against SARS-CoV-2, it is very important to also advance in the research of many other disorders including those affecting the central nervous system. Thus, the aim of this special issue will be to cover preclinical studies and basic science studies using gene therapy approaches for the treatment of different neurodegenerative diseases.

Prof. Dr. Javier Díaz-Nido
Dr. S. Herranz-Martin
Prof. Dr. Ahad Rahim
Guest Editors

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Keywords

Gene therapy
Neurodegeneration
Neuroprotection
Neurotoxicity
Viral vector
AAV
Transduction
Non-viral vector

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Published Papers (7 papers)

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Research

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24 pages, 4324 KiB

Open AccessArticle

Effects of a Cc2d1a/Freud-1 Knockdown in the Hippocampus on Behavior, the Serotonin System, and BDNF

by Elena M. Kondaurova, Alexandra V. Plyusnina, Tatiana V. Ilchibaeva, Dmitry V. Eremin, Alexander Ya. Rodnyy, Yulia D. Grygoreva and Vladimir S. Naumenko

Int. J. Mol. Sci. 2021, 22(24), 13319; https://doi.org/10.3390/ijms222413319 - 11 Dec 2021

Cited by 10 | Viewed by 2851

Abstract

The serotonin 5-HT_1A receptor is one of the most abundant and widely distributed brain serotonin (5-HT) receptors that play a major role in the modulation of emotions and behavior. The 5-HT_1A receptor gene (Htr1a) is under the control of transcription factor Freud-1 (also known as Cc2d1a/Freud-1). Here, using adeno-associated virus (AAV) constructs in vivo, we investigated effects of a Cc2d1a/Freud-1 knockdown in the hippocampus of C57BL/6J mice on behavior, the brain 5-HT system, and brain-derived neurotrophic factor (BDNF). AAV particles carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a short-hairpin RNA targeting mouse Cc2d1a/Freud-1 mRNA had an antidepressant effect in the forced swim test 5 weeks after virus injection. The knockdown impaired spatiotemporal memory as assessed in the Morris water maze. pAAV_H1-2_shRNA-Freud-1_Syn_EGFP decreased Cc2d1a/Freud-1 mRNA and protein levels. Furthermore, the Cc2d1a/Freud-1 knockdown upregulated 5-HT and its metabolite 5-hydroxyindoleacetic acid but not their ratio. The Cc2d1a/Freud-1 knockdown failed to increase mRNA and protein levels of Htr1a but diminished a 5-HT_1A receptor functional response. Meanwhile, the Cc2d1a/Freud-1 knockdown reduced Creb mRNA expression and CREB phosphorylation and upregulated cFos mRNA. The knockdown enhanced the expression of a BDNF precursor (proBDNF protein), which is known to play a crucial part in neuroplasticity. Our data indicate that transcription factor Cc2d1a/Freud-1 is implicated in the pathogenesis of depressive disorders not only via the 5-HT_1A receptor and transcription factor CREB but also through an influence on BDNF. Full article

(This article belongs to the Special Issue Gene Therapy for Neurodegenerative Disease)

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15 pages, 11337 KiB

Open AccessArticle

Functional Availability of ON-Bipolar Cells in the Degenerated Retina: Timing and Longevity of an Optogenetic Gene Therapy

by Jakub Kralik and Sonja Kleinlogel

Int. J. Mol. Sci. 2021, 22(21), 11515; https://doi.org/10.3390/ijms222111515 - 26 Oct 2021

Cited by 9 | Viewed by 3499

Abstract

Degenerative diseases of the retina are responsible for the death of photoreceptors and subsequent loss of vision in patients. Nevertheless, the inner retinal layers remain intact over an extended period of time, enabling the restoration of light sensitivity in blind retinas via the expression of optogenetic tools in the remaining retinal cells. The chimeric Opto-mGluR6 protein represents such a tool. With exclusive ON-bipolar cell expression, it combines the light-sensitive domains of melanopsin and the intracellular domains of the metabotropic glutamate receptor 6 (mGluR6), which naturally mediates light responses in these cells. Albeit vision restoration in blind mice by Opto-mGluR6 delivery was previously shown, much is left to be explored in regard to the effects of the timing of the treatment in the degenerated retina. We performed a functional evaluation of Opto-mGluR6-treated murine blind retinas using multi-electrode arrays (MEAs) and observed long-term functional preservation in the treated retinas, as well as successful therapeutical intervention in later stages of degeneration. Moreover, the treatment decreased the inherent retinal hyperactivity of the degenerated retinas to levels undistinguishable from healthy controls. Finally, we observed for the first time micro electroretinograms (mERGs) in optogenetically treated animals, corroborating the origin of Opto-mGluR6 signalling at the level of mGluR6 of ON-bipolar cells. Full article

(This article belongs to the Special Issue Gene Therapy for Neurodegenerative Disease)

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20 pages, 5147 KiB

Open AccessArticle

Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death

by Yang Zhao, Fulei Tang, Daehoon Lee and Wen-Cheng Xiong

Int. J. Mol. Sci. 2021, 22(16), 8394; https://doi.org/10.3390/ijms22168394 - 4 Aug 2021

Cited by 7 | Viewed by 2976

Abstract

Vps35 (vacuolar protein sorting 35) is a key component of retromer that consists of Vps35, Vps26, and Vps29 trimers, and sortin nexin dimers. Dysfunctional Vps35/retromer is believed to be a risk factor for development of various neurodegenerative diseases. Vps35^Neurod6 mice, which selectively knock out Vps35 in Neurod6-Cre+ pyramidal neurons, exhibit age-dependent impairments in terminal differentiation of dendrites and axons of cortical and hippocampal neurons, neuro-degenerative pathology (i.e., increases in P62 and Tdp43 (TAR DNA-binding protein 43) proteins, cell death, and reactive gliosis), and neonatal death. The relationships among these phenotypes and the underlying mechanisms remain largely unclear. Here, we provide evidence that expression of low level of VPS35-mCherry fusion protein in Vps35^Neurod6 mice could diminish the phenotypes in an age-dependent manner. Specifically, we have generated a conditional transgenic mouse line, LSL-Vps35-mCherry, which expresses VPS35-mCherry fusion protein in a Cre-dependent manner. Crossing LSL-Vps35-mCherry with Vps35^Neurod6 to obtain TgVPS35-mCherry, Vps35^Neurod6 mice prevent the neonatal death and diminish the dendritic morphogenesis deficit and gliosis at the neonatal, but not the adult age. Further studies revealed that the Vps35-mCherry transgene expression was low, and the level of Vps35 mRNA comprised only ~5–7% of the Vps35 mRNA of control mice. Such low level of VPS35-mCherry could restore the amount of other retromer components (Vps26a and Vps29) at the neonatal age (P14). Importantly, the neurodegenerative pathology presented in the survived adult TgVps35-mCherry; Vps35^Neurod6 mice. These results demonstrate the sufficiency of low level of VPS35-mCherry fusion protein to diminish the phenotypes in Vps35^Neurod6 mice at the neonatal age, verifying a key role of neuronal Vps35 in stabilizing retromer complex proteins, and supporting the view for Vps35 as a potential therapeutic target for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Gene Therapy for Neurodegenerative Disease)

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17 pages, 2794 KiB

Open AccessArticle

Synergistic Effect of the Long-Term Overexpression of Bcl-2 and BDNF Lentiviral in Cell Protecting against Death and Generating TH Positive and CHAT Positive Cells from MSC

by Paulina Borkowska, Aleksandra Zielinska, Monika Paul-Samojedny, Rafał Stojko and Jan Kowalski

Int. J. Mol. Sci. 2021, 22(13), 7086; https://doi.org/10.3390/ijms22137086 - 30 Jun 2021

Cited by 5 | Viewed by 2770

Abstract

Mesenchymal stem cells (MSC) are potentially a good material for transplantation in many diseases, including neurodegenerative diseases. The main problem with using them is the low percentage of surviving cells after the transplant procedure and the naturally poor ability of MSC to spontaneously differentiate into certain types of cells, which results in their poor integration with the host cells. The aim and the novelty of this work consists in the synergistic overexpression of two genes, BCL2 and BDNF, using lentiviral vectors. According to our hypothesis, the overexpression of the BCL2 gene is aimed at increasing the resistance of cells to stressors and toxic factors. In turn, the overexpression of the BDNF gene is suspected to direct the MSC into the neural differentiation pathway. As a result, it was shown that the overexpression of both genes and the overproduction of proteins is permanent and persists for at least 60 days. The synergistically transduced MSC were significantly more resistant to the action of staurosporine; 12 days after transduction, the synergistically transduced MSC had a six-times greater survival rate. The overexpression of the Bcl-2 and BDNF proteins was sufficient to stimulate a significant overexpression of the CHAT gene, and under specific conditions, the TH, TPH1, and SYP genes were also overexpressed. Modified MSC are able to differentiate into cholinergic and dopaminergic neurons, and the release of acetylcholine and dopamine may indicate their functionality. Full article

(This article belongs to the Special Issue Gene Therapy for Neurodegenerative Disease)

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10 pages, 2660 KiB

Open AccessArticle

Phototoxicities Caused by Continuous Light Exposure Were Not Induced in Retinal Ganglion Cells Transduced by an Optogenetic Gene

by Kitako Tabata, Eriko Sugano, Akito Hatakeyama, Yoshito Watanabe, Tomoya Suzuki, Taku Ozaki, Tomokazu Fukuda and Hiroshi Tomita

Int. J. Mol. Sci. 2021, 22(13), 6732; https://doi.org/10.3390/ijms22136732 - 23 Jun 2021

Cited by 10 | Viewed by 2522

Abstract

The death of photoreceptor cells is induced by continuous light exposure. However, it is unclear whether light damage was induced in retinal ganglion cells with photosensitivity by transduction of optogenetic genes. In this study, we evaluated the phototoxicities of continuous light exposure on retinal ganglion cells after transduction of the optogenetic gene mVChR1 using an adeno-associated virus vector. Rats were exposed to continuous light for a week, and visually evoked potentials (VEPs) were recorded. The intensities of continuous light (500, 1000, 3000, and 5000 lx) increased substantially after VEP recordings. After the final recording of VEPs, retinal ganglion cells (RGCs) were retrogradely labeled with a fluorescein tracer, FluoroGold, and the number of retinal ganglion cells was counted under a fluorescent microscope. There was no significant reduction in the amplitudes of VEPs and the number of RGCs after exposure to any light intensity. These results indicated that RGCs were photosensitive after the transduction of optogenetic genes and did not induce any phototoxicity by continuous light exposure. Full article

(This article belongs to the Special Issue Gene Therapy for Neurodegenerative Disease)

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22 pages, 5662 KiB

Open AccessArticle

Loss of HCN2 in Dorsal Hippocampus of Young Adult Mice Induces Specific Apoptosis of the CA1 Pyramidal Neuron Layer

by Matthias Deutsch, Carina Stegmayr, Sabine Balfanz and Arnd Baumann

Int. J. Mol. Sci. 2021, 22(13), 6699; https://doi.org/10.3390/ijms22136699 - 22 Jun 2021

Cited by 3 | Viewed by 2548

Abstract

Neurons inevitably rely on a proper repertoire and distribution of membrane-bound ion-conducting channels. Among these proteins, the family of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels possesses unique properties giving rise to the corresponding I_h-current that contributes to various aspects of neural signaling. In mammals, four genes (hcn1-4) encode subunits of HCN channels. These subunits can assemble as hetero- or homotetrameric ion-conducting channels. In order to elaborate on the specific role of the HCN2 subunit in shaping electrical properties of neurons, we applied an Adeno-associated virus (AAV)-mediated, RNAi-based knock-down strategy of hcn2 gene expression both in vitro and in vivo. Electrophysiological measurements showed that HCN2 subunit knock-down resulted in specific yet anticipated changes in I_h-current properties in primary hippocampal neurons and, in addition, corroborated that the HCN2 subunit participates in postsynaptic signal integration. To further address the role of the HCN2 subunit in vivo, we injected recombinant (r)AAVs into the dorsal hippocampus of young adult male mice. Behavioral and biochemical analyses were conducted to assess the contribution of HCN2-containing channels in shaping hippocampal network properties. Surprisingly, knock-down of hcn2 expression resulted in a severe degeneration of the CA1 pyramidal cell layer, which did not occur in mice injected with control rAAV constructs. This finding might pinpoint to a vital and yet unknown contribution of HCN2 channels in establishing or maintaining the proper function of CA1 pyramidal neurons of the dorsal hippocampus. Full article

(This article belongs to the Special Issue Gene Therapy for Neurodegenerative Disease)

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Review

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18 pages, 1138 KiB

Open AccessReview

Future Prospects of Gene Therapy for Friedreich’s Ataxia

by Gabriel Ocana-Santero, Javier Díaz-Nido and Saúl Herranz-Martín

Int. J. Mol. Sci. 2021, 22(4), 1815; https://doi.org/10.3390/ijms22041815 - 11 Feb 2021

Cited by 32 | Viewed by 7409

Abstract

Friedreich’s ataxia is an autosomal recessive neurogenetic disease that is mainly associated with atrophy of the spinal cord and progressive neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in the first intron of the frataxin gene leading to a decreased level of frataxin protein, which results in mitochondrial dysfunction. Currently, there is no effective treatment to delay neurodegeneration in Friedreich’s ataxia. A plausible therapeutic approach is gene therapy. Indeed, Friedreich’s ataxia mouse models have been treated with viral vectors en-coding for either FXN or neurotrophins, such as brain-derived neurotrophic factor showing promising results. Thus, gene therapy is increasingly consolidating as one of the most promising therapies. However, several hurdles have to be overcome, including immunotoxicity and pheno-toxicity. We review the state of the art of gene therapy in Friedreich’s ataxia, addressing the main challenges and the most feasible solutions for them. Full article

(This article belongs to the Special Issue Gene Therapy for Neurodegenerative Disease)

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