Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration

Fernandez-Parrilla, Manuel A.; Reyes-Corona, David; Flores-Martínez, Yazmin M.; Nadella, Rasajna; Bannon, Michael J.; Escobedo, Lourdes; Maldonado-Berny, Minerva; Santoyo-Salazar, J.; Soto-Rojas, Luis O.; Luna-Herrera, Claudia; Ayala-Dávila, José; González-Barrios, Juan Antonio; Flores, Gonzalo; Gutiérrez-Castillo, María Eugenia; Espadas-Álvarez, Armando J.; Martínez-Dávila, Irma A.; Nava, Porfirio; Martínez‐Fong, Daniel

doi:10.4103/1673-5374.321001

Cited by 4 publications

(6 citation statements)

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“…Previous studies [ 4 , 5 , 11 ] suggest that features that block NTS-polyplex NPs from passing the BBB when injected via blood circulation are their size of around 100 nm, positive electrical charge, and the lack of specific transporters in the BBB [ 3 – 5 , 11 , 13 ]. Here, we explored the size and surface electrical charge of NTS-polyplex NPs resulting from compaction of the pEGFP-N1 plasmid with NTS carrier and with KPRa, KPSV40, or without KPs.…”

Section: Resultsmentioning

confidence: 99%

“…S6). Therefore, the presence of GFP in dopaminergic neurons and axonal projections proves that FUS overcame BBB blockage and preserved NTS-polyplex NPs specificity for dopaminergic neurons [ 4 , 6 , 17 , 22 , 23 ]. Because the plasmid pEGFP-N1 lacks a cell-specific promoter, the specificity of transfection is provided by the NTS ligand, which internalizes NTS-polyplex NPs through endocytosis of NTSR1, highly expressed in dopaminergic neurons, as previously demonstrated in primary neuron cultures and animals [ 2 , 8 , 9 , 15 , 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…Neurotensin (NTS)-polyplex nanoparticles (NPs) constitute a specific gene delivery system to dopaminergic neurons that holds great promise for the therapy of Parkinson’s disease (PD) [ 1 ]. Those NPs result from the compaction of a plasmid DNA (pDNA) that contains the coding sequence of a neurotrophic factor gene under the control of dopamine transporter gene promoter (DAT) [ 2 , 3 ] or the synthetic NBRE3x promoter [ 4 – 6 ], both specific for dopaminergic neurons, or an eukaryotic promoter such as elongation factor α1 promoter [ 7 ]. pDNA compaction is mainly carried out by the electrostatic binding of linear poly-L-lysine conjugated with NTS and a fusogenic peptide [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Specificity is another advantage of NTS-polyplex NPs provided by the NTS ligand, which internalizes them through endocytosis of NTSR1, highly expressed in dopaminergic neurons [ 2 , 8 , 9 , 15 , 16 ]. The ligand-mediated specificity can be additionally reinforced with a tissue-specific promoter for dopaminergic neurons, such as DAT or NBRE3x promoters [ 4 , 6 , 16 , 17 ]; furthermore, an inducible doxycycline-regulated system can control the transgene expression if needed [ 5 ]. Moreover, the ability of dual transfection with unilateral administration is another advantage [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Preclinical studies with 6-hydroxydopamine (6-OHDA)-induced early parkinsonism have shown that the targeted delivery of genes coding for neurotrophic factors such as human (hGDNF) [ 22 ], rat brain-derived neurotrophic factor (rBDNF) [ 2 ], or hCDNF [ 6 ] can rescue dopaminergic neurons from neurodegeneration. Furthermore, gene delivery of hCDNF, rBDNF, or mNRTN in rats with 6-OHDA-induced advanced parkinsonism restores the structure and function of the dopaminergic nigrostriatal system [ 4 , 17 , 23 ]. A recent study in a novel PD model shows that the NTS-polyplex NP-mediated nurr1 gene transfection in dopaminergic neurons significantly reduces neuroinflammation, prion-like spreading of pathological α-synuclein aggregates, and degeneration of the dopaminergic nigrostriatal system, thus improving locomotor activity [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation

Mascotte-Cruz,

Vera,

Leija

et al. 2024

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Neurotensin-polyplex nanoparticles provide efficient gene transfection of nigral dopaminergic neurons when intracerebrally injected in preclinical trials of Parkinson’s disease because they do not cross the blood–brain barrier (BBB). Therefore, this study aimed to open BBB with focused ultrasound (FUS) on the substantia nigra to attain systemic and intranasal transfections and evaluate its detrimental effect in rats. Systemically injected Evans Blue showed that a two-pulse FUS opened the nigral BBB. Accordingly, 35 μL of neurotensin-polyplex nanoparticles encompassing the green fluorescent protein plasmid (79.6 nm mean size and + 1.3 mV Zeta-potential) caused its expression in tyrosine hydroxylase(+) cells (dopaminergic neurons) of both substantiae nigrae upon delivery via internal carotid artery, retro-orbital venous sinus, or nasal mucosa 30 min after FUS. The intracarotid delivery yielded the highest transgene expression, followed by intranasal and venous administration. However, FUS caused neuroinflammation displayed by infiltrated lymphocytes (positive to cluster of differentiation 45), activated microglia (positive to ionized calcium-binding adaptor molecule 1), neurotoxic A1 astrocytes (positive to glial fibrillary acidic protein and complement component 3), and neurotrophic A2 astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10), that ended 15 days after FUS. Dopaminergic neurons and axonal projections decreased but recuperated basal values on day 15 after transfection, correlating with a decrease and recovery of locomotor behavior. In conclusion, FUS caused transient neuroinflammation and reversible neuronal affection but allowed systemic and intranasal transfection of dopaminergic neurons in both substantiae nigrae. Therefore, FUS could advance neurotensin-polyplex nanotechnology to clinical trials for Parkinson’s disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation

Mascotte-Cruz,

Vera,

Leija

et al. 2024

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LPS Triggers Acute Neuroinflammation and Parkinsonism Involving NLRP3 Inflammasome Pathway and Mitochondrial CI Dysfunction in the Rat

Valenzuela-Arzeta

Soto-Rojas

Flores-Martínez

et al. 2023

IJMS

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Whether neuroinflammation leads to dopaminergic nigrostriatal system neurodegeneration is controversial. We addressed this issue by inducing acute neuroinflammation in the substantia nigra (SN) with a single local administration (5 µg/2 µL saline solution) of lipopolysaccharide (LPS). Neuroinflammatory variables were assessed from 48 h to 30 days after the injury by immunostaining for activated microglia (Iba-1 +), neurotoxic A1 astrocytes (C3 + and GFAP +), and active caspase-1. We also evaluated NLRP3 activation and Il-1β levels by western blot and mitochondrial complex I (CI) activity. Fever and sickness behavior was assessed for 24 h, and motor behavior deficits were followed up until day 30. On this day, we evaluated the cellular senescence marker β-galactosidase (β-Gal) in the SN and tyrosine hydroxylase (TH) in the SN and striatum. After LPS injection, Iba-1 (+), C3 (+), and S100A10 (+) cells were maximally present at 48 h and reached basal levels on day 30. NLRP3 activation occurred at 24 h and was followed by a rise of active caspase-1 (+), Il-1β, and decreased mitochondrial CI activity until 48 h. A significant loss of nigral TH (+) cells and striatal terminals was associated with motor deficits on day 30. The remaining TH (+) cells were β-Gal (+), suggesting senescent dopaminergic neurons. All the histopathological changes also appeared on the contralateral side. Our results show that unilaterally LPS-induced neuroinflammation can cause bilateral neurodegeneration of the nigrostriatal dopaminergic system and are relevant for understanding Parkinson’s disease (PD) neuropathology.

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Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review

García-González,

Gonçalves-Sánchez,

Gómez-Nieto

et al. 2024

IJMS

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This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson’s disease (n = 12), spinal muscular atrophy (n = 8), Huntington’s disease (n = 3), Alzheimer’s disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.

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Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration

Cited by 4 publications

References 70 publications

Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation

Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation

LPS Triggers Acute Neuroinflammation and Parkinsonism Involving NLRP3 Inflammasome Pathway and Mitochondrial CI Dysfunction in the Rat

Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review

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