Treatment of Parkinson’s disease with biologics that penetrate the blood–brain barrier via receptor-mediated transport
Parkinson’s disease (PD) is characterized by neurodegeneration of nigral-striatal neurons in parallel with the formation of intra-neuronal α-synuclein aggregates, and these processes are exacerbated by neuro-inflammation. All 3 components of PD pathology are potentially treatable with biologics. Neu...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1276376/full |
| _version_ | 1797628056992481280 |
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| author | William M. Pardridge |
| author_facet | William M. Pardridge |
| author_sort | William M. Pardridge |
| collection | DOAJ |
| description | Parkinson’s disease (PD) is characterized by neurodegeneration of nigral-striatal neurons in parallel with the formation of intra-neuronal α-synuclein aggregates, and these processes are exacerbated by neuro-inflammation. All 3 components of PD pathology are potentially treatable with biologics. Neurotrophins, such as glial derived neurotrophic factor or erythropoietin, can promote neural repair. Therapeutic antibodies can lead to disaggregation of α-synuclein neuronal inclusions. Decoy receptors can block the activity of pro-inflammatory cytokines in brain. However, these biologic drugs do not cross the blood–brain barrier (BBB). Biologics can be made transportable through the BBB following the re-engineering of the biologic as an IgG fusion protein, where the IgG domain targets an endogenous receptor-mediated transcytosis (RMT) system within the BBB, such as the insulin receptor or transferrin receptor. The receptor-specific antibody domain of the fusion protein acts as a molecular Trojan horse to ferry the biologic into brain via the BBB RMT pathway. This review describes the re-engineering of all 3 classes of biologics (neurotrophins, decoy receptor, therapeutic antibodies) for BBB delivery and treatment of PD. Targeting the RMT pathway at the BBB also enables non-viral gene therapy of PD using lipid nanoparticles (LNP) encapsulated with plasmid DNA encoding therapeutic genes. The surface of the lipid nanoparticle is conjugated with a receptor-specific IgG that triggers RMT of the LNP across the BBB in vivo. |
| first_indexed | 2024-03-11T10:33:07Z |
| format | Article |
| id | doaj.art-efb8bef39da14e3489ae7e4319e22b58 |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-03-11T10:33:07Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-efb8bef39da14e3489ae7e4319e22b582023-11-14T14:02:58ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652023-11-011510.3389/fnagi.2023.12763761276376Treatment of Parkinson’s disease with biologics that penetrate the blood–brain barrier via receptor-mediated transportWilliam M. PardridgeParkinson’s disease (PD) is characterized by neurodegeneration of nigral-striatal neurons in parallel with the formation of intra-neuronal α-synuclein aggregates, and these processes are exacerbated by neuro-inflammation. All 3 components of PD pathology are potentially treatable with biologics. Neurotrophins, such as glial derived neurotrophic factor or erythropoietin, can promote neural repair. Therapeutic antibodies can lead to disaggregation of α-synuclein neuronal inclusions. Decoy receptors can block the activity of pro-inflammatory cytokines in brain. However, these biologic drugs do not cross the blood–brain barrier (BBB). Biologics can be made transportable through the BBB following the re-engineering of the biologic as an IgG fusion protein, where the IgG domain targets an endogenous receptor-mediated transcytosis (RMT) system within the BBB, such as the insulin receptor or transferrin receptor. The receptor-specific antibody domain of the fusion protein acts as a molecular Trojan horse to ferry the biologic into brain via the BBB RMT pathway. This review describes the re-engineering of all 3 classes of biologics (neurotrophins, decoy receptor, therapeutic antibodies) for BBB delivery and treatment of PD. Targeting the RMT pathway at the BBB also enables non-viral gene therapy of PD using lipid nanoparticles (LNP) encapsulated with plasmid DNA encoding therapeutic genes. The surface of the lipid nanoparticle is conjugated with a receptor-specific IgG that triggers RMT of the LNP across the BBB in vivo.https://www.frontiersin.org/articles/10.3389/fnagi.2023.1276376/fullblood–brain barrierParkinson’s diseasedrug deliveryneurotrophinsdecoy receptor |
| spellingShingle | William M. Pardridge Treatment of Parkinson’s disease with biologics that penetrate the blood–brain barrier via receptor-mediated transport Frontiers in Aging Neuroscience blood–brain barrier Parkinson’s disease drug delivery neurotrophins decoy receptor |
| title | Treatment of Parkinson’s disease with biologics that penetrate the blood–brain barrier via receptor-mediated transport |
| title_full | Treatment of Parkinson’s disease with biologics that penetrate the blood–brain barrier via receptor-mediated transport |
| title_fullStr | Treatment of Parkinson’s disease with biologics that penetrate the blood–brain barrier via receptor-mediated transport |
| title_full_unstemmed | Treatment of Parkinson’s disease with biologics that penetrate the blood–brain barrier via receptor-mediated transport |
| title_short | Treatment of Parkinson’s disease with biologics that penetrate the blood–brain barrier via receptor-mediated transport |
| title_sort | treatment of parkinson s disease with biologics that penetrate the blood brain barrier via receptor mediated transport |
| topic | blood–brain barrier Parkinson’s disease drug delivery neurotrophins decoy receptor |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1276376/full |
| work_keys_str_mv | AT williammpardridge treatmentofparkinsonsdiseasewithbiologicsthatpenetratethebloodbrainbarrierviareceptormediatedtransport |