Recent developments in antibody therapeutics against prion disease

Frontzek, Karl; Aguzzi, Adriano

doi:10.1042/etls20200002

Cited by 10 publications

(7 citation statements)

References 47 publications

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“…For some ADAM10 substrates acting as cell surface receptors, binding of antibodies to their extracellular domains leads to their increased proteolytic release [49, 50]. Furthermore, as introduced earlier, PrP-directed antibodies show beneficial effects in different models of Alzheimer’s and prion diseases (reviewed in [72, 73]) and are even employed in the framework of a clinical trial [74]. These two seemingly ‘unrelated’ aspects prompted us to assess whether some selected PrP-directed antibodies (scheme in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…As introduced in detail above, anti-PrP antibodies have been proposed as potential prion and AD therapeutics (reviewed in [73, 118]) and, in fact, in a number of studies anti-PrP antibodies led to delay of disease onset and reduced signs of neurodegeneration [59, 65, 119, 120]. Although details are not completely understood, for prion diseases this beneficial effect is generally attributed to reduced PrP Sc replication thought to be caused by either direct sterical hindrance of the critical PrP Sc -to-PrP C interaction, stabilization of the native conformation and/or altered cellular trafficking of PrP C [53, 54, 121].…”

Section: Discussionmentioning

confidence: 99%

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Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

Linsenmeier

Mohammadi

Shafiq

et al. 2021

Preprint

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The cellular prion protein (PrPC) is a central player in neurodegenerative diseases caused by protein misfolding, such as prion diseases or Alzheimer's disease (AD). Expression levels of this GPI-anchored glycoprotein, especially at the neuronal cell surface, critically correlate with various pathomechanistic aspects underlying these diseases, such as templated misfolding (in prion diseases) and neurotoxicity and, hence, with disease progression and severity. In stark contrast to cell-associated PrPC, soluble extracellular forms or fragments of PrP are linked with neuroprotective effects, which is likely due to their ability to interfere with neurotoxic disease-associated protein conformers in the interstitial fluid. Fittingly, the endogenous proteolytic release of PrPC by the metalloprotease ADAM10 ('shedding') was characterized as a protective mechanism. Here, using a recently generated cleavage-site specific antibody, we shed new light on earlier studies by demonstrating that shed PrP (sPrP) negatively correlates with conformational conversion (in prion disease) and is markedly redistributed in murine brain in the presence of prion deposits or AD-associated amyloid plaques indicating a blocking and sequestrating activity. Importantly, we reveal that administration of certain PrP-directed antibodies and other ligands results in increased PrP shedding in cells and organotypic brain slice cultures. We also provide mechanistic and structural insight into this shedding-stimulating effect. In addition, we identified a striking exception to this, as one particular neuroprotective antibody, due to its special binding characteristics, did not cause increased shedding but rather strong surface clustering followed by fast endocytosis and degradation of PrPC. Both mechanisms may contribute to the beneficial action described for some PrP-directed antibodies/ligands and pave the way for new therapeutic strategies against devastating and currently incurable neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

Linsenmeier

Mohammadi

Shafiq

et al. 2021

Preprint

Self Cite

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“…Persistent prion infected ScN2a cells have been commonly used as a pre-screening step to discover new anti-prion agents. To date, an assay system using ScN2a cells has been used to classify anti-prion agents such as antibodies [ 28 ], dominant-negative molecules [ 29 , 30 ] and low molecular weight compounds [ 31 ]. However, despite so many attempts, no successful cure and clinically beneficial drugs for prion disease have been found.…”

Section: Discussionmentioning

confidence: 99%

Volatile Anesthetic Sevoflurane Precursor 1,1,1,3,3,3-Hexafluoro-2-Propanol (HFIP) Exerts an Anti-Prion Activity in Prion-Infected Culture Cells

et al. 2021

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Prion disease is a neurodegenerative disorder with progressive neurologic symptoms and accelerated cognitive decline. The causative protein of prion disease is the prion protein (PrP), and structural transition of PrP from the normal helix rich form (PrPC) to the abnormal β-sheet rich form (PrPSc) occurs in prion disease. While so far numerous therapeutic agents for prion diseases have been developed, none of them are still useful. A fluorinated alcohol, hexafluoro isopropanol (HFIP), is a precursor to the inhalational anesthetic sevoflurane and its metabolites. HFIP is also known as a robust α-helix inducer and is widely used as a solvent for highly aggregated peptides. Here we show that the α-helix-inducing activity of HFIP caused the conformational transformation of the fibrous structure of PrP into amorphous aggregates in vitro. HFIP added to the ScN2a cell medium, which continuously expresses PrPSc, reduced PrPSc protease resistance after 24-h incubation. It was also clarified that ScN2a cells are more susceptible to HFIP than any of the cells being compared. Based on these findings, HFIP is expected to develop as a therapeutic agent for prion disease.

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“…Conversely, a range of studies have raised the credible prospect that immunotherapeutic approaches, such as passive or active immunisation, may have efficacy against these currently untreatable and devastating disorders (reviewed in [ 256 , 257 ]). For example, transgenic mice that are engineered to secrete anti-PrP antibodies are protected against peripheral prion infections [ 258 ].…”

Section: Discussionmentioning

confidence: 99%

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

Mabbott

Bradford

Pal

et al. 2020

IJMS

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Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.

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Recent developments in antibody therapeutics against prion disease

Cited by 10 publications

References 47 publications

Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

Volatile Anesthetic Sevoflurane Precursor 1,1,1,3,3,3-Hexafluoro-2-Propanol (HFIP) Exerts an Anti-Prion Activity in Prion-Infected Culture Cells

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

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