Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease

Vallabh, Sonia M; Zou, Dan; Pitstick, Rose; O’Moore, Jill; Peters, J.F.; Silvius, Derek; Križ, Jasna; Jackson, Walker S.; Carlson, George A.; Minikel, Eric Vallabh; Cabin, Deborah E.

doi:10.1128/jvi.01672-22

Cited by 10 publications

(10 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed that PSCMA potently inhibited D177N PrP Sc propagation in recombinant sPMCA reactions, but PSCMA had no therapeutic effect in vivo . Our results also suggest that the novel knock-in models of FFI and fCJD that we used for these studies may be generally advantageous for pre-clinical in vivo testing because they have physiological PrP expression levels and shortened lifespans, thereby providing an objective and quantifiable endpoint for evaluating therapeutic efficacy, as recently suggested by Vallabh and Minikel(25). Finally, our results suggest that less easily administered therapies which lower PrP levels (such as anti-sense oligonucleotides delivered by lumbar puncture) may ultimately be required to escape the ability of both wild-type and mutant prions to undergo strain-adaptation leading to anti-prion drug failure(32, 44, 45).…”

Section: Discussionsupporting

confidence: 66%

“…Although treatment of inherited prion diseases appears to be a tractable goal, there have been no drugs specifically developed to target mutant prions. Recently, Vallabh et al accurately noted that a longstanding barrier to developing and testing such drugs pre-clinically has been the lack of animal models of inherited prion disease that exhibit shortened lifespans without transgene overexpression (25). Here, we evaluate several drug regimens that can either inhibit wild-type PrP Sc accumulation and prolong incubation time in scrapie-infected animals or inhibit mutant PrP Sc propagation in sPMCA reactions for their ability to treat new knock-in mouse models of FFI and fCJD with shortened lifespans.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Anti-prion drugs do not improve survival in knock-in models of inherited prion disease

Walsh,

Rees,

Mehra

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found.In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prionsin vivoas well as a brain-penetrant compound that inhibits mutant PrPScpropagationin vitro. None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPScaccumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Paradoxically, the combination of Anle138b and IND24 appeared to accelerate disease by 16% and 26% in kiBVIE200Kand kiBVID178Nmice, respectively, and accelerated the aggregation of mutant PrP moleculesin vitro. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions.

show abstract

Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 99%

Anti-prion drugs do not improve survival in knock-in models of inherited prion disease

Walsh,

Rees,

Mehra

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…We observed that PSCMA potently inhibited D178N PrP Sc propagation in recombinant sPMCA reactions, but PSCMA had no therapeutic effect in vivo . Our results also suggest that the novel knock-in models of FFI and fCJD that we used for these studies may be generally advantageous for pre-clinical in vivo testing because they have physiological PrP expression levels and shortened lifespans, thereby providing an objective and quantifiable endpoint for evaluating therapeutic efficacy, as recently suggested by Vallabh and Minikel [ 25 ]. Finally, our results suggest that less easily administered therapies which lower PrP levels (such as anti-sense oligonucleotides delivered by lumbar puncture) may ultimately be required to escape the ability of both wild-type and mutant prions to undergo strain-adaptation leading to anti-prion drug failure [ 31 , 50 , 51 ].…”

Section: Discussionsupporting

confidence: 55%

“…Theoretically, using animal models with lower expression levels and fewer plaques should improve our ability to detect a therapeutic effect and therefore increase our confidence about the negative results observed in this study. A more recent study testing Anle138b in alternative knock-in mouse models of FFI and fCJD expressing mutant mouse PrP molecules rather than bank vole PrP molecules was limited by the relatively normal lifespan of those mutant mice [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease

Walsh,

Rees,

Mehra

et al. 2024

PLoS Pathog

Self Cite

View full text Add to dashboard Cite

Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found. In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prions in vivo as well as a brain-penetrant compound that inhibits mutant PrPSc propagation in vitro. None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPSc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent.

show abstract

“…Although the compound showed effectiveness in several animal models, it failed to fully restore neural function in an acute neurotoxin-based MSA model [ 270 ]; therefore, combination with another compound, somewhat more specific to oxidative-stress-related apoptosis, should be considered. Also, in mouse models of genetic prion disease, anle138b appeared to be less effective as compared to sporadic model of this disorder [ 271 ]. The molecule has already completed two phase I trials in PD patients and healthy volunteers (NCT04685265; NCT04208152).…”

Section: Drugs Targeting α-Synucleinmentioning

confidence: 99%

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Siwecka,

Saramowicz,

Galita

et al. 2023

Pharmaceutics

View full text Add to dashboard Cite

α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson’s disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies.

show abstract

Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease

Abstract: There is an urgent need to develop drugs for prion disease, a currently untreatable neurodegenerative disease. In this effort, there is a debate over which animal models can best support a drug development program.

Cited by 10 publications

References 56 publications

Anti-prion drugs do not improve survival in knock-in models of inherited prion disease

Anti-prion drugs do not improve survival in knock-in models of inherited prion disease

Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Contact Info

Product

Resources

About