ION717 for Prion Diseases
Recruiting in Palo Alto (17 mi)
+15 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Waitlist Available
Sponsor: Ionis Pharmaceuticals, Inc.
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial involves injecting a drug called ION717 into the spinal fluid of people with prion disease. The goal is to see how the drug behaves in the body and its effects on the disease. Prion disease has few treatment options, making this study important.
Do I have to stop taking my current medications for the trial?
The trial protocol does not specify whether you need to stop taking your current medications.
What data supports the idea that ION717 for Prion Diseases is an effective treatment?
The available research does not provide any data on the effectiveness of ION717 for Prion Diseases. The studies listed focus on other treatments and conditions, such as psoriatic arthritis and cholesterol management, without mentioning ION717 or Prion Diseases.
12345What safety data exists for ION717 treatment for Prion Diseases?
The provided research does not contain specific safety data for ION717 or its evaluation under different names. The studies focus on ionizable lipid nanoparticles and their safety in RNA delivery, but do not mention ION717 or its application in prion diseases.
678910Eligibility Criteria
This trial is for adults over 18 with early-stage prion disease, confirmed as probable or definite. Participants need to commit to the study schedule and travel requirements. They must have a caregiver willing to support their involvement throughout the trial.Inclusion Criteria
I am willing to follow all study requirements, including traveling.
I am 18 years old or older.
I have been diagnosed with prion disease.
+4 more
Participant Groups
The study is testing ION717, delivered directly into the spinal fluid (intrathecal delivery), against a placebo. It aims to assess how safe it is, how well tolerated by patients, its movement in the body (pharmacokinetics), and its effects on prion disease (pharmacodynamics).
2Treatment groups
Experimental Treatment
Group I: ION717 + Placebo, Regimen 2Experimental Treatment2 Interventions
Participants will receive multiple doses of study drug (ION717 and placebo) during the 30-week double-blind treatment period; the order of doses is blinded. Participants will then receive multiple doses of ION717 during the 70-week open-label extension period.
Group II: ION717 + Placebo, Regimen 1Experimental Treatment2 Interventions
Participants will receive multiple doses of study drug (ION717 and placebo) during the 30-week double-blind treatment period; the order of doses is blinded. Participants will then receive multiple doses of ION717 during the 70-week open-label extension period.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Colorado HospitalDenver, CO
NYU Langone HealthNew York, NY
University Hospitals Cleveland Medical CenterCleveland, OH
McGill University Health CentreMontréal, Canada
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Ionis Pharmaceuticals, Inc.Lead Sponsor
References
Ixekizumab treatment of biologic-naïve patients with active psoriatic arthritis: 3-year results from a phase III clinical trial (SPIRIT-P1). [2021]The aim was to assess the safety and efficacy of up to 156 weeks of ixekizumab (an IL-17A antagonist) treatment in PsA patients.
Impact of PCSK9 monoclonal antibodies on circulating hs-CRP levels: a systematic review and meta-analysis of randomised controlled trials. [2019]To evaluate the potential effects of proprotein convertase subtilisin/kexin type 9 monoclonal antibody (PCSK9-mAb) on high-sensitivity C reactive protein (hs-CRP) concentrations.
Effect of alirocumab dose increase on LDL lowering and lipid goal attainment in patients with dyslipidemia. [2019]The objective of this study is to report the dose response in ODYSSEY phase 3 clinical trials of proprotein convertase subtilisin kexin type 9 inhibition with alirocumab in patients not at prespecified lipid goals who received a per-protocol dose increase from 75 every 2 weeks (Q2W) to 150 mg Q2W.
The New Face of Hyperlipidemia and the Role of PCSK9 Inhibitors. [2021]To review the clinical rationale for use of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors in clinical practice.
A Phase I Randomized Study of a Specifically Engineered, pH-Sensitive PCSK9 Inhibitor RN317 (PF-05335810) in Hypercholesterolemic Subjects on Statin Therapy. [2021]This phase I study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of RN317 (PF-05335810), a specifically engineered, pH-sensitive, humanized proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody, in hypercholesterolemic subjects (low-density lipoprotein cholesterol (LDL-C) ≥ 80 mg/dl) 18-70 years old receiving statin therapy. Subjects were randomized to: single-dose placebo, RN317 (subcutaneous (s.c.) 0.3, 1, 3, 6, or intravenous (i.v.) 1, 3, 6 mg/kg), or bococizumab (s.c. 1, 3, or i.v. 1 mg/kg); or multiple-dose RN317 (s.c. 300 mg every 28 days; three doses). Of 133 subjects randomized, 127 completed the study. RN317 demonstrated a longer half-life, greater exposure, and increased bioavailability vs. bococizumab. RN317 was well tolerated, with no subjects discontinuing because of treatment-related adverse events. RN317 lowered LDL-C by up to 52.5% (day 15) following a single s.c. dose of 3.0 mg/kg vs. a maximum of 70% with single-dose bococizumab s.c. 3.0 mg/kg. Multiple dosing of RN317 produced LDL-C reductions of ∼50%, sustained over an 85-day dosing interval.
Novel piperazine-based ionizable lipid nanoparticles allow the repeated dose of mRNA to fibrotic lungs with improved potency and safety. [2023]mRNA-based protein replacement therapy has received much attention as a novel intervention in clinical disease treatment. Lipid nanoparticles (LNPs) are widely used for their therapeutic potential to efficiently deliver mRNA. However, clinical translation has been hampered by the immunogenicity of LNPs that may aggravate underlying disease states. Here, we report a novel ionizable LNP with enhanced potency and safety. The piperazine-based biodegradable ionizable lipid (244cis) was developed for LNP formulation and its level of protein expression and immunogenicity in the target tissue was evaluated. It was found that 244cis LNP enabled substantial expression of the target protein (human erythropoietin), while it minimally induced the secretion of monocyte chemoattractant protein 1 (MCP-1) as compared to other conventional LNPs. Selective lung targeting of 244cis LNP was further investigated in tdTomato transgenic mice with bleomycin-induced pulmonary fibrosis (PF). The repeated administration of 244cis LNP with Cre recombinase mRNA achieved complete transfection of lung endothelial cells (~80%) and over 40% transfection of Sca-1-positive fibroblasts. It was shown that 244cis LNP allows the repeated dose of mRNA without the loss of activity due to its low immunogenicity. Our results demonstrate that 244cis LNP has great potential for the treatment of chronic diseases in the lungs with improved potency and safety.
Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells. [2023]Ionizable cationic lipids are essential for efficient in vivo delivery of RNA by lipid nanoparticles (LNPs). DLin-MC3-DMA (MC3), ALC-0315, and SM-102 are the only ionizable cationic lipids currently clinically approved for RNA therapies. ALC-0315 and SM-102 are structurally similar lipids used in SARS-CoV-2 mRNA vaccines, while MC3 is used in siRNA therapy to knock down transthyretin in hepatocytes. Hepatocytes and hepatic stellate cells (HSCs) are particularly attractive targets for RNA therapy because they synthesize many plasma proteins, including those that influence blood coagulation. While LNPs preferentially accumulate in the liver, evaluating the ability of different ionizable cationic lipids to deliver RNA cargo into distinct cell populations is important for designing RNA-LNP therapies with minimal hepatotoxicity. Here, we directly compared LNPs containing either ALC-0315 or MC3 to knock-down coagulation factor VII (FVII) in hepatocytes and ADAMTS13 in HSCs. At a dose of 1 mg/kg siRNA in mice, LNPs with ALC-0315 achieved a 2- and 10-fold greater knockdown of FVII and ADAMTS13, respectively, compared to LNPs with MC3. At a high dose (5 mg/kg), ALC-0315 LNPs increased markers of liver toxicity (ALT and bile acids), while the same dose of MC3 LNPs did not. These results demonstrate that ALC-0315 LNPs achieves potent siRNA-mediated knockdown of target proteins in hepatocytes and HSCs, in mice, though markers of liver toxicity can be observed after a high dose. This study provides an initial comparison that may inform the development of ionizable cationic LNP therapeutics with maximal efficacy and limited toxicity.
Rational design and combinatorial chemistry of ionizable lipids for RNA delivery. [2023]In 2018, LNPs enabled the first FDA approval of a siRNA drug (Onpattro); two years later, two SARS-CoV-2 vaccines (Comirnaty, Spikevax) based on LNPs containing mRNA also arrived at the clinic, saving millions of lives during the COVID-19 pandemic. Notably, each of the three FDA-approved LNP formulations uses a unique ionizable lipid while the other three components, i.e., cholesterol, helper lipid, and PEGylated lipid, are almost identical. Therefore, ionizable lipids are critical to the delivery efficiency of mRNA. This review covers recent advances in ionizable lipids used in RNA delivery over the past several decades. We will discuss chemical structures, synthetic routes, and structure-activity relationships of ionizable lipids.
Influence of the Composition of Plasticizer-Free Silicone-Based Ion-Selective Membranes on Signal Stability in Aqueous and Blood Plasma Samples. [2023]Solid-contact ion-selective electrodes (SC-ISEs) in direct long-term contact with physiological samples must be biocompatible and resistant to biofouling, but most wearable SC-ISEs proposed to date contain plasticized poly(vinyl chloride) (PVC) membranes, which have poor biocompatibility. Silicones are a promising alternative to plasticized PVC because of their excellent biocompatibility, but little work has been done to study the relationship between silicone composition and ISE performance. To address this, we prepared and tested K+ SC-ISEs with colloid-imprinted mesoporous (CIM) carbon as the solid contact and three different condensation-cured silicones: a custom silicone prepared in-house (Silicone 1), a commercial silicone (Dow 3140, Silicone 2), and a commercial fluorosilicone (Dow 730, Fluorosilicone 1). SC-ISEs prepared with each of these polymers and the ionophore valinomycin and added ionic sites exhibited Nernstian responses, excellent selectivities, and signal drifts as low as 3 μV/h in 1 mM KCl solution. All ISEs maintained Nernstian response slopes and had only very slightly worsened selectivities after 41 h exposure to porcine plasma (log KK,Na values of -4.56, -4.58, and -4.49, to -4.04, -4.00, and -3.90 for Silicone 1, Silicone 2, and Fluorosilicone 1, respectively), confirming that these sensors retain the high selectivity that makes them suitable for use in physiological samples. When immersed in porcine plasma, the SC-ISEs exhibited emf drifts that were still fairly low but notably larger than when measurements were performed in pure water. Interestingly, despite the very similar structures of these matrix polymers, SC-ISEs prepared with Silicone 2 showed lower drift in porcine blood plasma (-55 μV/h, over 41 h) compared to Silicone 1 (-495 μV/h) or Fluorosilicone 1 (-297 μV/h).
Effect of carboxylate and/or sulphonate ion incorporation on the physical and blood-contacting properties of a polyetherurethane. [2019]Propyl sulphonate and ethyl carboxylate groups were grafted on to the backbone of a polytetramethylene oxide-based polyurethane (PEU). The effects of ion type and ion content on the polymer's bulk, surface, and blood-contacting properties were evaluated. Ion incorporation disrupted the packing of the hard segment but had little effect on the overall microphase separation of the polymers. The mechanical properties of the ionomers were improved relative to the base PEU, although the carboxylate-containing ionomers were weaker than the sulphonate-containing polymers. As expected, the polymer's water absorption and surface polarity increased with increasing ion content. Dynamic and static contact angle analysis indicated that the propyl sulphonate-containing polymers were more polar than the ethyl carboxylate-containing polymers at the same ion content which is attributed to the higher ionic strength of the sulphonate ion. The carboxylate-containing polymers had no statistically significant effect on the polymer's canine ex vivo blood-contacting response. At the same ion content, propyl sulphonate incorporation significantly reduced platelet deposition for very short blood-contacting times. When both ion types were present in the polymer, the propyl sulphonate group appeared to be the primary factor determining the polymer's blood-contacting response. The polymer containing 20 mol% propyl sulphonate groups significantly reduced platelet deposition and activation while also exhibiting enhanced fibrinogen deposition.
Accessibility of a critical prion protein region involved in strain recognition and its implications for the early detection of prions. [2020]Human prion diseases are characterized by the accumulation in the brain of proteinase K (PK)-resistant prion protein designated PrP27 - 30 detectable by the 3F4 antibody against human PrP109 - 112. We recently identified a new PK-resistant PrP species, designated PrP*20, in uninfected human and animal brains. It was preferentially detected with the 1E4 antibody against human PrP 97 - 108 but not with the anti-PrP 3F4 antibody, although the 3F4 epitope is adjacent to the 1E4 epitope in the PrP*20 molecule. The present study reveals that removal of the N-terminal amino acids up to residue 91 significantly increases accessibility of the 1E4 antibody to PrP of brains and cultured cells. In contrast to cells expressing wild-type PrP, cells expressing pathogenic mutant PrP accumulate not only PrP*20 but also a small amount of 3F4-detected PK-resistant PrP27 - 30. Remarkably, during the course of human prion disease, a transition from an increase in 1E4-detected PrP*20 to the occurrence of the 3F4-detected PrP27 - 30 was observed. Our study suggests that an increase in the level of PrP*20 characterizes the early stages of prion diseases.
Normal cellular prion protein with a methionine at position 129 has a more exposed helix 1 and is more prone to aggregate. [2021]The human prion gene, PRNP, has two allelic forms that encode either a methionine or valine at codon 129. This polymorphism strongly influences the pathogenesis of prion disease. However, the underlying mechanism remains unclear. We compared the conformation between wild-type human prion protein (rPrP(C)) with either a valine or methionine at position 129, using a panel of monoclonal antibodies that are specific for epitopes along the entire protein. We found that rPrP(C(129M)) has a more exposed helix 1 region compared to rPrP(C(129V)). Helix 1 is important in the aggregation process. Accordingly, rPrP(C(129M)) aggregates at a faster rate and forms more aggregate than rPrP(C(129V)). In addition, by using a rPrP with a pathogenic mutation of five additional octapeptide repeat insertions, rPrP((129M)/10OR), as "seeds", we showed that rPrP((129M)/10OR) promotes the aggregation of rPrP(C(129M)) more efficiently than rPrP(C(129V)). These findings provide a possible mechanism underlying the influence of residue 129 on human prion disease.
Fundamentals of prion biology and diseases. [2019]One of the most remarkable changes in medicine during the last 20 years of the 20th century was the shift from the clinical-neuropathological classification of Creutzfeldt-Jakob disease (CJD) and related disorders as 'transmissible spongiform encephalopathies' to a molecular-etiologic classification as 'prion diseases'. We now know that these diseases are caused by abnormalities of the prion protein (PrP). Specifically, CJD is caused by the conversion of the normal, protease-sensitive PrP isoform, designated PrP(C), to a protease resistant isoform, designated PrP(Sc). PrP(Sc) forms into an infectious particle, named a 'prion', that can transmit the disease. Accumulation of PrP(Sc) in the brain causes neurodegeneration. The main goals of this review are to summarize our understanding of the attributes of the PrP molecule that give it the properties of an infectious agent and to describe how different alterations of the PrP molecule cause the multiple known prion disease variants. Finally, the emergence of a new variant of CJD in Great Britain and to a lesser extent in Europe and its relationship to the emergence of a particularly virulent form of bovine spongiform encephalopathy will be discussed.
Isolation of infectious, non-fibrillar and oligomeric prions from a genetic prion disease. [2023]Prions are transmissible agents causing lethal neurodegenerative diseases that are composed of aggregates of misfolded cellular prion protein (PrPSc). Despite non-fibrillar oligomers having been proposed as the most infectious prion particles, prions purified from diseased brains usually consist of large and fibrillar PrPSc aggregates, whose protease-resistant core (PrPres) encompasses the whole C-terminus of PrP. In contrast, PrPSc from Gerstmann-Sträussler-Scheinker disease associated with alanine to valine substitution at position 117 (GSS-A117V) is characterized by a small protease-resistant core, which is devoid of the C-terminus. We thus aimed to investigate the role of this unusual PrPSc in terms of infectivity, strain characteristics, and structural features. We found, by titration in bank voles, that the infectivity of GSS-A117V is extremely high (109.3 ID50 U/g) and is resistant to treatment with proteinase K (109.0 ID50 U/g). We then purified the proteinase K-resistant GSS-A117V prions and determined the amount of infectivity and PrPres in the different fractions, alongside the morphological characteristics of purified PrPres aggregates by electron microscopy. Purified pellet fractions from GSS-A117V contained the expected N- and C-terminally cleaved 7 kDa PrPres, although the yield of PrPres was low. We found that this low yield depended on the low density/small size of GSS-A117V PrPres, as it was mainly retained in the last supernatant fraction. All fractions were highly infectious, thus confirming the infectious nature of the 7 kDa PrPres, with infectivity levels that directly correlated with the PrPres amount detected. Finally, electron microscopy analysis of these fractions showed no presence of amyloid fibrils, but only very small and indistinct, non-fibrillar PrPresparticles were detected and confirmed to contain PrP via immunogold labelling. Our study demonstrates that purified aggregates of 7 kDa PrPres, spanning residues ∼90-150, are highly infectious oligomers that encode the biochemical and biological strain features of the original sample. Overall, the autocatalytic behaviour of the prion oligomers reveals their role in the propagation of neurodegeneration in patients with Gerstmann-Sträussler-Scheinker disease and implies that the C-terminus of PrPSc is dispensable for infectivity and strain features for this prion strain, uncovering the central PrP domain as the minimal molecular component able to encode infectious prions. These findings are consistent with the hypothesis that non-fibrillar prion particles are highly efficient propagators of disease and provide new molecular and morphological constraints on the structure of infectious prions.
Progress and problems in the biology, diagnostics, and therapeutics of prion diseases. [2019]The term "prion" was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word "prion" has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the "mad cow" crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields.