Explore the vast range of titles available.

This phase 3 trial tested inotersen, a modified oligonucleotide that targets TTR messenger RNA, in the treatment of hereditary transthyretin amyloidosis, a disease in which misfolded transthyretin proteins are deposited in peripheral nerves and other tissues.

Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically. A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio in the overall population, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). Among the patients in the overall population, 125 in the vutrisiran group and 159 in the placebo group had at least one primary end-point event. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group. Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.).

In this randomized, controlled, phase 3 trial of tafamidis for transthyretin amyloid cardiomyopathy, tafamidis was associated with lower all-cause mortality and lower rates of cardiovascular-related hospitalizations and decline in functional capacity and quality of life.

First-in-class drug that inhibits protein misfolding approved in Europe for the treatment of familial amyloid polyneuropathy. In November 2011, tafamidis (Vyndaqel; Pfizer), a small molecule that inhibits the dissociation of transthyretin tetramers, was granted marketing authorization by the European Commission for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurological impairment.

Key Points The misfolding and/or misassembly of more than 30 human proteins — for example, transthyretin, immunoglobulin light chain, serum amyloid A and amyloid-β — into various aggregate structures, a process known as amyloidogenesis, cause a range of degenerative disorders, collectively called amyloid diseases. Amyloidogenesis is a dynamic process; thus, the protein aggregates produced adopt a range of structures ranging from small, relatively unstructured oligomers to structurally well-defined cross-β-sheet amyloid fibrils. Some structures may only be produced in humans. Although there is mounting genetic and pharmacological evidence that the process of protein aggregation is an important driver of neurodegeneration, a structure–proteotoxicity relationship is lacking for all human amyloid diseases. Moreover, we do not understand how the process of aggregation leads to the loss of postmitotic tissue in any human amyloid disease. In this Review, we summarize current and emerging strategies to ameliorate degenerative disorders associated with protein aggregation, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Potential therapeutic strategies for degenerative disorders associated with protein aggregation include: protein stabilization to prevent the conformational changes that enable aggregation, protein reduction to lower the concentration of the aggregation-prone protein and thereby slow aggregation, aggregate clearance or remodelling to reduce proteotoxicity, cellular proteostasis network adaptation to enhance proteome quality control, and reducing seeding and cell-to-cell spreading. The misfolding and aggregation of specific proteins — a process known as amyloidogenesis — seem to underlie a range of degenerative disorders. Here, Kelly and colleagues discuss the current understanding of the process and pathological role of protein aggregation, focusing on emerging disease-modifying strategies to ameliorate aggregation-associated degenerative disorders. The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the mechanistic connection between the process of protein aggregation and tissue degeneration is not yet fully understood. Here, we review current and emerging strategies to ameliorate aggregation-associated degenerative disorders, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Persuasive pharmacological and genetic evidence now supports protein aggregation as the cause of postmitotic tissue dysfunction or loss. However, a more detailed understanding of the factors that trigger and sustain aggregate formation and of the structure–activity relationships underlying proteotoxicity is needed to develop future disease-modifying therapies.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare, multisystem, progressive, debilitating, and fatal disease characterized by tissue deposition of misfolded transthyretin (TTR) in peripheral nerves. Nexiguran ziclumeran (nex-z) is an investigational in vivo therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) that is designed to reduce serum TTR levels through selective inactivation of in the liver. In this phase 1, open-label study, we administered one infusion of nex-z to patients with ATTRv-PN. Primary objectives included assessment of the safety and pharmacodynamics of nex-z. Secondary end points included changes in the familial amyloid polyneuropathy stage, polyneuropathy disability score, serum neurofilament light chain (NfL) level, modified body-mass index (modified BMI, defined as the conventional BMI [weight in kilograms divided by square of height in meters] multiplied by the albumin level in grams per liter), and modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment). A total of 36 patients received nex-z; the mean follow-up was 27 months. The mean percent change from baseline in the serum TTR level was -90% at day 28, which was sustained through month 24 (-92%). Treatment-related adverse events included transient infusion-related reactions (in 21 patients), decreased thyroxine level without hypothyroidism or elevated thyrotropin level (in 8), and headache (in 4). One participant died from cardiac amyloidosis, and one withdrew owing to progressive decline in motor function. Serious adverse events were reported in 11 patients. At month 24, the familial amyloid polyneuropathy stage and polyneuropathy disability score remained stable in 29 and 27 patients, respectively; improved in 2 and 5, respectively; and worsened in 2 and 2, respectively. The mean change in the serum NfL level was -9.0 pg per milliliter, and the change in the modified BMI was 24.7. The mean change from baseline in the mNIS+7 was -8.5. A single administration of nex-z in patients with ATTRv-PN was associated with rapid, deep, and durable reductions in serum TTR levels. The results support further investigation of nex-z to treat ATTRv-PN. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).

The deposition of amyloid β-protein (Aβ) in the brain is the main pathogenesis of Alzheimer’s disease (AD). The development of potent inhibitors against Aβ aggregation is one of the effective strategies to combat AD. Endogenous transthyretin (TTR) can inhibit Aβ fibrillization via hydrophobic interactions, but its weak inhibitory potency hinders its application in AD therapy. Here, different recombinant TTRs were designed by cationic surface charge engineering. Compared with TTR, all positively charged recombinant TTRs showed enhanced capability in inhibiting Aβ aggregation, especially the recombinant protein obtained by mutating the acidic amino acid in TTR to arginine (TTR-nR) exhibited excellent inhibitory effect. Among them, TTR-7R remarkably increased the inhibitory potency against Aβ, which could effectively inhibit Aβ40 fibrillization at a very low concentration (0.5 μM). In addition, TTR-7R increased cultured cell viability from 62% to 89%, scavenged amyloid plaques in AD nematodes, and prolonged nematode lifespan by 5 d at 2 μM. Thermodynamic studies demonstrated that TTR-7R, enriching in positive charges, presented hydrophobic interactions and enhanced electrostatic interactions with Aβ40, leading to a significantly enhanced inhibitory capacity of TTR-7R. The research provided insights into the development of efficient recombinant protein inhibitors for AD treatment.

Genetic evidence suggests that inhibition of amyloid fibril formation by small molecules should be effective against amyloid diseases. Known amyloid inhibitors appear to function by shifting the aggregation equilibrium away from the amyloid state. Here, we describe a series of transthyretin amyloidosis inhibitors that functioned by increasing the kinetic barrier associated with misfolding, preventing amyloidogenesis by stabilizing the native state. The trans-suppressor mutation, threonine 119 → methionine 119, which is known to ameliorate familial amyloid disease, also functioned through kinetic stabilization, implying that this small-molecule strategy should be effective in treating amyloid diseases.

Selenium (Se), as a nutritionally essential trace element, has been shown to decrease with age and is closely related to Alzheimer’s disease (AD). To probe the effects of Se on AD pathology, two-dimensional fluorescence difference gel electrophoresis was applied to the serum samples collected from the wild-type (WT) mice and the triple transgenic (PS1M146V/AβPPSwe/TauP301L) AD mice (3xTg-AD), treated with or without sodium selenate in drinking water for 4 months beginning at 2 months of age. Proteomics results revealed 17 differentially expressed proteins between WT and 3xTg-AD mice. It was found that the administration of selenate reversed the alterations of the differentially expressed serum proteins by up-regulating 13 proteins and down-regulating 2 proteins which were reported to be involved in the key pathogenesis of AD, including regulation of Aβ production, lipid metabolism regulation, and anti-inflammation. These results suggested that a dietary supplement with selenate is effective for prevention and treatment of AD, and the mechanism was maybe related to its role in Aβ regulation, lipid metabolism, and anti-inflammation. Moreover, we also presented that α-2 macroglobulin, transthyretin, haptoglobin, alpha-2-HS-glycoprotein, and alpha-1-antitrypsin in the serum can be used to evaluate the effect of selenate on AD pathology.

Carboranes represent a potentially rich but underutilized class of inorganic and catabolism-inert pharmacophores. The regioselectivity and ease of derivatization of carboranes allows for facile syntheses of a wide variety of novel structures. The steric bulk, rigidity, and ease of B- and C-derivatization and lack of π-interactions associated with hydrophobic carboranes may be exploited to enhance the selectivity of previously identified bioactive molecules. Transthyretin (TTR) is a thyroxine-transport protein found in the blood that has been implicated in a variety of amyloid related diseases. Previous investigations have identified a variety of nonsteroidal antiinflammatory drugs (NSAIDs) and structurally related derivatives that imbue kinetic stabilization to TTR, thus inhibiting its dissociative fragmentation and subsequent aggregation to form putative toxic amyloid fibrils. However, the cyclooxygenase (COX) activity associated with these pharmaceuticals may limit their potential as long-term therapeutic agents for TTR amyloid diseases. Here, we report the synthesis and evaluation of carborane-containing analogs of the promising NSAID pharmaceuticals previously identified. The replacement of a phenyl ring in the NSAIDs with a carborane moiety greatly decreases their COX activity with the retention of similar efficacy as an inhibitor of TTR dissociation. The most promising of these compounds, 1-carboxylic acid-7-[3-fluorophenyl]-1,7-dicarba-closo-dodecaborane, showed effectively no COX-1 or COX-2 inhibition at a concentration more than an order of magnitude larger than the concentration at which TTR dissociation is nearly completely inhibited. This specificity is indicative of the potential for the exploitation of the unique properties of carboranes as potent and selective pharmacophores.