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Background: ISIS 814907 (BIIB080) is an antisense oligonucleotide (ASO) that hybridizes to a complementary nucleotide sequence of mRNA of the human microtubule‐associated protein tau (MAPT) gene, preventing production of tau protein. Accumulation of hyperphosphorylated tau is associated with cognitive decline and brain atrophy in Alzheimer's Disease (AD). The placebo controlled period of the Phase 1b multiple ascending dose (MAD) study of ISIS 814907 in patients with mild AD is complete and the open‐label long term extension (LTE) is ongoing in the UK, Canada, Germany, Sweden, Netherlands and Finland (EudraCT: 2016‐002713‐22; NCT03186989). Methods: The study is divided into 2 parts. Part 1 is the MAD study, comprising a 3‐month Treatment Evaluation (TE) Period and a 6‐month Post‐Treatment (PT) Period. Part 2 is the open‐label LTE, comprising a 12‐month TE Period and a 4‐ or 6‐month PT Period. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal (IT) bolus administrations of ISIS 814907 or placebo. Male or female patients aged 50‐74 years with mild AD and confirmed amyloid positivity (via CSF) at Screening were considered eligible. The primary objective was to assess safety and tolerability of multiple IT bolus administrations of ISIS 814907. The secondary objective was to evaluate CSF pharmacokinetics (PK). Exploratory objectives include assessment of plasma PK, target engagement and disease biomarkers, genotype and clinical endpoints relevant to AD. Results: All subjects (N=46) completed the MAD TE Period and 43 subjects completed the PT Period. All AEs were mild/moderate in severity. No serious AEs occurred in subjects receiving ISIS 814907. Dose‐dependent mean reduction from baseline in CSF total tau and phospho‐tau was observed in the TE period and continued in the PT period. CSF total tau and phospho‐tau reductions were comparable. Conclusions: IT bolus administration of multiple ascending doses of ISIS 814907 over 3 months was well‐tolerated in patients with mild AD. The robust lowering of CSF total tau and phospho‐tau warrants further investigation for the treatment of AD. [ABSTRACT FROM AUTHOR]

Many patients with major depressive disorder (MDD) only partially respond, and some have no clinically meaningful response, to current widely used antidepressant drugs. Due to the purported role of dopamine in the pathophysiology of depression, triple-reuptake inhibitors (TRIs) that simultaneously inhibit serotonin (5-HT), norepinephrine (NE) and dopamine reuptake could be a useful addition to the armamentarium of treatments for MDD. A TRI should more effectively activate mesolimbic dopamine-related reward-networks, restore positive mood and reduce potent 5-HT reuptake blockade associated “hypodopaminergic” adverse effects of decreased libido, weight gain and “blunting” of emotions. On the other hand, dopaminergic effects raise concern over abuse liability and TRIs may have many of the cardiovascular effects associated with NET inhibition. Several clinical development programs for potential TRI antidepressants have failed to demonstrate significantly greater efficacy than placebo or standard of care. Successful late-stage clinical development of a TRI is more likely if experimental research studies in the target population of depressed patients have demonstrated target engagement that differentially and dose-dependently improves assessments of reward-network dysfunction relative to existing antidepressants. TRI treatment could be individualized on the basis of predictive markers such as the burden of decreased positive mood symptoms and/or neuroimaging evidence of reward network dysfunction. This review focuses on how the next generation of monoamine-based treatments could be efficiently developed to address unmet medical need in MDD. [ABSTRACT FROM AUTHOR]

Disease-specific assessments are not currently available for patients with Parkinson's disease dementia (PDD). This study evaluated the criterion-related validity and test-retest reliability of the Alzheimer's Disease Assessment scale cognitive subscale (ADAS-cog) in terms of sensitivity for differentiation between mild and moderate severity impairment in PDD. Six other dementia rating scales and cognitive tests were also examined. A total of 113 patients with PDD or Alzheimer disease were recruited into this 4-week, multicenter study, segregated into 2 severity groups based on Mini-Mental State Examination (MMSE) score. Mean ADAS-cog scores showed a statistically significant separation between mild and moderate severity patients in both dementias (P < .001). For the ADAS-cog, test-retest Spearman correlation coefficients were significant for each dementia type and severity. This study demonstrated the criterion-related validity and test-retest reliability for ADAS-cog in patients with PDD and strong correlations with MMSE. This supports the validity of previous results obtained with these measures in studies of patients with PDD. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT , resulting in a mutant huntingtin protein. IONIS-HTT Rx (hereafter, HTT Rx ) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin., Methods: We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease. Patients were randomly assigned in a 3:1 ratio to receive HTT Rx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTT Rx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF., Results: Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTT Rx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTT Rx -treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTT Rx in CSF showed dose dependence up to doses of 60 mg. HTT Rx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTT Rx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively)., Conclusions: Intrathecal administration of HTT Rx to patients with early Huntington's disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02519036.)., (Copyright © 2019 Massachusetts Medical Society.)

Advances in molecular biology and genetics have been used to elucidate the fundamental genetic mechanisms underlying central nervous system (CNS) diseases, yet disease-modifying therapies are currently unavailable for most CNS conditions. Antisense oligonucleotides (ASOs) are synthetic single stranded chains of nucleic acids that bind to a specific sequence on ribonucleic acid (RNA) and regulate posttranscriptional gene expression. Decreased gene expression with ASOs might be able to reduce production of the disease-causing protein underlying dominantly inherited neurodegenerative disorders. Huntington's disease (HD), which is caused by a CAG repeat expansion in exon 1 of the huntingtin (HTT) gene and leads to the pathogenic expansion of a polyglutamine (PolyQ ) tract in the N terminus of the huntingtin protein (Htt), is a prime candidate for ASO therapy.State-of-the art translational science techniques can be applied to the development of an ASO targeting HTT RNA, allowing for a data-driven, stepwise progression through the drug development process. A deep and wide-ranging understanding of the basic, preclinical, clinical, and epidemiologic components of drug development will improve the likelihood of success. This includes characterizing the natural history of the disease, including evolution of biomarkers indexing the underlying pathology; using predictive preclinical models to assess the putative gain-of-function of mutant Htt protein and any loss-of-function of the wild-type protein; characterizing toxicokinetic and pharmacodynamic effects of ASOs in predictive animal models; developing sensitive and reliable biomarkers to monitor target engagement and effects on pathology that translate from animal models to patients with HD; establishing a drug delivery method that ensures reliable distribution to relevant CNS tissue; and designing clinical trials that move expeditiously from proof of concept to proof of efficacy. This review focuses on the translational science techniques that allow for efficient and informed development of an ASO for the treatment of HD.

Until recently, the only established function of acetylcholinesterase (AChE) was the termination of cholinergic neurotransmission. Therefore, the use of AChE inhibitors to treat symptoms caused by cholinergic imbalances in Alzheimer disease (AD) represented a rational approach. However, it is now clear that AChE and the cholinergic system may have broader effects in AD. Of particular interest may be signal transduction pathways mediated through cholinergic receptors that promote nonamyloidogenic amyloid precursor protein processing and decrease tau phosphorylation, and the role of AChE in the aggregation of beta-amyloid (Abeta) peptide. In addition, the neuronal and nonneuronal cholinergic systems have important roles in the modulation of regional cerebral blood flow. These findings may modify the overly simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment and ignores the potential of cholinergic therapies as disease-modifying agents. Chronic increases in AChE activity may exacerbate neurodegenerative processes, make clinically relevant levels of AChE inhibition more difficult to achieve, and cause the therapeutic value of cholinesterase inhibitors (ChE-Is) to be limited and temporary. Rapidly reversible ChE-Is appear to increase AChE activity over the longer term whereas, remarkably, irreversible or very slowly reversible ChE-Is do not seem to have this effect. If such differences between ChE-Is are shown to have clinical correlates, this may prompt reconsideration of the rationale and expectations of some agents in the long-term management of AD.