Author: Jarrah, Sabrina I ; Schuster, Kristen H ; Zhang, Hanrui ; Haque, Zaid ; Putka, Alexandra F ; Stec, Nicholas R ; Naeem, Arsal ; Zalon, Annie J ; McLoughlin, Hayley S ; Guan, Yuanfang ; DiFranco, Danielle M

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventive or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in premanifest and symptomatic SCA3 mice. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results highlight the promising use of an ASO therapy across neurodegenerative diseases that requires glial targeting in addition to affected neuronal populations.

01 Mar 2024·Current Opinion in Clinical Nutrition & Metabolic Care

The 10 essential questions regarding lipoprotein(a)

Review

Author: Kostner, Karam M. ; Kostner, Gerhard M.

Purpose of reviewLp(a) is one of the most atherogenic lipoproteins, and significant progress has been made to understand its pathophysiology over the last 20 years. There are now selective therapies in late-stage clinical trials to lower Lp(a). Yet there are many outstanding questions about Lp(a). This review outlines 10 of the most burning questions and tries to answer some of them.Recent findingsAntisense oligonucleotide (ASO) treatment is currently the most advanced therapy to lower plasma Lp(a) by 60–80%. There are, however, also two small molecule medications in early stage of development with similar efficacy.SummaryThis review aims to answer important preclinical and clinical questions about the metabolism and physiological role of Lp(a) and also outlines possible therapeutic approaches with nutraceuticals, currently available lipid-lowering therapies and new medications. In addition, ways are illustrated to use Lp(a) as a marker to better predict cardiovascular risk.

01 Oct 2023·Annals of Neurology

Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice

Article

Author: Eberly, Lynn E. ; Wellik, Isabel G. ; Schuster, Kristen H. ; Öz, Gülin ; Rainwater, Orion ; Benneyworth, Michael A. ; McLoughlin, Hayley S. ; Gundry, Katherine ; Zalon, Annie J.

ObjectiveSpinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia, and biomarkers are needed to noninvasively monitor disease progression and treatment response. Anti‐ATXN3 antisense oligonucleotide (ASO) treatment has been shown to mitigate neuropathology and rescue motor phenotypes in SCA3 mice. Here, we investigated whether repeated ASO administration reverses brainstem and cerebellar neurochemical abnormalities by magnetic resonance spectroscopy (MRS).MethodsSymptomatic SCA3 mice received intracerebroventricular treatment of ASO or vehicle and were compared to wild‐type vehicle‐treated littermates. To quantify neurochemical changes in treated mice, longitudinal 9.4T MRS of cerebellum and brainstem was performed. Acquired magnetic resonance (MR) group means were analyzed by 2‐way analysis of variance mixed‐effects sex‐adjusted analysis with post hoc Sidak correlation for multiple comparisons. Pearson correlations were used to relate SCA3 pathology and behavior.ResultsMR spectra yielded 15 to 16 neurochemical concentrations in the cerebellum and brainstem. ASO treatment in SCA3 mice resulted in significant total choline rescue and partial reversals of taurine, glutamine, and total N‐acetylaspartate across both regions. Some ASO‐rescued neurochemicals correlated with reduction in diseased protein and nuclear ATXN3 accumulation. ASO‐corrected motor activity correlated with total choline and total N‐acetylaspartate levels early in disease.InterpretationSCA3 mouse cerebellar and brainstem neurochemical trends parallel those in patients with SCA3. Decreased total choline may reflect oligodendrocyte abnormalities, decreased total N‐acetylaspartate highlights neuronal health disturbances, and high glutamine may indicate gliosis. ASO treatment fully or partially reversed select neurochemical abnormalities in SCA3 mice, indicating the potential for these measures to serve as noninvasive treatment biomarkers in future SCA3 gene silencing trials. ANN NEUROL 2023;94:658–671

100 Deals associated with Rett Syndrome (ACADIA/Stoke Therapeutics)

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Indication	Highest Phase	Country/Location	Organization	Date
Rett Syndrome	Preclinical	US	Stoke Therapeutics, Inc.	30 Oct 2023
Rett Syndrome	Preclinical	US	ACADIA Pharmaceuticals, Inc.	30 Oct 2023

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