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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
Ataxin-3 is a 42 kDa, widely expressed protein that resides in both the nucleus and the cytoplasm of cells. It has been implicated in many aspects of intracellular protein quality control pathways that rely on ubiquitin, a small modifier protein. Ataxin-3 is a deubiquitinating enzyme (DUB) that cleaves ubiquitin from ubiquitinated substrates or polyubiquitin chains. Another proposed role for ataxin-3 is in the regulation of gene transcription.
Hereditary Spastic Paraparesis and Other Hereditary Myelopathies
Published in Anand D. Pandyan, Hermie J. Hermens, Bernard A. Conway, Neurological Rehabilitation, 2018
Jon Marsden, Lisa Bunn, Amanda Denton, Krishnan Padmakumari Sivaraman Nair
Depending on ethnicity, SCA3 accounts for between 21 and 56% of SCA cases.107 Prevalence varies according to founder effects. It is a polyglutamate (polyQ) disease caused by a CAG repeated expansion of the ATXN3 gene on chromosome 14q. The protein encoded by ATXN3, ataxin-3, is a deubiquitinating enzyme that cleaves ubiquitin off substrates. It is felt that this enzyme’s function, and thus biochemical pathways dependent upon ubiquitin, are affected in SCA3.108 The age of onset varies from childhood to late adult life and there is an inverse correlation between the number of CAG repeats and the age of onset and disease severity.109
Lipid Nanocarriers for Oligonucleotide Delivery to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Andreia F. Jorge, Santiago Grijalvo, Alberto Pais, Ramón Eritja
Stable nucleic acid lipid particles (SNALPs) were first developed in 2001 by Semple and colleagues and are considered an evolution of the cationic liposomes for delivering nucleic acids. Driven by this initial proposal, a lipid formulation composed of DO DAP/disaturated-phosphatidylcholine (DSPC)/chol/C16 mPEG2000 was devised to encapsulate LNA-modified anti-miR-21 or siRNA followed by postinsertion of micelles functionalised with chlorotoxin (CTX) to bind selectively to glioma cells. The assembled SNALPs displayed high encapsulation yields attributed to the complexation of ODNs with positive charged DODAP, a net surface charge close to neutrality and small sizes (<180 nm). Study outcomes described an increased cellular association and internalisation of CTX-targeted SNALPs by tumour cells, while sparing normal cells, increased tumour suppressor expression and caspase activity and a reduction in tumour cell proliferation [133]. The CTX-functionalised SNALPs with miR-21 were shown to accumulate preferentially within brain tumours and induce miR-21 silencing and decreased the tumour cell proliferation and tumour size, while showing no signs of systemic immunogenicity [134]. The same authors have used the same strategy to address Machado-Joseph disease (MJD) to deliver siRNA designed to target the ataxin-3 gene in neuronal cells. Initially, siRNA was encapsulated inside ceramide-PEGylated liposomes constituted by DODAP, DSPC and chol. In a second step, the resultant liposomes were involved by micelles made of DSPE-PEG functionalised with rabies virus glycoprotein-derived peptide RVG-r9. The intravenous administration of these SNALPs targeting neurons resulted in a significant knockdown of mutant ataxin-3 expression and aggregate formation [135].
Emerging therapeutic targets for narcolepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Marieke Vringer, Birgitte Rahbek Kornum
Behavioral data from mouse models offer some further insight into the functions of HcrtR1 and HcrtR2. Mice lacking the Hcrt peptide have a phenotype similar to human narcoleptic patients. The Hcrt-peptide-KO mice have fragmented sleep and wake states, cataplexy-like episodes of behavioral arrest during active wake, and SOREM periods [26]. Although these mice show a narcolepsy phenotype, the underlying cause is rather different from human narcolepsy since only the Hcrt gene is missing but the Hcrt neurons are still intact. In Hcrt/ataxin-3 (ATAX) mice, the development of narcolepsy symptoms is more similar to the human pathology. The toxic Ataxin-3 transgene causes apoptosis in Hcrt-containing cells resulting in degeneration of the neurons and symptom development starting around 6 weeks of age [5,58]. Gradual development of cataplexy and sleep fragmentation also occurs in the diphtheria toxin A (DTA) model. This model includes DTA expression in Hcrt neurons resulting in cell death under the control of doxycycline. These mice express the tetracycline-controlled transcriptional activator (tTA) exclusively in Hcrt neurons, which can induce DTA expression by binding to the tetracycline operator (TetO). However, tTA is unable to bind to TetO in the presence of doxycycline, and therefore Hcrt neuron degeneration can be controlled by adding or removing doxycycline from the diet [59]. Both the ATAX and the DTA model show fragmented sleep and wake states, behavioral cataplexy-like arrest and SOREM periods [58,59].
Current and emerging treatment modalities for spinocerebellar ataxias
Published in Expert Review of Neurotherapeutics, 2022
Shaila D. Ghanekar, Sheng-Han Kuo, Joseph S. Staffetti, Theresa A Zesiewicz
Despite these promising prospects, there are challenges to be overcome to increase the chance of success for clinical trials. Specifically, there is insufficient validated biomarkers for SCAs. Biomarkers are critical for target engagement and to track disease progression. Current biomarkers include molecules involved in autophagy, growth factors, enzymes, inflammatory and oxidative stress response, and chaperones [64]. Recently, the measurement of mutant ataxin-3 levels has been validated in patient spinal fluid as a target engagement biomarker for gene therapies or ASOs to reduce mutant ataxin-3 protein levels [110]. In addition, neurofilament light chains in the serum and magnetic resonance spectroscopy may be useful as a biomarker for disease progression [111]. Furthermore, recent investigation into volumetric biomarkers has revealed potential utility, specifically of fixel-based analysis [112]. One study found that volumetric changes in the brain, specifically in the brain stem and striatum, among SCA1 individuals were reliably differentiated from unaffected controls and were detected under a year [113]. All these developments can help to further accelerate therapeutic development. One major gap for biomarker development is a physiological biomarker, which can track the function of the cerebellum and can potentially provide more direct measurements of responses to therapies. The discovery of a physiological biomarker would be a huge step in treatment of SCA as it would allow for objective evaluation of therapies and direct evaluation of treatments’ effects on brain structure and function. Other challenges include a lack of patient reported outcomes and a lack of symptomatic therapies to treat ataxia.
Pharmacotherapy for the management of the symptoms of Machado-Joseph Disease
Published in Expert Opinion on Pharmacotherapy, 2022
Jessica Blanc Leite Oliveira, Alberto R.M. Martinez, Marcondes Cavalcante França Jr
Spinocerebellar ataxias (SCA) represent a heterogeneous group of neurodegenerative disorders that share cerebellar ataxia and autosomal dominant inheritance as the core features [1]. Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) is the most frequent SCA worldwide [2]. It is caused by (CAG) expansions (typically >51 repeats) in exon 10 of ATXN3, which lead to an abnormally long polyglutamine (polyQ) tract in the encoded protein, ataxin-3 [3]. Neurodegeneration in multiple regions within the central and peripheral nervous system then follows [4]. The cerebellum and its connections are major targets, explaining why ataxia is a hallmark of this disease.