Bibliography

  • Peripheral neuropathy in ataxia-telangiectasia: Newly characterized, has potential as a biomarker
    Hits: 13
    Comment
     
    . 2023 Dec;30(12):3643.
     doi: 10.1111/ene.16032. Epub 2023 Aug 17.

    Peripheral neuropathy in ataxia-telangiectasia: Newly characterized, has potential as a biomarker

    William Whitehouse1
     

    In this issue, Dr Marius Theis and colleagues from Goethe University, Frankfurt, characterize the clinical and electrophysiological age-related features of the peripheral polyneuropathy in 42 patients with classical ataxia-telangiectasia (A-T) aged 1–28 years old [1].

    Ataxia-telangiectasia is a rare autosomal recessive progressive and life-shortening multisystem disease due to mutations in the ataxia-telangiectasia mutated gene (ATM). This codes for a key serine/threonine protein kinase involved in DNA repair and a host of other nuclear, cytoplasmic and mitochondrial functions [2]. Clinically the progressive polyneuropathy is overshadowed by ever more florid and disabling cerebellar ataxia, dystonia and movement disorders, affecting fine and gross motor function, eye movements, speech and swallowing, from early childhood. In addition to the neurodegenerative features, patients develop immune deficiency, cancer susceptibility and chronic lung disease reminiscent of cystic fibrosis [3]. Most people with classical A-T and no kinase function die before they reach 30 years of age, although a mild variant A-T, usually with residual kinase function, is increasingly being recognized [4].

    Until now the peripheral neuropathy was not well described, but this careful cross-sectional prospective study included a detailed history of neuropathic symptoms, a clinical examination for neuropathic signs in the extremities, as well as non-invasive nerve conduction studies of both median and tibial motor and sensory amplitudes and velocities.

    As expected, symptoms, signs and neurophysiological abnormalities progressed with age, but what was not expected was that neurophysiological abnormalities could be picked up long before symptoms and signs, even within the first 2 years of life, that is, before some children will have been diagnosed. The progressive motor neuropathy in both upper and lower limbs was mainly denervating early on, becoming mainly mixed axonal and denervating with age. The progressive sensory neuropathy was often axonal early on, becoming mixed axonal and denervating with age.

    This highlights the potential for non-invasive nerve conduction studies to be used as a biomarker in future clinical trials in people with A-T of all ages, although it remains to be seen if improvements in neurophysiological indices can be achieved

  • Peripheral polyneuropathy in children and young adults with ataxia-telangiectasia
    Hits: 19

    Abstract

    Background and purpose: Ataxia-telangiectasia (A-T) is a rare, autosomal recessive, multisystem disorder that leads to progressive neurodegeneration with cerebellar ataxia and peripheral polyneuropathy. Cerebellar neurodegeneration is well described in A-T. However, peripheral nervous system involvement is an underdiagnosed but important additional target for supportive and systemic therapies. The aim of this study was to conduct neurophysiological measurements to assess peripheral neurodegeneration and the development of age-dependent neuropathy in A-T.

    Methods: In this prospective study, 42 classical A-T patients were assessed. The motor and sensory nerve conduction of the median and tibial nerves was evaluated. Data were compared to published standard values and a healthy age- and gender-matched control group of 23 participants. Ataxia scores (Klockgether, Scale for the Assessment and Rating of Ataxia) were also assessed.

    Results: In A-T, neurophysiological assessment revealed neuropathic changes as early as the first year of life. Subjective symptomatology of neuropathy is rarely described. In the upper extremities, motor neuropathy was predominantly that of a demyelinating type and sensory neuropathy was predominantly that of a mixed type. In the lower extremities, motor and sensory neuropathy was predominantly that of a mixed type. We found significant correlations between age and the development of motor and sensory polyneuropathy in A-T compared with healthy controls (p < 0.001).

    Conclusions: In A-T, polyneuropathy occurs mostly subclinically as early as the first year of life. The current study of a large national A-T cohort demonstrates that development of neuropathy in A-T differs in the upper and lower extremities.

    Keywords: ataxia scores; ataxia-telangiectasia; disease progression; neurodegeneration; neurography; polyneuropathy.

  • Transcriptional profiling of peripheral blood mononuclear cells identifies inflammatory phenotypes in Ataxia Telangiectasia
    Hits: 15
    . 2024 Feb 14;19(1):67.
     doi: 10.1186/s13023-024-03073-5.

    Transcriptional profiling of peripheral blood mononuclear cells identifies inflammatory phenotypes in Ataxia Telangiectasia

    Nigel S Michki1, Benjamin D Singer2, Javier V Perez1, Aaron J Thomas1, Valerie Natale3, Kathryn A Helmin2, Jennifer Wright4, Leon Cheng4, Lisa R Young1, Howard M Lederman4, Sharon A McGrath-Morrowmcgrathmos@chop.edu.">5
    Affiliations 
      • PMID: 38360726 

    Abstract

    Introduction: Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy.

    Methods: Participants with classic A-T (n = 77), mild A-T (n = 13), and unaffected controls (n = 15) were recruited from two outpatient clinics. PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features.

    Results: People with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4 + T cells and CD8 + T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls.

    Conclusion: Using a transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy.

    Keywords: Bioinformatics; Genetic diseases; T cells.

  • FDA Lifts Hold on IND for Phase 3 Trial of Ataxia Agent EryDex
    Hits: 206

     

    News

    The phase 3 study is expected to include 86 children with ataxia-telangiectasia who will be assessed on changes in a rescored modified International Cooperative Ataxia Rating Scale.

     
     

    According to a recent announcement, the FDA has lifted its clinical hold on the investigational new drug application (IND) for Quince Therapeutics agent EryDex, a unique autologous drug/device combination agent in development for patients with ataxia-telangiectasia (A-T). The company will now proceed with its phase 3 NEAT trial assessing the safety and efficacy of the therapeutic in A-T, with a potential new drug application submission at the end of 2025, pending positive results.1

    EryDex is an automated outpatient bedside technology to ex-vivo encapsulate dexamethasone sodium phosphate (DSP) into patient’s red blood cells, which are then re-infused, allowing for the circulation of controlled, slow release, low doses of dexamethasone over the subsequent several weeks following treatment. To date, the therapy has gained orphan drug designation for the treatment of A-T both from the FDA and European Medicines Agency. EryDex is part of a larger technology platform, the EryDex System, that is capable of expansion to other drugs or biologics, including enzyme replacement therapy.

    "We are pleased with the FDA’s decision to lift the partial clinical hold related to EryDel’s lead asset, EryDex. We look forward to completing the clinical and regulatory activities necessary to advance EryDex into the Phase 3 NEAT study – with patient enrollment beginning as soon as the second quarter of 2024,” Dirk Thye, MD, chief executive officer, Quince, said in a statement.1 "Notably, this pivotal trial will be conducted under a Special Protocol Assessment (SPA) that has already been reviewed with the FDA, which should allow for the submission of a New Drug Application (NDA) following completion of this single study, assuming positive results."

    NEAT, a phase 3 study, is double-blinded, placebo-controlled in design, and is expected to include 86 patients with A-T aged 6 to 9 years old, with up to an additional 20 patients aged 10 years or older to potentially expand the label. The primary end point, an evaluation of patient’s function, will be based on changes on a rescored modified International Cooperative Ataxia Rating Scale (RmICARS). Secondary end points include measures of Clinical Global Impression scores for severity and change, as well as EuroQol quality of life scoring.

    READ MORE: Omaveloxolone Sustains Benefit Effect in Friedreich Ataxia at 3 Years

    In late July, Quince announced the acquisition of EryDel SpA, a privately-held, late-stage biotech company, and its lead assess EryDex. In the company’s latest update, they noted the acquisition is expected to close in the fourth quarter of 2023, and is subject to certain regulatory approvals, including the foreign direct investment screening clearance in Italy, and other closing conditions.2

    The safety and efficacy of EryDex was documented in the phase 3 ATTeST study (NCT02770807), the largest such study of patients with A-T. Conducted between March 2017 and March 2020, 175 patients were enrolled and 164 were randomized; 132 (80.5%) completed the 24 weeks of the primary efficacy period. All told, the full analysis set (n = 164) showed favorable outcomes on the primary end point of mICARS and RmICARS in the treated groups compared with placebo, but did not reach statistical significance.

    The per-protocol analysis (n = 107) showed slower rate of neurologic deterioration for both the 5-10 mg dose or 14-22 mg dosed groups compared with placebo (low dose: mICARS: P = .004; RmICARS = P = .003; high dose: mICARS: P = .019; RmICARS = P = .036). The a priori age 6-9 year olds’ intent-to-treat analysis (n = 89) showed a statistically significant favorable outcome for high dose vs placebo (mICARS: P = .019; RmICARS: P = 0.28). Treatment-emergent adverse events occurred in 73%, 82%, and 73% of patients in the low dose, high dose, and placebo groups, respectively.3

    REFERENCES
    1. US FDA partial clinical hold lifted on IND for EryDel’s lead phase 3 asset EryDex for the treatment of ataxia-telangiectasia. News release. Quince Therapeutics. September 28, 2023. Accessed October 4, 2023. https://ir.quincetx.com/news-releases/news-release-details/us-fda-partial-clinical-hold-lifted-ind-erydels-lead-phase-3
    2. Quince Therapeutics to acquire EryDel SpA and its phase 3 asset targeting ataxia-telangiectasia with no currently approved treatments and estimated $1+ billion peak sales opportunity. News release. Quince Therapeutics. July 24, 2023. Accessed October 4, 2023. https://www.sec.gov/Archives/edgar/data/1662774/000119312523191839/d542769dex992.htm
    3. Zielen S, Whitehouse W, Magnani M, Perlman SL, Leuzzi V, Lederman HM. The pivotal multi-center, randomized, double-blind, placebo-controlled trial of intra-Erythrocyte Dexamethasone Sodium Phosphate (ATTeST) on the neurological motor function of people with Ataxia Telangiectasia. Presented at: 2022 AAN Annual Meeting. Abstract 52072
  • Correction of ATM mutations in iPS cells from two ataxia-telangiectasia patients restores DNA damage and oxidative stress responses
    Hits: 335
    . 2020 Apr 15;29(6):990-1001.
     doi: 10.1093/hmg/ddaa023.

    Correction of ATM mutations in iPS cells from two ataxia-telangiectasia patients restores DNA damage and oxidative stress responses

    Dmitry A Ovchinnikov12, Sarah L Withey1, Hannah C Leeson1, U Wang Lei1, Ashmitha Sundarrajan1, Keerat Junday1, Michelle Pewarchuk1, Abrey J Yeo3, Amanda W Kijas1, Martin F Lavin3, Ernst J Wolvetang1
    Affiliations 

    Affiliations

    • 1Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia.
    • 2StemCore, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia.
    • 3UQ Centre for Clinical Research (UQCCR), The University of Queensland, Herston, Brisbane, QLD 4006, Australia.
      • PMID: 32037450

     

    Abstract

    Patients with ataxia-telangiectasia (A-T) lack a functional ATM kinase protein and exhibit defective repair of DNA double-stranded breaks and response to oxidative stress. We show that CRISPR/Cas9-assisted gene correction combined with piggyBac (PB) transposon-mediated excision of the selection cassette enables seamless restoration of functional ATM alleles in induced pluripotent stem cells from an A-T patient carrying compound heterozygous exonic missense/frameshift mutations, and from a patient with a homozygous splicing acceptor mutation of an internal coding exon. We show that the correction of one allele restores expression of ~ 50% of full-length ATM protein and ameliorates DNA damage-induced activation (auto-phosphorylation) of ATM and phosphorylation of its downstream targets, KAP-1 and H2AX. Restoration of ATM function also normalizes radiosensitivity, mitochondrial ROS production and oxidative-stress-induced apoptosis levels in A-T iPSC lines, demonstrating that restoration of a single ATM allele is sufficient to rescue key ATM functions. Our data further show that despite the absence of a functional ATM kinase, homology-directed repair and seamless correction of a pathogenic ATM mutation is possible. The isogenic pairs of A-T and gene-corrected iPSCs described here constitute valuable tools for elucidating the role of ATM in ageing and A-T pathogenesis.

  • ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia
    Hits: 46

    Jenny Lai , Didem Demirbas Junho Kim, Ailsa M. Jeffries, Allie Tolles, Junseok Park, Thomas W. Chittenden , Patrick G. Buckley, Timothy W. Yu, Michael A. Lodato, Eunjung Alice Lee

    While ATM loss of function has long been identified as the genetic cause of ataxia-telangiectasia (A-T), how it leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear. ATM expression is enriched in microglia throughout cerebellar development and adulthood. Here, we find evidence of microglial inflammation in the cerebellum of patients with A-T using single-nucleus RNA sequencing. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis-related genes in granule and Purkinje neurons and that microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we performed transcriptomic profiling of A-T induced pluripotent stem cell (iPSC)-derived microglia, which revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, A-T microglia co-culture with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may promote neurodegeneration in A-T.

  • SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs
    Hits: 23

    Peiyee Lee, Nathan T. Martin, Kotoka Nakamura, Soheila Azghadi, Mandana Amiri, Uri Ben-David, Susan Perlman, Richard A. Gatti, Hailiang Hu , William E. Lowry

    Ataxia telangiectasia is a devastating neurodegenerative disease caused primarily by loss of function mutations in ATM, a hierarchical DNA repair gene and tumour suppressor. So far, murine models of ataxia telangiectasia have failed to accurately recapitulate many aspects of the disease, most notably, the progressive cerebellar ataxia. Here we present a model of human ataxia telangiectasia using induced pluripotent stem cells, and show that small molecule read-through compounds, designed to induce read-through of mRNA around premature termination codons, restore ATM activity and improve the response to DNA damage. This platform allows for efficient screening of novel compounds, identification of target and off-target effects, and preclinical testing on relevant cell types for the pathogenic dissection and treatment of ataxia telangiectasia.

  • MicroRNA dysregulation in ataxia telangiectasia
    Hits: 27

    Abstract

    Introduction: Ataxia telangiectasia (AT) is a rare disorder characterized by neurodegeneration, combined immunodeficiency, a predisposition to malignancies, and high clinical variability. Profiling of microRNAs (miRNAs) may offer insights into the underlying mechanisms of complex rare human diseases, as miRNAs play a role in various biological functions including proliferation, differentiation, and DNA repair. In this study, we investigate the differential expression of miRNAs in samples from AT patients to identify miRNA patterns and analyze how these patterns are related to the disease.

    Methods: We enrolled 20 AT patients (mean age 17.7 ± 9.6 years old) and collected clinical and genetic data. We performed short non-coding RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and fibroblasts to compare the miRNA expression profile between AT patients and controls.

    Results: We observed 42 differentially expressed (DE)-miRNAs in blood samples and 26 in fibroblast samples. Among these, three DE-miRNAs, miR-342-3p, miR-30a-5p, and miR-195-5p, were further validated in additional AT samples, confirming their dysregulation.

    Discussion: We identified an AT-related miRNA signature in blood cells and fibroblast samples collected from a group of AT patients. We also predicted several dysregulated pathways, primarily related to cancer, immune system control, or inflammatory processes. The findings suggest that miRNAs may provide insights into the pathophysiology and tumorigenesis of AT and have the potential to serve as useful biomarkers in cancer research.

    Keywords: DNA repair; ataxia telangiectasia; cancer; immunodeficiency; microRNA.

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