Peroxisomal Disorders: Development of Targeted Therapies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Intracellular and Plasma Membranes".

Deadline for manuscript submissions: closed (15 April 2022) | Viewed by 30281

Special Issue Editors


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Guest Editor
Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Interests: peroxisomal disorders; gene therapy; gene editing; small-molecule screening; stem cell biology
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Guest Editor
University of Nebraska Medical Center, Omaha, NE, USA
Interests: Sjogren–Larsson Syndrome and other inherited metabolic diseases, including peroxisomal disorders

Special Issue Information

Dear Colleagues,

The purpose of this Special Issue is to provide an innovative forum to discuss emerging therapies of possible relevance to the treatment of inherited peroxisomal disorders. Peroxisomes are metabolic organelles that act as a central hub of cell signaling pathways and play essential roles in the functions and development of virtually all mammalian organ systems. Due to the advent of clinical genomics, there is an expanding group of genetic disorders caused by impaired peroxisome assembly and/or downstream functions. These include peroxisome biogenesis disorders (PBDs) such as Zellweger spectrum disorder (ZSD) and rhizomelic chondrodysplasia punctata (RCDP), which can affect numerous peroxisome functions, as well as peroxisomal single-protein deficiencies such as adrenoleukodystrophy (ALD) which can have a more targeted effect on specific peroxisomal metabolic activities. While there is a strong developmental component to disease in individuals with severe ZSD, most patients have milder forms of disease compatible with survival through adulthood. These individuals have a degenerative condition where it may be possible to slow and/or halt disease progression in order to maintain or improve quality of life. Newborn screening for ALD can also detect ZSD, and offers hopes for early interventions and the development of novel targeted therapies to address their clinical manifestations.

Here, our overall goal is to accelerate the process of developing roadmaps for therapeutic development for various peroxisomal disorders by engaging in a critical evaluation of emerging therapeutic modalities including gene-, small-molecule-, and cell-based therapies. We will place a special focus on discussions of research infrastructure required for the development and eventual testing of these therapies in the clinic. This includes defining and establishing cell-based and animal models of disease, clinical biomarkers, therapeutic windows, and clinical endpoints. We will also highlight fundamental gaps in the scientific knowledge base that need to be bridged in order to develop more effective rational therapeutic interventions for peroxisomal disorders.

Dr. Joseph G. Hacia
Prof. William B. Rizzo
Guest Editors

Manuscript Submission Information

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Keywords

  • peroxisomes
  • gene therapy
  • small-molecule therapies
  • stem cell transplantation
  • animal models
  • clinical biomarkers
  • clinical trials

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Published Papers (7 papers)

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Research

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21 pages, 4751 KiB  
Article
Peroxisome Metabolism Contributes to PIEZO2-Mediated Mechanical Allodynia
by Yi Gong, Fiza Laheji, Anna Berenson, April Qian, Sang-O Park, Rene Kok, Martin Selig, Ryan Hahn, Reza Sadjadi, Stephan Kemp and Florian Eichler
Cells 2022, 11(11), 1842; https://doi.org/10.3390/cells11111842 - 4 Jun 2022
Cited by 3 | Viewed by 2995
Abstract
Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodystrophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal [...] Read more.
Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodystrophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal root ganglia (DRG), with satellite glial cells (SGCs) displaying higher expression than neurons. We subsequently examined sensory behavior and DRG pathophysiology in mice deficient in ABCD1 compared to wild-type mice. Beginning at 8 months of age, Abcd1−/y mice developed persistent mechanical allodynia. DRG had a greater number of IB4-positive nociceptive neurons expressing PIEZO2, the mechanosensitive ion channel. Blocking PIEZO2 partially rescued the mechanical allodynia. Beyond affecting neurons, ABCD1 deficiency impacted SGCs, as demonstrated by high levels of VLCFA, increased glial fibrillary acidic protein (GFAP), as well as genes disrupting neuron-SGC connectivity. These findings suggest that lack of the peroxisomal half-transporter ABCD1 leads to PIEZO2-mediated mechanical allodynia as well as SGC dysfunction. Given the known supportive role of SGCs to neurons, this elucidates a novel mechanism underlying pain in X-linked adrenoleukodystrophy. Full article
(This article belongs to the Special Issue Peroxisomal Disorders: Development of Targeted Therapies)
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10 pages, 965 KiB  
Article
Evaluation of Neurofilament Light Chain as a Biomarker of Neurodegeneration in X-Linked Childhood Cerebral Adrenoleukodystrophy
by Hongge Wang, Matthew D. Davison, Martin L. Kramer, Weiliang Qiu, Tatiana Gladysheva, Ruby M. S. Chiang, Can Kayatekin, David R. Nascene, Leyla A. Taghizadeh, Carina J. King, Erin E. Nolan, Ashish O. Gupta, Paul J. Orchard and Troy C. Lund
Cells 2022, 11(5), 913; https://doi.org/10.3390/cells11050913 - 7 Mar 2022
Cited by 7 | Viewed by 3757
Abstract
Cerebral adrenoleukodystrophy (CALD) is a devastating, demyelinating neuroinflammatory manifestation found in up to 40% of young males with an inherited mutation in ABCD1, the causative gene in adrenoleukodystrophy. The search for biomarkers which correlate to CALD disease burden and respond to intervention [...] Read more.
Cerebral adrenoleukodystrophy (CALD) is a devastating, demyelinating neuroinflammatory manifestation found in up to 40% of young males with an inherited mutation in ABCD1, the causative gene in adrenoleukodystrophy. The search for biomarkers which correlate to CALD disease burden and respond to intervention has long been sought after. We used the Olink Proximity Extension Assay (Uppsala, Sweden) to explore the cerebral spinal fluid (CSF) of young males with CALD followed by correlative analysis with plasma. Using the Target 96 Neuro Exploratory panel, we found that, of the five proteins significantly increased in CSF, only neurofilament light chain (NfL) showed a significant correlation between CSF and plasma levels. Young males with CALD had a 11.3-fold increase in plasma NfL compared with controls. Importantly, 9 of 11 young males with CALD who underwent HCT showed a mean decrease in plasma NfL of 50% at 1 year after HCT compared with pre-HCT levels. In conclusion, plasma NfL could be a great value in determining outcomes in CALD and should be scrutinized in future studies in patients prior to CALD development and after therapeutic intervention. Full article
(This article belongs to the Special Issue Peroxisomal Disorders: Development of Targeted Therapies)
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13 pages, 2587 KiB  
Article
Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy
by Eric J. Mallack, Kerry Gao, Marc Engelen and Stephan Kemp
Cells 2022, 11(2), 283; https://doi.org/10.3390/cells11020283 - 14 Jan 2022
Cited by 23 | Viewed by 4347
Abstract
The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management [...] Read more.
The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype–phenotype correlation in ALD. Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in ABCD1. The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1–2 (transmembrane domain spanning region) and 6–9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonrandom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource. Full article
(This article belongs to the Special Issue Peroxisomal Disorders: Development of Targeted Therapies)
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Review

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29 pages, 4271 KiB  
Review
Insights into the Structure and Function of the Pex1/Pex6 AAA-ATPase in Peroxisome Homeostasis
by Ryan M. Judy, Connor J. Sheedy and Brooke M. Gardner
Cells 2022, 11(13), 2067; https://doi.org/10.3390/cells11132067 - 29 Jun 2022
Cited by 6 | Viewed by 5470
Abstract
The AAA-ATPases Pex1 and Pex6 are required for the formation and maintenance of peroxisomes, membrane-bound organelles that harbor enzymes for specialized metabolism. Together, Pex1 and Pex6 form a heterohexameric AAA-ATPase capable of unfolding substrate proteins via processive threading through a central pore. Here, [...] Read more.
The AAA-ATPases Pex1 and Pex6 are required for the formation and maintenance of peroxisomes, membrane-bound organelles that harbor enzymes for specialized metabolism. Together, Pex1 and Pex6 form a heterohexameric AAA-ATPase capable of unfolding substrate proteins via processive threading through a central pore. Here, we review the proposed roles for Pex1/Pex6 in peroxisome biogenesis and degradation, discussing how the unfolding of potential substrates contributes to peroxisome homeostasis. We also consider how advances in cryo-EM, computational structure prediction, and mechanisms of related ATPases are improving our understanding of how Pex1/Pex6 converts ATP hydrolysis into mechanical force. Since mutations in PEX1 and PEX6 cause the majority of known cases of peroxisome biogenesis disorders such as Zellweger syndrome, insights into Pex1/Pex6 structure and function are important for understanding peroxisomes in human health and disease. Full article
(This article belongs to the Special Issue Peroxisomal Disorders: Development of Targeted Therapies)
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32 pages, 1864 KiB  
Review
Fission Impossible (?)—New Insights into Disorders of Peroxisome Dynamics
by Ruth E. Carmichael, Markus Islinger and Michael Schrader
Cells 2022, 11(12), 1922; https://doi.org/10.3390/cells11121922 - 14 Jun 2022
Cited by 6 | Viewed by 3788
Abstract
Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to cellular needs. Peroxisome multiplication in mammalian cells involves the concerted action of the membrane-shaping protein PEX11β and division proteins, such as the membrane [...] Read more.
Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to cellular needs. Peroxisome multiplication in mammalian cells involves the concerted action of the membrane-shaping protein PEX11β and division proteins, such as the membrane adaptors FIS1 and MFF, which recruit the fission GTPase DRP1 to the peroxisomal membrane. The latter proteins are also involved in mitochondrial division. Patients with loss of DRP1, MFF or PEX11β function have been identified, showing abnormalities in peroxisomal (and, for the shared proteins, mitochondrial) dynamics as well as developmental and neurological defects, whereas the metabolic functions of the organelles are often unaffected. Here, we provide a timely update on peroxisomal membrane dynamics with a particular focus on peroxisome formation by membrane growth and division. We address the function of PEX11β in these processes, as well as the role of peroxisome–ER contacts in lipid transfer for peroxisomal membrane expansion. Furthermore, we summarize the clinical phenotypes and pathophysiology of patients with defects in the key division proteins DRP1, MFF, and PEX11β as well as in the peroxisome–ER tether ACBD5. Potential therapeutic strategies for these rare disorders with limited treatment options are discussed. Full article
(This article belongs to the Special Issue Peroxisomal Disorders: Development of Targeted Therapies)
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26 pages, 2182 KiB  
Review
Characterization of Severity in Zellweger Spectrum Disorder by Clinical Findings: A Scoping Review, Meta-Analysis and Medical Chart Review
by Mousumi Bose, Christine Yergeau, Yasmin D’Souza, David D. Cuthbertson, Melisa J. Lopez, Alyssa K. Smolen and Nancy E. Braverman
Cells 2022, 11(12), 1891; https://doi.org/10.3390/cells11121891 - 10 Jun 2022
Cited by 12 | Viewed by 4524
Abstract
Zellweger spectrum disorder (ZSD) is a rare, debilitating genetic disorder of peroxisome biogenesis that affects multiple organ systems and presents with broad clinical heterogeneity. Although severe, intermediate, and mild forms of ZSD have been described, these designations are often arbitrary, presenting difficulty in [...] Read more.
Zellweger spectrum disorder (ZSD) is a rare, debilitating genetic disorder of peroxisome biogenesis that affects multiple organ systems and presents with broad clinical heterogeneity. Although severe, intermediate, and mild forms of ZSD have been described, these designations are often arbitrary, presenting difficulty in understanding individual prognosis and treatment effectiveness. The purpose of this study is to conduct a scoping review and meta-analysis of existing literature and a medical chart review to determine if characterization of clinical findings can predict severity in ZSD. Our PubMed search for articles describing severity, clinical findings, and survival in ZSD resulted in 107 studies (representing 307 patients) that were included in the review and meta-analysis. We also collected and analyzed these same parameters from medical records of 136 ZSD individuals from our natural history study. Common clinical findings that were significantly different across severity categories included seizures, hypotonia, reduced mobility, feeding difficulties, renal cysts, adrenal insufficiency, hearing and vision loss, and a shortened lifespan. Our primary data analysis also revealed significant differences across severity categories in failure to thrive, gastroesophageal reflux, bone fractures, global developmental delay, verbal communication difficulties, and cardiac abnormalities. Univariable multinomial logistic modeling analysis of clinical findings and very long chain fatty acid (VLCFA) hexacosanoic acid (C26:0) levels showed that the number of clinical findings present among seizures, abnormal EEG, renal cysts, and cardiac abnormalities, as well as plasma C26:0 fatty acid levels could differentiate severity categories. We report the largest characterization of clinical findings in relation to overall disease severity in ZSD. This information will be useful in determining appropriate outcomes for specific subjects in clinical trials for ZSD. Full article
(This article belongs to the Special Issue Peroxisomal Disorders: Development of Targeted Therapies)
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18 pages, 973 KiB  
Review
Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need
by Madison I. J. Honey, Yorrick R. J. Jaspers, Marc Engelen, Stephan Kemp and Irene C. Huffnagel
Cells 2021, 10(12), 3427; https://doi.org/10.3390/cells10123427 - 6 Dec 2021
Cited by 14 | Viewed by 4240
Abstract
X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the ABCD1 gene and the accumulation of very long-chain fatty acids in plasma and tissues. Patients present with heterogeneous clinical manifestations which can include adrenal insufficiency, myelopathy, and/or cerebral demyelination. [...] Read more.
X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the ABCD1 gene and the accumulation of very long-chain fatty acids in plasma and tissues. Patients present with heterogeneous clinical manifestations which can include adrenal insufficiency, myelopathy, and/or cerebral demyelination. In the absence of a genotype-phenotype correlation, the clinical outcome of an individual cannot be predicted and currently there are no molecular markers available to quantify disease severity. Therefore, there is an unmet clinical need for sensitive biomarkers to monitor and/or predict disease progression and evaluate therapy efficacy. The increasing amount of biological sample repositories (‘biobanking’) as well as the introduction of newborn screening creates a unique opportunity for identification and evaluation of new or existing biomarkers. Here we summarize and review the many studies that have been performed to identify and improve knowledge surrounding candidate molecular biomarkers for ALD. We also highlight several shortcomings of ALD biomarker studies, which often include a limited sample size, no collection of longitudinal data, and no validation of findings in an external cohort. Nonetheless, these studies have generated a list of interesting biomarker candidates and this review aspires to direct future biomarker research. Full article
(This article belongs to the Special Issue Peroxisomal Disorders: Development of Targeted Therapies)
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