Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development

Spyros Papapetropoulos; Angela Pontius; Elizabeth Finger; Virginija Karrenbauer; David S. Lynch; Matthew Brennan; Samantha Zappia; Wolfgang Koehler; Ludger Schoels; Stefanie N. Hayer; Takuya Konno; Takeshi Ikeuchi; Troy Lund; Jennifer Orthmann-Murphy; Florian Eichler; Zbigniew K. Wszolek

doi:10.3389/fneur.2021.788168

Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development

Spyros Papapetropoulos, Angela Pontius, Elizabeth Finger, Virginija Karrenbauer, David S. Lynch, Matthew Brennan, Samantha Zappia, Wolfgang Koehler, Ludger Schoels, Stefanie N. Hayer, Takuya Konno, Takeshi Ikeuchi, Troy Lund, Jennifer Orthmann-Murphy, Florian Eichler, Zbigniew K. Wszolek

Pediatric Blood & Marrow Transplant & Cellular Therapy

Research output: Contribution to journal › Review article › peer-review

18 Scopus citations

Abstract

A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.

Original language	English (US)
Article number	788168
Journal	Frontiers in Neurology
Volume	12
DOIs	https://doi.org/10.3389/fneur.2021.788168
State	Published - Feb 3 2022

Bibliographical note

Funding Information:
The authors wish to thank Lillian Neff and Serena Hung for content suggestions and edits for this manuscript.

Funding Information:
Conflict of Interest: Unrelated to this study, EF received personal compensation for serving on a PSP Scientific Advisory or Data Safety Monitoring board for Biogen, Vigil Neuroscience, Inc., and Denali Therapeutics, as a section editor for NeuroImage Clinical and as a course director for the AAN Annual Meeting. EF has received research support paid to her institution (UWO) from CIHR and the Weston Foundation to conduct an ongoing study of oxytocin in FTD, from Alzheimer Society of Canada and the Physicians and Services Incorporated Foundation, the Ministry of Research and Innovation of Ontario for research and for site participation in clinical trials sponsored by Alector, Biogen, and TauRx. VK was funded by the Stockholm County Council. WK received consulting honoraria from Vigil Neuroscience. LS was funded by the German Research council (DFG grant SCHO754/6-2), German Ministryof Health (BMG grant ZMVI1-2520DAT94E to LeukoExpert), German Ministry of Education and Research (BMBF grant 01GM1905A to Treat HSP and grant 01GM1907A to Treat ION), European Commission (EU grant 947588 to the ERNRND registry and JPND grant 01ED16028 to ESMI). LS was a member of the European Reference Network for Rare Neurological Diseases (Project No 739510). SH was funded by the Hertie Network of Excellence in Clinical Neuroscience (GHST grant P1200021). TK and TI are funded by AMED JP21dk0207045, a public grant from the Japanese government to support research on ALSP. JO-M was funded by the Conrad N. Hilton Foundation, the Institute for Translational Medicine and Therapeutics Transdisciplinary (ITMAT) and serves as a principal investigator on Vigil Neuroscience, Inc. sponsored clinical studies (VGL101-01.001; VGL101-01.002). FE is the principal investigator of Bluebird Bio and Minoryx Therapeutics clinical trials; consultant to Ionis, Alnylam, Sanofi Genzyme, Minoryx, and SwanBio Therapeutics; director of the Third Rock MGH Neuroscience Fellowship; and founder of SwanBio Therapeutics. ZW was partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, gifts from the Sol Goldman Charitable Trust and Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and the Albertson Parkinson’s Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301), Neuraly, Inc. (NLY01-PD-1), and Vigil Neuroscience, Inc. (VGL101-01.001) clinical studies. He serves as an external advisory board member for Vigil Neuroscience, Inc.

Publisher Copyright:
Copyright © 2022 Papapetropoulos, Pontius, Finger, Karrenbauer, Lynch, Brennan, Zappia, Koehler, Schoels, Hayer, Konno, Ikeuchi, Lund, Orthmann-Murphy, Eichler and Wszolek.

Keywords

ALSP
CSF1R
HDLS
adult-onset
axonal spheroids
leukodystrophy
leukoencephalopathy
pigmented glia

PubMed: MeSH publication types

Journal Article
Review

Publisher link

10.3389/fneur.2021.788168

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Papapetropoulos, S., Pontius, A., Finger, E., Karrenbauer, V., Lynch, D. S., Brennan, M., Zappia, S., Koehler, W., Schoels, L., Hayer, S. N., Konno, T., Ikeuchi, T., Lund, T., Orthmann-Murphy, J., Eichler, F., & Wszolek, Z. K. (2022). Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development. Frontiers in Neurology, 12, Article 788168. https://doi.org/10.3389/fneur.2021.788168

Papapetropoulos, S, Pontius, A, Finger, E, Karrenbauer, V, Lynch, DS, Brennan, M, Zappia, S, Koehler, W, Schoels, L, Hayer, SN, Konno, T, Ikeuchi, T, Lund, T, Orthmann-Murphy, J, Eichler, F & Wszolek, ZK 2022, 'Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development', Frontiers in Neurology, vol. 12, 788168. https://doi.org/10.3389/fneur.2021.788168

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title = "Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development",

abstract = "A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.",

keywords = "ALSP, CSF1R, HDLS, adult-onset, axonal spheroids, leukodystrophy, leukoencephalopathy, pigmented glia",

author = "Spyros Papapetropoulos and Angela Pontius and Elizabeth Finger and Virginija Karrenbauer and Lynch, {David S.} and Matthew Brennan and Samantha Zappia and Wolfgang Koehler and Ludger Schoels and Hayer, {Stefanie N.} and Takuya Konno and Takeshi Ikeuchi and Troy Lund and Jennifer Orthmann-Murphy and Florian Eichler and Wszolek, {Zbigniew K.}",

note = "Funding Information: The authors wish to thank Lillian Neff and Serena Hung for content suggestions and edits for this manuscript. Funding Information: Conflict of Interest: Unrelated to this study, EF received personal compensation for serving on a PSP Scientific Advisory or Data Safety Monitoring board for Biogen, Vigil Neuroscience, Inc., and Denali Therapeutics, as a section editor for NeuroImage Clinical and as a course director for the AAN Annual Meeting. EF has received research support paid to her institution (UWO) from CIHR and the Weston Foundation to conduct an ongoing study of oxytocin in FTD, from Alzheimer Society of Canada and the Physicians and Services Incorporated Foundation, the Ministry of Research and Innovation of Ontario for research and for site participation in clinical trials sponsored by Alector, Biogen, and TauRx. VK was funded by the Stockholm County Council. WK received consulting honoraria from Vigil Neuroscience. LS was funded by the German Research council (DFG grant SCHO754/6-2), German Ministryof Health (BMG grant ZMVI1-2520DAT94E to LeukoExpert), German Ministry of Education and Research (BMBF grant 01GM1905A to Treat HSP and grant 01GM1907A to Treat ION), European Commission (EU grant 947588 to the ERNRND registry and JPND grant 01ED16028 to ESMI). LS was a member of the European Reference Network for Rare Neurological Diseases (Project No 739510). SH was funded by the Hertie Network of Excellence in Clinical Neuroscience (GHST grant P1200021). TK and TI are funded by AMED JP21dk0207045, a public grant from the Japanese government to support research on ALSP. JO-M was funded by the Conrad N. Hilton Foundation, the Institute for Translational Medicine and Therapeutics Transdisciplinary (ITMAT) and serves as a principal investigator on Vigil Neuroscience, Inc. sponsored clinical studies (VGL101-01.001; VGL101-01.002). FE is the principal investigator of Bluebird Bio and Minoryx Therapeutics clinical trials; consultant to Ionis, Alnylam, Sanofi Genzyme, Minoryx, and SwanBio Therapeutics; director of the Third Rock MGH Neuroscience Fellowship; and founder of SwanBio Therapeutics. ZW was partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, gifts from the Sol Goldman Charitable Trust and Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and the Albertson Parkinson{\textquoteright}s Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301), Neuraly, Inc. (NLY01-PD-1), and Vigil Neuroscience, Inc. (VGL101-01.001) clinical studies. He serves as an external advisory board member for Vigil Neuroscience, Inc. Publisher Copyright: Copyright {\textcopyright} 2022 Papapetropoulos, Pontius, Finger, Karrenbauer, Lynch, Brennan, Zappia, Koehler, Schoels, Hayer, Konno, Ikeuchi, Lund, Orthmann-Murphy, Eichler and Wszolek.",

year = "2022",

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doi = "10.3389/fneur.2021.788168",

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T2 - Review of Clinical Manifestations as Foundations for Therapeutic Development

AU - Papapetropoulos, Spyros

AU - Pontius, Angela

AU - Finger, Elizabeth

AU - Karrenbauer, Virginija

AU - Lynch, David S.

AU - Brennan, Matthew

AU - Zappia, Samantha

AU - Koehler, Wolfgang

AU - Schoels, Ludger

AU - Hayer, Stefanie N.

AU - Konno, Takuya

AU - Ikeuchi, Takeshi

AU - Lund, Troy

AU - Orthmann-Murphy, Jennifer

AU - Eichler, Florian

AU - Wszolek, Zbigniew K.

N1 - Funding Information: The authors wish to thank Lillian Neff and Serena Hung for content suggestions and edits for this manuscript. Funding Information: Conflict of Interest: Unrelated to this study, EF received personal compensation for serving on a PSP Scientific Advisory or Data Safety Monitoring board for Biogen, Vigil Neuroscience, Inc., and Denali Therapeutics, as a section editor for NeuroImage Clinical and as a course director for the AAN Annual Meeting. EF has received research support paid to her institution (UWO) from CIHR and the Weston Foundation to conduct an ongoing study of oxytocin in FTD, from Alzheimer Society of Canada and the Physicians and Services Incorporated Foundation, the Ministry of Research and Innovation of Ontario for research and for site participation in clinical trials sponsored by Alector, Biogen, and TauRx. VK was funded by the Stockholm County Council. WK received consulting honoraria from Vigil Neuroscience. LS was funded by the German Research council (DFG grant SCHO754/6-2), German Ministryof Health (BMG grant ZMVI1-2520DAT94E to LeukoExpert), German Ministry of Education and Research (BMBF grant 01GM1905A to Treat HSP and grant 01GM1907A to Treat ION), European Commission (EU grant 947588 to the ERNRND registry and JPND grant 01ED16028 to ESMI). LS was a member of the European Reference Network for Rare Neurological Diseases (Project No 739510). SH was funded by the Hertie Network of Excellence in Clinical Neuroscience (GHST grant P1200021). TK and TI are funded by AMED JP21dk0207045, a public grant from the Japanese government to support research on ALSP. JO-M was funded by the Conrad N. Hilton Foundation, the Institute for Translational Medicine and Therapeutics Transdisciplinary (ITMAT) and serves as a principal investigator on Vigil Neuroscience, Inc. sponsored clinical studies (VGL101-01.001; VGL101-01.002). FE is the principal investigator of Bluebird Bio and Minoryx Therapeutics clinical trials; consultant to Ionis, Alnylam, Sanofi Genzyme, Minoryx, and SwanBio Therapeutics; director of the Third Rock MGH Neuroscience Fellowship; and founder of SwanBio Therapeutics. ZW was partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, gifts from the Sol Goldman Charitable Trust and Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and the Albertson Parkinson’s Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301), Neuraly, Inc. (NLY01-PD-1), and Vigil Neuroscience, Inc. (VGL101-01.001) clinical studies. He serves as an external advisory board member for Vigil Neuroscience, Inc. Publisher Copyright: Copyright © 2022 Papapetropoulos, Pontius, Finger, Karrenbauer, Lynch, Brennan, Zappia, Koehler, Schoels, Hayer, Konno, Ikeuchi, Lund, Orthmann-Murphy, Eichler and Wszolek.

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AB - A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.

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KW - CSF1R

KW - HDLS

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KW - leukodystrophy

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Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

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