Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit

Rita Sattler¹, Bryan J Traynor², Janice Robertson³, Ludo Van Den Bosch^{4

5}, Sami J Barmada⁶, Clive N Svendsen⁷, Matthew D Disney⁸, Tania F Gendron⁹, Philip C Wong¹⁰, Martin R Turner¹¹, Adam Boxer¹², Suma Babu¹³, Michael Benatar¹⁴, Michael Kurnellas¹⁵, Jonathan D Rohrer¹⁶, Christopher J Donnelly^{17

18}, Lynette M Bustos¹⁹, Kendall Van Keuren-Jensen²⁰, Penny A Dacks²¹, Marwan N Sabbagh²²; Attendees of the inaugural C9ORF72 FTD/ALS Summit

Collaborators, Affiliations

Collaborators

Affiliations

¹ Barrow Neurological Institute, 2910 N Third Ave, Phoenix, AZ, 85013, USA. rita.sattler@barrowneuro.org.
² Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
⁴ VIB, Center for Brain & Disease Research, Laboratory of Neurobiology and KU Leuven, Leuven, Belgium.
⁵ Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), University of Leuven, Leuven, Belgium.
⁶ Department of Neurology, Neuroscience Program, University of Michigan, Ann Arbor, MI, USA.
⁷ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁸ Department of Chemistry, The Herbert Wertheim UF-Scripps Institute for Biomedical Research and Innovation, The Scripps Research Institute, Jupiter, FL, USA.
⁹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
¹⁰ Departments of Pathology and Neuroscience, Johns Hopkins Medicine, Baltimore, MD, USA.
¹¹ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹² Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of San Francisco, San Francisco, CA, USA.
¹³ Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital-Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33129, USA.
¹⁵ Alector Inc., South San Francisco, CA, USA.
¹⁶ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹⁷ LiveLikeLou Center for ALS Research, Brain Institute, University of Pittsburgh, Pittsburgh, USA.
¹⁸ Department of Neurobiology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁹ Barrow Neurological Institute, 2910 N Third Ave, Phoenix, AZ, 85013, USA.
²⁰ Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
²¹ The Association for Frontotemporal Degeneration and FTD Disorders Registry, King of Prussia, PA, USA.
²² Barrow Neurological Institute, 2910 N Third Ave, Phoenix, AZ, 85013, USA. Marwan.Sabbagh@barrowneuro.org.

PMID: 37847372
PMCID: PMC10630271
DOI: 10.1007/s40120-023-00548-8

Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit

Rita Sattler et al. Neurol Ther. 2023 Dec.

. 2023 Dec;12(6):1821-1843.

doi: 10.1007/s40120-023-00548-8. Epub 2023 Oct 17.

Authors

Collaborators

Affiliations

¹ Barrow Neurological Institute, 2910 N Third Ave, Phoenix, AZ, 85013, USA. rita.sattler@barrowneuro.org.
² Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
⁴ VIB, Center for Brain & Disease Research, Laboratory of Neurobiology and KU Leuven, Leuven, Belgium.
⁵ Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), University of Leuven, Leuven, Belgium.
⁶ Department of Neurology, Neuroscience Program, University of Michigan, Ann Arbor, MI, USA.
⁷ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁸ Department of Chemistry, The Herbert Wertheim UF-Scripps Institute for Biomedical Research and Innovation, The Scripps Research Institute, Jupiter, FL, USA.
⁹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
¹⁰ Departments of Pathology and Neuroscience, Johns Hopkins Medicine, Baltimore, MD, USA.
¹¹ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹² Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of San Francisco, San Francisco, CA, USA.
¹³ Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital-Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33129, USA.
¹⁵ Alector Inc., South San Francisco, CA, USA.
¹⁶ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹⁷ LiveLikeLou Center for ALS Research, Brain Institute, University of Pittsburgh, Pittsburgh, USA.
¹⁸ Department of Neurobiology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁹ Barrow Neurological Institute, 2910 N Third Ave, Phoenix, AZ, 85013, USA.
²⁰ Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
²¹ The Association for Frontotemporal Degeneration and FTD Disorders Registry, King of Prussia, PA, USA.
²² Barrow Neurological Institute, 2910 N Third Ave, Phoenix, AZ, 85013, USA. Marwan.Sabbagh@barrowneuro.org.

PMID: 37847372
PMCID: PMC10630271
DOI: 10.1007/s40120-023-00548-8

Abstract

A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers. The C9ORF72-associated hexanucleotide repeat expansion is an important locus for both ALS and FTD. C9ORF72-FTD/ALS may be characterized by loss of function of the C9ORF72 protein and toxic gain of functions caused by both dipeptide repeat (DPR) proteins and hexanucleotide repeat RNA. C9ORF72-FTD/ALS therapeutic strategies discussed at the summit included the use of antisense oligonucleotides, adeno-associated virus (AAV)-mediated gene silencing and gene delivery, and engineered small molecules targeting RNA structures associated with the C9ORF72 expansion. Neurofilament light chain, DPR proteins, and transactive response (TAR) DNA-binding protein 43 (TDP-43)-associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance imaging [MRI] and positron emission tomography [PET]) measuring structural, functional, and metabolic changes were discussed as important tools to monitor individuals affected with C9ORF72-FTD/ALS, at both pre-symptomatic and symptomatic disease stages. Finally, summit attendees evaluated current clinical trial designs available for FTD or ALS patients and concluded that therapeutics relevant to FTD/ALS patients, such as those specifically targeting C9ORF72, may need to be tested with composite endpoints covering clinical symptoms of both FTD and ALS. The latter will require novel clinical trial designs to be inclusive of all patient subgroups spanning the FTD/ALS spectrum.

Keywords: Biomarker; C9ORF72; Dipeptide repeat protein; Gene therapy; Neurofilament; Prevention; RNA toxicity; TDP-43.

Plain language summary

The C9ORF72 Summit was held in March 2023 in Scottsdale, Arizona (USA). Some people who have the disease frontotemporal dementia or the disease amyotrophic lateral sclerosis have a change in one of their genes; the name of the gene is C9ORF72. People who carry this genetic difference usually inherited it from a parent. Researchers are improving their understanding of how the change in the C9ORF72 gene affects people, and efforts are being made to use this knowledge to develop treatments for amyotrophic lateral sclerosis and frontotemporal dementia. In addition to studying the cellular and molecular mechanisms of how the C9ORF72 mutation leads to cellular dysfunction and frontotemporal dementia and amyotrophic lateral sclerosis clinical symptoms, a large effort of the research community is aimed at developing measurements, called biomarkers, that could enhance therapy development efforts in multiple ways. Examples include monitoring of disease activity, identifying those at risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, predicting which people might benefit from a particular treatment, and showing that a drug has had a biological effect. Markers that identify healthy people who are at risk of developing amyotrophic lateral sclerosis or frontotemporal dementia could be used to test treatments that would start before a person shows any symptoms and hopefully would delay or even prevent their onset.

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Conflict of interest statement

Janice Robertson, Sami J. Barmada, Clive Svendsen, Tania F. Gendron, Philip C. Wong, Martin R. Turner, Adam Boxer, Michael Kurnellas, Lynette M Bustos, Kendall Van Keuren-Jensen have nothing to disclose. Rita Sattler is a member of the Scientific Advisory Board of Spinogenix Inc, the LiveLikeLou Foundation, the Robert Packard Center and Northeast ALS consortium. Bryan J. Traynor holds patents on the diagnostic and therapeutic implications of the C9orf72 repeat expansion. Ludo Van Den Bosch is head of the Scientific Advisory Board of Augustine Therapeutics (Leuven, Belgium) and is part of the Investment Advisory Board of Droia Ventures (Meise, Belgium). Jonathan D Rohrer has provided consultancy or been on an advisory board for Novartis, Wave Life Sciences, Prevail, Alector, Aviado Bio, Arkuda Therapeutics, and Denali Therapeutics. Matthew D. Disney is a founder of Expansion Therapeutics. Christopher J Donnelly is cofounder and advisor for Confluence Therapeutics. Michael Benatar reports grants from the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association; and receives consulting fees for Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and UniQure. The University of Miami has licensed intellectual property to Biogen Inc. to support the design of the ATLAS study. He has a provisional patent ‘Determining Onset of ALS’ (US Patent No. 17/941,117). He serves as a member of the Board of Trustees for the ALS Association. Suma Babu has received research funding from Biogen Inc. (including the BIIB078 ASO trial for C9ORF72 ALS), AI therapeutics, Novartis, Orion, Voyager Therapeutics, Medicinova, Ionis, American Academy of Neurology, AANEM Foundation, and Muscular Dystrophy Association. Penny A. Dacks is an employee of the Association for Frontotemporal Degeneration (AFTD), King of Prussia, PA, USA. Marwan N. Sabbagh is a consultant for Roche-Genentech, Eisai, Lilly, Synaptogenix, NeuroTherapia, T3D, Signant Health, Novo Nordisk, Corium, Prothena, KeiferRx; is on the board of directors at CervoMed; and receives stock options/owns stocks from Athira, Lighthouse Pharmaceuticals, Alzheon. Michael Kurnellas, new affiliation: Neuron23, Inc., South San Francisco, CA, USA. Lynette M Bustos, new affiliation: Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA.

Figures

**Fig. 1**
Proposed C9ORF72 disease mechanisms. The *C9ORF72* (GGGGCC) hexanucleotide repeat expansion is thought to contribute to disease pathogenesis in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) via three non-mutually exclusive mechanisms: (1) a loss of function due to impaired transcription leading to a reduction in C9ORF72 protein levels; (2) a toxic gain of function due to the formation of secondary RNA structures which sequester RNA binding proteins and consequently a loss of function of these proteins; (3) a toxic gain of function due to repeat-associated non-ATG (RAN) translation from both the sense and antisense strand, which generates potentially toxic dipeptide repeats (DPRs; poly-GP, poly-GA, poly-GR, poly-PA, poly-PR)

See this image and copyright information in PMC

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Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit

Collaborators

Affiliations

Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit

Authors

Collaborators

Affiliations

Abstract

Plain language summary

Conflict of interest statement

Figures

References

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