An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich's ataxia

Kevin C Kemp; Anastasia Georgievskaya; Kelly M Hares; Juliana Redondo; Steven Bailey; Claire M Rice; Neil J Scolding; Chris Metcalfe; Alastair Wilkins

doi:10.1038/s41467-022-31450-w

An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich's ataxia

Kevin C Kemp^*, Anastasia Georgievskaya, Kelly M Hares, Juliana Redondo, Steven Bailey, Claire M Rice, Neil J Scolding, Chris Metcalfe, Alastair Wilkins^*

^*Corresponding author for this work

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Abstract

Friedreich’s ataxia (FA) is an inherited progressive neurodegenerative disease for which there is no proven disease-modifying treatment. Here we perform an open-label, pilot study of recombinant human granulocyte-colony stimulating factor (G-CSF) administration in seven people with FA (EudraCT: 2017-003084-34); each participant receiving a single course of G-CSF (Lenograstim; 1.28 million units per kg per day for 5 days). The primary outcome is peripheral blood mononuclear cell frataxin levels over a 19-day period. The secondary outcomes include safety, haematopoietic stem cells (HSC) mobilisation, antioxidant levels and mitochondrial enzyme activity. The trial meets pre-specified endpoints. We show that administration of G- CSF to people with FA is safe. Mobilisation of HSCs in response to G-CSF is comparable to that of healthy individuals. Notably, sustained increases in cellular frataxin concentrations and raised PGC-1α and Nrf2 expression are detected. Our findings show potential for G-CSF therapy to have a clinical impact in people with FA.

Original language	English
Article number	4655 (2022)
Number of pages	8
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31450-w
Publication status	Published - 9 Aug 2022

Bibliographical note

Funding Information:
We thank Ataxia UK for their assistance with recruiting participants and the North Bristol NHS Trust Research and Innovation for hosting the trial. The authors thank the participants, their families and carers for their generous time and commitment to this study. We thank Nigel Noel and Paul Virgo, at The Department of Immunology and Immunogenetics, North Bristol NHS Trust (Southmead Hospital, Bristol, UK), for their assistance with flow cytometry data acquisition. The study was funded by Ataxia UK; the Friedreich’s Ataxia Research Alliance (FARA); The Burden Institute; the Elizabeth Blackwell Institute; the Wellcome Trust [204813/Z/16/Z - ISSF3].

Funding Information:
We thank Ataxia UK for their assistance with recruiting participants and the North Bristol NHS Trust Research and Innovation for hosting the trial. The authors thank the participants, their families and carers for their generous time and commitment to this study. We thank Nigel Noel and Paul Virgo, at The Department of Immunology and Immunogenetics, North Bristol NHS Trust (Southmead Hospital, Bristol, UK), for their assistance with flow cytometry data acquisition. The study was funded by Ataxia UK; the Friedreich’s Ataxia Research Alliance (FARA); The Burden Institute; the Elizabeth Blackwell Institute; the Wellcome Trust [204813/Z/16/Z - ISSF3].

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© 2022, The Author(s).

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Dr Claire M Rice
- C.M.Ricebristol.acuk
- Bristol Medical School (THS) - Associate Professor in Neuroinflammation
- Multiple Sclerosis and Stem Cell Group
- Bristol Neuroscience
Person: Academic , Member, Group lead

Cite this

@article{382529d8aa1f4d3683248eda883e9625,

title = "An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich's ataxia",

abstract = "Friedreich{\textquoteright}s ataxia (FA) is an inherited progressive neurodegenerative disease for which there is no proven disease-modifying treatment. Here we perform an open-label, pilot study of recombinant human granulocyte-colony stimulating factor (G-CSF) administration in seven people with FA (EudraCT: 2017-003084-34); each participant receiving a single course of G-CSF (Lenograstim; 1.28 million units per kg per day for 5 days). The primary outcome is peripheral blood mononuclear cell frataxin levels over a 19-day period. The secondary outcomes include safety, haematopoietic stem cells (HSC) mobilisation, antioxidant levels and mitochondrial enzyme activity. The trial meets pre-specified endpoints. We show that administration of G- CSF to people with FA is safe. Mobilisation of HSCs in response to G-CSF is comparable to that of healthy individuals. Notably, sustained increases in cellular frataxin concentrations and raised PGC-1α and Nrf2 expression are detected. Our findings show potential for G-CSF therapy to have a clinical impact in people with FA. ",

author = "Kemp, {Kevin C} and Anastasia Georgievskaya and Hares, {Kelly M} and Juliana Redondo and Steven Bailey and Rice, {Claire M} and Scolding, {Neil J} and Chris Metcalfe and Alastair Wilkins",

note = "Funding Information: We thank Ataxia UK for their assistance with recruiting participants and the North Bristol NHS Trust Research and Innovation for hosting the trial. The authors thank the participants, their families and carers for their generous time and commitment to this study. We thank Nigel Noel and Paul Virgo, at The Department of Immunology and Immunogenetics, North Bristol NHS Trust (Southmead Hospital, Bristol, UK), for their assistance with flow cytometry data acquisition. The study was funded by Ataxia UK; the Friedreich{\textquoteright}s Ataxia Research Alliance (FARA); The Burden Institute; the Elizabeth Blackwell Institute; the Wellcome Trust [204813/Z/16/Z - ISSF3]. Funding Information: We thank Ataxia UK for their assistance with recruiting participants and the North Bristol NHS Trust Research and Innovation for hosting the trial. The authors thank the participants, their families and carers for their generous time and commitment to this study. We thank Nigel Noel and Paul Virgo, at The Department of Immunology and Immunogenetics, North Bristol NHS Trust (Southmead Hospital, Bristol, UK), for their assistance with flow cytometry data acquisition. The study was funded by Ataxia UK; the Friedreich{\textquoteright}s Ataxia Research Alliance (FARA); The Burden Institute; the Elizabeth Blackwell Institute; the Wellcome Trust [204813/Z/16/Z - ISSF3]. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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AU - Kemp, Kevin C

AU - Georgievskaya, Anastasia

AU - Hares, Kelly M

AU - Redondo, Juliana

AU - Bailey, Steven

AU - Rice, Claire M

AU - Scolding, Neil J

AU - Metcalfe, Chris

AU - Wilkins, Alastair

N1 - Funding Information: We thank Ataxia UK for their assistance with recruiting participants and the North Bristol NHS Trust Research and Innovation for hosting the trial. The authors thank the participants, their families and carers for their generous time and commitment to this study. We thank Nigel Noel and Paul Virgo, at The Department of Immunology and Immunogenetics, North Bristol NHS Trust (Southmead Hospital, Bristol, UK), for their assistance with flow cytometry data acquisition. The study was funded by Ataxia UK; the Friedreich’s Ataxia Research Alliance (FARA); The Burden Institute; the Elizabeth Blackwell Institute; the Wellcome Trust [204813/Z/16/Z - ISSF3]. Funding Information: We thank Ataxia UK for their assistance with recruiting participants and the North Bristol NHS Trust Research and Innovation for hosting the trial. The authors thank the participants, their families and carers for their generous time and commitment to this study. We thank Nigel Noel and Paul Virgo, at The Department of Immunology and Immunogenetics, North Bristol NHS Trust (Southmead Hospital, Bristol, UK), for their assistance with flow cytometry data acquisition. The study was funded by Ataxia UK; the Friedreich’s Ataxia Research Alliance (FARA); The Burden Institute; the Elizabeth Blackwell Institute; the Wellcome Trust [204813/Z/16/Z - ISSF3]. Publisher Copyright: © 2022, The Author(s).

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N2 - Friedreich’s ataxia (FA) is an inherited progressive neurodegenerative disease for which there is no proven disease-modifying treatment. Here we perform an open-label, pilot study of recombinant human granulocyte-colony stimulating factor (G-CSF) administration in seven people with FA (EudraCT: 2017-003084-34); each participant receiving a single course of G-CSF (Lenograstim; 1.28 million units per kg per day for 5 days). The primary outcome is peripheral blood mononuclear cell frataxin levels over a 19-day period. The secondary outcomes include safety, haematopoietic stem cells (HSC) mobilisation, antioxidant levels and mitochondrial enzyme activity. The trial meets pre-specified endpoints. We show that administration of G- CSF to people with FA is safe. Mobilisation of HSCs in response to G-CSF is comparable to that of healthy individuals. Notably, sustained increases in cellular frataxin concentrations and raised PGC-1α and Nrf2 expression are detected. Our findings show potential for G-CSF therapy to have a clinical impact in people with FA.

AB - Friedreich’s ataxia (FA) is an inherited progressive neurodegenerative disease for which there is no proven disease-modifying treatment. Here we perform an open-label, pilot study of recombinant human granulocyte-colony stimulating factor (G-CSF) administration in seven people with FA (EudraCT: 2017-003084-34); each participant receiving a single course of G-CSF (Lenograstim; 1.28 million units per kg per day for 5 days). The primary outcome is peripheral blood mononuclear cell frataxin levels over a 19-day period. The secondary outcomes include safety, haematopoietic stem cells (HSC) mobilisation, antioxidant levels and mitochondrial enzyme activity. The trial meets pre-specified endpoints. We show that administration of G- CSF to people with FA is safe. Mobilisation of HSCs in response to G-CSF is comparable to that of healthy individuals. Notably, sustained increases in cellular frataxin concentrations and raised PGC-1α and Nrf2 expression are detected. Our findings show potential for G-CSF therapy to have a clinical impact in people with FA.

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DO - 10.1038/s41467-022-31450-w

M3 - Article (Academic Journal)

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SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4655 (2022)

ER -

An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich's ataxia

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