G-CSF Stem Cell Therapy Safely Raises Frataxin Levels in Pilot Trial

6 adults show prolonged protein production after five G-CSF treatments

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by Steve Bryson, PhD |

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Repeat use of G-CSF stem cell therapy, an approved medicine, was safe in adults with Friedreich’s ataxia and associated with significant elevations in frataxin protein and disease-related biomarkers, a pilot study in the U.K. reported.

Because interventions that increase frataxin and reverse the harmful effects of the protein’s deficiency are attractive treatment approaches, these findings demonstrate the potential for G-CSF in treating people with FA, the researchers said.

Future studies need to evaluate G-CSF, at a range of doses, on disease-affected tissues such as the heart and brain, they added.

The study, “An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich’s ataxia,” was published in the journal Nature Communications.

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Genetic defects in Friedreich’s ataxia patients lead to abnormally low levels of frataxin, an essential protein for the functioning of mitochondria — the energy-producing structures within cells. Low frataxin causes mitochondrial dysfunction, impaired energy production, and disease symptoms primarily affecting the nervous system and muscles.

Stem cells have the potential to transform into many different cell types in the body and play a role in the healing process. Granulocyte-colony stimulating factor (G-CSF) is a regulatory protein that stimulates the release of bone marrow stem cells and their circulation in the blood.

G-CSF currently given to cancer patients, bone marrow donors

G-CSF is an approved medication widely used to help blood cancer patients recover from chemotherapy and to boost the number of stem cells in the blood of healthy people before donating bone marrow. As such, G-CSF has a well-established safety record, and its pharmacology has been extensively studied.

Researchers at the University of Bristol, working in a mouse model of FA, previously demonstrated that G-CSF increased frataxin levels and eased FA symptoms.

Building on these findings, the Bristol team conducted a pilot study (EudraCT: 2017-003084-34) to evaluate the impact of G-CSF on FA-related biomarkers in three men and four women with this disease. The age of FA onset among participants ranged from 2 to 45 years old, and all were treated with G-CSF at doses given healthy donors.

Before treatment (baseline measures), blood samples were collected, and participants underwent a basic clinical examination. Lenograstim, a lab-made version of G-CSF sold as Granocyte, was administered by subcutaneous (under-the-skin) injection once daily for five consecutive days. Further blood sample collections and examinations occurred over the next two weeks.

On day six, one day after completing the last G-CSF dose, blood tests confirmed a sevenfold rise in the total number of white blood cells, and the mobilization of bone marrow stem cells in the bloodstream.

The mean baseline level of frataxin protein in isolated mononuclear cells (MNCs), which include immune lymphocytes and monocytes that arise from bone marrow stem cells, was 2.43 picograms per microgram (pg/mcg) of total protein, and 1.60 pg/mcg in platelets.

After G-CSF treatments, there was a prolonged rise in frataxin production, which reached a maximum mean increase of 2.11-times in MNCs by day 10 and 1.94 times in platelets by day eight. Increases in frataxin were seen in all six patients who completed the study.

The team then tested the levels of two enzymes — aconitase and succinate dehydrogenase — that rely on frataxin to function correctly. In response to G-CSF, a 3.70-times increase in aconitase activity was seen over the study period, while succinate dehydrogenase activity rose 3.04 times.

Frataxin deficiency results in reduced activity of the cell regulatory proteins PGC-1-alpha, NRF1, and Nrf2. G-CSF treatment led to a “marked, rapid, and sustained” increase in PGC-1-alpha production, with an almost threefold (2.94 times) maximum increase. Likewise, Nrf2 rose 1.98 times. NRF1 showed greater variability in response and no evidence of change.

Three patients reported a single, mild adverse event during the study, with muscle-skeletal pain, predominantly in the legs, reported for two individuals and a mild headache in the other. All these are known G-CSF side effects, the team noted. No serious adverse events were reported.

An expected elevation in alkaline phosphatase levels was seen following G-CSF administration, but they were not related to symptoms and resolved by day 19. All other clinical tests for pulse rate, blood pressure, or body temperature were within normal ranges.

“This study provides proof-of-principle evidence to support an efficacy study of G-CSF administration in FA, using repeated courses over a longer period,” the team wrote. “Nevertheless, the need for future assessment of G-CSF administration on affected tissues, such as the heart and brain, using a range of dose levels and dosing frequencies is required.”