Potential drug treatment for SPG5

Corrects lipid disturbance & axon degeneration in stem cells

Chenodeoxycholic acid restores lipid balance and stops axonal degeneration in stem cell-derived SPG5 neurons in the lab. The research established a cause-and-effect relationship between gene deficiency and axonal degeneration. Neuro filament expression and organisation was also found to be impaired and was restored to normal by the treatment.

Chenodeoxycholic acid is already an established treatment for a related genetic disease cerebrotendinous xanthomatosis (CTX).

Xue-Jun Li

Background: Biallelic mutations in CYP27A1 and CYP7B1, two critical genes regulating cholesterol and bile acid metabolism, cause cerebrotendinous xanthomatosis (CTX) and hereditary spastic paraplegia type 5 (SPG5), respectively. These rare diseases are characterized by progressive degeneration of corticospinal motor neuron axons, yet the underlying pathogenic mechanisms and strategies to mitigate axonal degeneration remain elusive.

Methods: To generate induced pluripotent stem cell (iPSC)-based models for CTX and SPG5, we reprogrammed patient skin fibroblasts into iPSCs by transducing fibroblast cells with episomal vectors containing pluripotency factors. These patient-specific iPSCs, as well as control iPSCs, were differentiated into cortical projection neurons (PNs) and examined for biochemical alterations and disease-related phenotypes.

Results: CTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases. Notably, the bile acid chenodeoxycholic acid (CDCA) effectively mitigated the biochemical alterations and rescued axonal degeneration in patient iPSC-derived neurons. To further examine underlying disease mechanisms, we developed CYP7B1 knockout human embryonic stem cell (hESC) lines using CRISPR-cas9-mediated gene editing and, following differentiation, examined hESC-derived cortical PNs. Knockout of CYP7B1 resulted in similar axonal vesiculation and degeneration in human cortical PN axons, confirming a cause-effect relationship between gene deficiency and axonal degeneration. Interestingly, CYP7B1 deficiency led to impaired neurofilament expression and organization as well as axonal degeneration, which could be rescued with CDCA, establishing a new disease mechanism and therapeutic target to mitigate axonal degeneration.

Conclusions: Our data demonstrate disease-specific lipid disturbances and axonopathy mechanisms in human pluripotent stem cell-based neuronal models of CTX and SPG5 and identify CDCA, an established treatment of CTX, as a potential pharmacotherapy for SPG5. We propose this novel treatment strategy to rescue axonal degeneration in SPG5, a currently incurable condition.

SOURCE:  Orphanet J Rare Dis. 2023 Apr 6;18(1):72. doi: 10.1186/s13023-023-02666-w. PMID: 37024986 © 2023. The Author(s).

Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients

Yongchao Mou #  1   2 Ghata Nandi #  1 Sukhada Mukte  1 Eric Chai  1 Zhenyu Chen  1   2 Jorgen E Nielsen  3 Troels T Nielsen  3 Chiara Criscuolo  4 Craig Blackstone  5   6 Matthew J Fraidakis  7 Xue-Jun Li  8   9

1. Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA.

2. Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA.

3. Neurogenetics Clinic & Research Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

4. Department of Neuroscience, Reproductive Sciences and Odontostomatology, Federico II University, Naples, Italy.

5. Movement Disorders Division, Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.

6. MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Boston, MA, 02129, USA.

7. Rare Neurological Diseases Unit, Department of Neurology, Attikon University Hospital, Medical School of the University of Athens, Athens, Greece.

8. Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA.

9. Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA.

#. Contributed equally.


    1. Editor’s note: The drug is a common treatment for cerebrotendinous xanthomatosis (CTX) which is a type of leukodystrophy. The Leukodystrophies have some common or closely related genetics and disease-causing mechanisms to the SPs. A quick search of the TGA website did not turn up Chenodeoxycholic acid, although it may exist under a brand name for treating CTX. It is certainly not available for treating any form of HSP (nothing is at this stage) however this is worth talking through with your neurologist. Your neurologist can get further information on the potential use of the drug for SPG5. They could also investigate sources of the drug and write a prescription for its use “off label”. If the drug is not available in Australia, they could help you apply to get it under the Special Access Scheme (TGA) so it may be possible to get the drug if the potential risks and benefits can be assessed.

    1. Editor’s note: As mentioned in the article, a lot is still to be learned about the disease mechanism that causes SPG5. However based on what is known, the disease-causing mechanisms of SPG5 and SPG7 are different. SPG5 is primarily related to impaired lipid metabolism, whereas for SPG7 it is mitochondrial impairment. Based on that, it is probably unlikely that this drug would be an effective treatment for SPG7.

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