Could fingolimod be repurposed for Huntington’s disease?

Written by Andrés Miguez & Jordi Alberch (University of Barcelona, Spain)

Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by a triad of motor, psychiatric and cognitive symptoms. It is usually manifested between 30–50 years of age, with an estimated prevalence of 10 per 100,000 inhabitants in Europe. HD is caused by a CAG repeat expansion in the huntingtin gene (HTT) that translates to a repeat of polyglutamines, resulting in the formation of aggregates of the mutant protein within the cell. Although huntingtin is expressed throughout the brain, the pathology is most prominent in the striatum, cortex and, as evidenced more recently, in the hippocampus [1, 2]. The gradual deterioration of the physical, intellectual, and emotional capacity of HD patients, whose life expectancy is 15–20 years following diagnosis, has an important social and economic impact in sufferers, people at risk and relatives. Unfortunately, current HD treatments only temporarily relieve motor impairment, but do not delay or halt the progression of the disease. Therefore, it is important to develop treatments aimed at alleviating or delaying the symptoms from its beginning, in order to improve patients’ quality of life.
For the past decade, efforts to find new treatments for HD have been focused on blocking neuronal death. However, compelling evidence demonstrates that cellular dysfunction precedes overt cell death by many years in humans and animal models [3, 4]. This suggests that early deficits in HD are likely caused by synaptic dysfunction, rather than as a consequence of neuronal death. Accordingly, cognitive impairment appears long before physical decline in HD patients and mice [5, 6]. In light of this evidence, we have focused our work on the identification of harmful mechanisms triggered by mutant huntingtin that affect neuronal plasticity from the early stages of the disease. The specific aim of this investigation was to search for drugs able to enhance synaptic plasticity and improve cognitive dysfunction in HD.

Mutant huntingtin has detrimental effects on cell survival, synaptic transmission, gene transcription and the production of neurotrophins, particularly brain derived neurotrophic factor (BDNF) [7]. Fingolimod (also known as Gilenya®) was the first oral drug approved for treating Multiple Sclerosis (MS). It was marketed as a functional antagonist of sphingosine 1-phosphate receptors, acting on the peripheral immune system through the prevention of lymphocytes entering the brain [8]. But importantly, Fingolimod can cross the blood-brain barrier and accumulate in the central nervous system, exerting additional effects that are not fully understood [9]. One such effect is the potential to modulate BDNF [10], a key factor in the regulation of synaptic plasticity, learning and memory. Bearing this in mind, we decided to test the therapeutic potential of Fingolimod to improve synaptic plasticity and cognitive function in HD through the modulation of BDNF signaling.

In order to reliably address the utility of Fingolimod chronic treatment in a preclinical model, the drug was administered to mice with HD over a 3 month period, commencing at presymptomatic stages. We combined behavioral, histological and biochemical analysis to explore Fingolimod effects on long-term memory and structural synaptic plasticity. Interestingly, we found that HD mice treated with Fingolimod exhibited better performance on memory tests, including spatial and object recognition tasks.

These behavioral observations correlated with remarkable effects of the drug at the cellular level within the mouse hippocampus. In particular, Fingolimod prevented the loss of neuronal dendritic spines and attenuated the activation of astrocytes.

Apart from its role in reducing neuroinflammation, we associated the therapeutic effects of Fingolimod to its action on BDNF receptors: p75NTR and TrkB. Notably, previous work from our research group, in both patients and animals with HD, linked synaptic and cognitive deficits to an upregulation of p75NTR and a concomitant downregulation of TrkB [11, 12]. Now we have shown that restoring BDNF receptors balance with Fingolimod is a promising strategy for treating synaptic and cognitive dysfunction in this devastating disorder.

Importantly, Fingolimod has also been reported to rescue motor deficits and improve striatal neuropathology in HD mice [13]. In this regard, one feature that may make Fingolimod superior to other drugs in the market is that it has shown benefits for different brain regions that are especially affected in HD, namely the striatum, cortex and hippocampus [13, 14]. Furthermore, the targeting of both neurons and glial cells highlights Fingolimod’s potential to act on key signaling processes involving neuron-glia crosstalk, which are more likely to succeed in maintaining neuronal function and survival.

Altogether, preclinical data indicate that Fingolimod could help to slow both motor and cognitive deficits in HD patients, transforming a currently incurable neurodegenerative disorder into a more chronic disease. In addition, the drug offers the advantage of ease of administration, since it can be given to patients by oral route. Because Fingolimod has already been tested in healthy volunteers and more than 100,000 MS patients, we have substantial data about its safety and potential adverse effects. This is a significant advantage over other compounds currently in the pipeline [15], and will help with moving quickly into trials with HD patients.

In light of our findings, Fingolimod could potentially improve learning and memory in people who have other neurological disorders affecting the hippocampus, such as Alzheimer’s disease. Indeed, recent research suggests a therapeutic effect of the drug on Alzheimer’s disease rodent models [16, 17]. Finally, our results point to a possible contribution of Fingolimod to the enhancement of cognitive function in MS patients, an issue that is currently under investigation in a Phase IV clinical trial (https://clinicaltrials.gov/ct2/show/study/NCT01333501).
References

  1. Van den Bogaard SJA, Dumas EM, Ferrarini L et al. Shape analysis of subcortical nuclei in Huntington’s disease, global versus local atrophy: results from the TRACK-HD study. Neurol. Sci. 307, 60–68 (2011).
  2. Giralt A, Saavedra A, Alberch J, Pérez-Navarro E. Cognitive dysfunction in Huntington’s disease: humans, mouse models and molecular mechanisms. Huntingtons Dis. 1, 155–173 (2012).
  3. Milnerwood AJ, Raymond, LA. Early synaptic pathophysiology in neurodegeneration: insights from Huntington’s disease. Trends Neurosci. 33, 513–523 (2010).
  4. Orth M, Schippling S, Schneider SA, Bhatia KP, Talelli P, Tabrizi SJ et al. Abnormal motor cortex plasticity in premanifest and very early manifest Huntington disease. Neurol. Neurosurg. Psychiatry. 81, 267–270 (2010).
  5. Lawrence AD, Hodges JR, Rosser AE et al. Evidence for specific cognitive deficits in preclinical Huntington’s disease. 121, 1329–1341 (1998).
  6. Paulsen JS. Cognitive impairment in Huntington disease: diagnosis and treatment. Neurol. Neurosci. Rep. 11, 474–483 (2011).
  7. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Rev. 90, 905–981 (2010).
  8. Brinkmann V, Billich A, Baumruker T et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Rev. Drug Discov. 9, 883–897 (2010).
  9. Brunkhorst R, Vutukuri R, Pfeilschifter W. Fingolimod for the treatment of neurological diseases-state of play and future perspectives. Front Cell Neurosci. 8, 283 (2014).
  10. Deogracias R., Yazdani M., Dekkers MPJ et al. Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Natl Acad. Sci. 109, 14230–14235 (2012).
  11. Brito V, Puigdellívol M, Giralt A, del Toro D, Alberch J, Ginés S. Imbalance of p75(NTR)/TrkB protein expression in Huntington’s disease: implication for neuroprotective therapies. Cell Death Dis. 4, e595 (2013).
  12. Brito V, Giralt A, Enriquez-Barreto L et al. Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction. Clin. Invest. 124, 4411–4428 (2014).
  13. Di Pardo A, Amico E, Favellato M et al. FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease. Mol. Genet. 23, 2251–2265 (2014).
  14. Miguez A, García Díaz-Barriga G, Brito V et al. Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington’s disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation. Mol. Genet. 24, 4948–4957 (2015).
  15. Wild EJ, Tabrizi SJ. Targets for future clinical trials in Huntington’s disease: what’s in the pipeline? Disord. 29, 1434–45 (2014).
  16. Asle-Rousta M, Kolahdooz Z, Oryan S, Ahmadiani A,Dargahi L. FTY720 (fingolimod) attenuates beta-amyloid peptide (Aβ42)-induced impairment of spatial learning and memory in rats. Mol. Neurosci. 50, 524–532 (2013).
  17. Fukumoto K, Mizoguchi H, Takeuchi H et al. Fingolimod increases brain-derived neurotrophic factor levels and ameliorates amyloid β-induced memory impairment. Brain Res. 268, 88–93 (2014).

Comment on:

Miguez, A., García Díaz-Barriga, G., Brito, V., Straccia, M., Giralt, A., Ginés, S., Canals, J. M., Alberch, J. Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington’s disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation. Hum. Mol. Genet. 24, 4948–4957 (2015) (Cover).

Highlighted in: Wood, H. (2015) Neurodegenerative disease: Could fingolimod provide cognitive benefits in patients with Huntington disease? Nat. Rev. Neurol., 11, 426.

Financial disclosure/Acknowledgements

Dr. A. Miguez is the recipient of an IDIBAPS Postdoctoral Fellowship-BIOTRACK supported by the European Community’s Seventh Framework Program (EC FP7/2007-2013) under the grant agreement number 229673 and the Spanish Ministry of Economy and Competitiveness (MINECO) through the grant COFUND2013-40261. Research in Dr. J. Alberch’s lab is supported by funds from MINECO, ISCIII-Subdirección General de Evaluación and European Regional Development Fund (RETICS and CIBERNED), Generalitat de Catalunya, Marató TV3, CHDI Foundation (USA).