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Improving Huntington's Disease Therapy with Mesenchymal Stem Cells

Review of “Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice” from STEM CELLS by Stuart P. Atkinson

The reduction of mutant huntingtin (mHTT) levels represents a promising means to block Huntington's disease progression and reverse disease phenotypes. Approaches include the implementation of antisense oligonucleotides directed against HTT mRNA; however, delivery to the deeper regions of the brain affected by Huntington's disease remains a challenging prospect [1]. The glymphatic system, a newly discovered pathway in the brain for the clearance of extracellular soluble proteins and metabolites [2, 3], represents a potentially exciting new delivery route and has been employed to enhance the delivery of therapeutic antibodies into deep brain regions [4].

In a new STEM CELLS study, researchers led by Zhong Pei (Sun Yat‐Sen University, Guangzhou, China) sought to take advantage of the glymphatic system to enhance antisense oligonucleotides brain distribution in Huntington's disease model mice but found impaired glymphatic function as a significant obstacle [5]. However, the team also discovered that systemic administration of mesenchymal stem cells (MSCs) could enhance glymphatic function via the modulation of Aquaporin‐4 (AQP‐4) expression [6], and thereby improve the distribution and efficacy of the mHTT targeting antisense oligonucleotides.

Wu et al. initially demonstrated that fluorescently-labeled antisense oligonucleotides passed through the perivascular space and spread through the brain parenchyma following their injection into the cerebrospinal fluid of wild-type mouse brains; however, AQP4-null mice exhibited a significantly attenuated glymphatic distribution of antisense oligonucleotides when compared to their wild-type counterparts. 

Huntington's disease model mice with reduced expression of the AQP‐4 M23 isoform also displayed a disrupted glymphatic system and poor antisense oligonucleotide distribution; however, the intravenous administration of MSCs restored AQP‐4 M23 expression, improved the brain distribution of antisense oligonucleotides, and led to the suppression of mHTT levels. Furthermore, MSC infusions reversed the increased astrogliosis and phosphorylation of nuclear factor κB (NF‐κB) p65 also observed in Huntington's disease model mice. As MSCs do not enter the brain, the authors hypothesize that paracrine acting MSC-secreted factors acting on the glymphatic system combine with the antisense oligonucleotides to explain the increased therapeutic effect.

Overall, the authors provide ample evidence for the potential of the MSC-mediated modulation of glymphatic activity to improve the treatment of Huntington's disease using antisense oligonucleotides and next hope to explore the relevance of AQP-4 and NF‐κB activity in human Huntington's disease patients.

For more on how MSCs may provide for improved outcomes in Huntington's disease patients, stay tuned to the Stem Cells Portal!


  1. Kordasiewicz Holly B, Stanek Lisa M, Wancewicz Edward V, et al., Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin Synthesis. Neuron 2012;74:1031-1044.
  2. Iliff JJ, Wang M, Liao Y, et al., A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Science Translational Medicine 2012;4:147ra111-147ra111.
  3. Xie L, Kang H, Xu Q, et al., Sleep Drives Metabolite Clearance from the Adult Brain. Science 2013;342:373-377.
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  5. 5.Wu T-t, Su F-j, Feng Y-q, et al., Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice. STEM CELLS 2020;38:218-230.
  6. Tang G, Liu Y, Zhang Z, et al., Mesenchymal Stem Cells Maintain Blood-Brain Barrier Integrity by Inhibiting Aquaporin-4 Upregulation After Cerebral Ischemia. STEM CELLS 2014;32:3150-3162.