microRNA gene therapy to treat Huntington’s disease

microRNA gene therapy Huntington's disease

Date: 14th April 2021

Huntington’s disease (HD) is a genetic neurodegenerative disorder, symptoms usually first appear between ages 30 and 50 and include the progressive development of psychiatric, motor, and cognitive symptoms.  It is caused by an extended CAG repeat in exon 1 of the huntingtin (HTT) gene, and currently only symptomatic treatments are available.  Now, researchers demonstrate the long-term durability of an adeno-associated viral vector (AAV)–mediated strategy to deliver microRNA (miRNA) targeting human mutant HTT (mHTT) in a preclinical model for up to a year after treatment.

HTT-lowering therapies are of particular interest for the treatment of HD as they knock down the expression of the disease causative gene.  Whilst, most in clinical development are based on antisense oligonucleotides (ASO), other technologies such as small interfering RNAs (siRNAs) are also being explored.  One such investigational therapy is AAV5-miHTT, a recombinant AAV-based gene therapy expressing an engineered microRNA (miRNA) specifically designed to bind to the HTT exon.  It lowers both wild-type and mutant HTT (mHTT) mRNA, and has recently been shown to be efficacious in vitro and in small and large animal models, supporting its translation to investigational clinical trials.

Now, researchers from uniQure, Netherlands, in collaboration with scientists from the Czech Republic and Italy, have shown that magnetic resonance imaging (MRI)–guided convention-enhanced delivery (CED) of rAAV5-miHTT in a minipig model for HD showed extensive brain biodistribution, sustained reduction of mutant HTT (mHTT) protein, which was associated with biomarker changes.

rAAV5-miHTT is a gene therapy candidate from uniQure, also known as AMT-130, for the treatment of HD. The recent work published in Science Translational Medicine journal has examined the translatability and long-term durability of AMT-130.  A key success factor for this type of gene therapy is to ensure precise administration and spread of the AAV, unlike other approaches, AAVs can be administered locally into the brain region.  For precision, the team used magnetic resonance imaging–guided convention-enhanced delivery of the therapy, targeting the caudate and putamen which are regions of the brain primarily affected in HD, and have relevant connections to areas of the brain that are affected later during progression of the disease.

A single dose of AMT-130 was given, and widespread biodistribution of vector DNA was observed at both 6 and 12 months post treatment. The highest concentrations were found in targeted regions of the brain however, all key brain regions that are affected at the different stages of HD were transduced.

Next, the team wanted to determine expression of the therapeutic miRNA.  At 1 year post treatment they found mature miHTT RNA molecules in nearly all regions where the vector DNA was distributed, suggesting that accurate processing was occurring.

This widespread biodistribution of vector and mature guide strand RNA, should result in an efficient decrease in mHTT protein. Indeed when they checked at 12 months, there was a pronounced protein reduction found in the putamen (85%) and caudate (80%) with several other regions also showing a substantial decrease.

One particularly challenging aspect of CNS diseases are they are hard to monitor and assess for therapeutic efficacy as the brain is inaccessible.  However, as endogenous miRNAs can be detected in the cerebrospinal fluid (CSF) and can therefore be relatively easily sampled, the team reasoned that their therapeutic miRNA miHTT might also be detected here.  This was in fact the case, and from 3-12 months post injection the CSF had sustained concentrations of miHTT.  Furthermore, mHTT protein was also reduced in the CSF, which could be used as a biofluid biomarker to follow disease progression and treatment effectiveness.

Conclusions and future applications

The team here have demonstrated the therapeutic potential of rAAV5-miHTT to lower levels of mutant huntingtin protein in the brain which are associated with Huntington’s disease.  The clinically translatable intracranial MRI-guided CED showed successful delivery of the gene therapy for the first time in this model, with the therapeutic agent recorded at the highest concentrations in the targeted regions of the brain.

This preclincial data, was also announced by uniQure alongside two other recent publications, a toxicity study of AMT-130 in non-human primates and rats that was published in the journal Brain Science, and another in Brain Communications examining the potential use of measuring therapeutic miHTT in extracellular vesicles in CSF as sources to monitor the expression and durability of gene therapies in the brain.  Together with the work described here, these publications demonstrate widespread biodistribution and strong, durable efficiency of AMT-130 in disease-relevant regions in a large brain, and support their Phase I/II clinical trial of AMT-130 in patients with Huntington’s disease, which has just completed the enrolment of the first cohort of participants.

The treatment of neurodegenerative disorders is particularly difficult due to inaccessibility and therapeutics having to cross the blood-brain barrier.  Formulated nanoparticles have now been developed that can cross this once impenetrable barrier,  now the use of MRI-guided CED offers an efficient form of administration into the brain.  Last year, researchers made advances for HD using gene therapy to convert and reprogramme striatal astrocytes into neurons that could replace the diseased ‘faulty’ neurons.  Whilst, this of type of gene therapy offers great potential as a disease-modifying therapy for HD sufferers, it alleviates symptoms rather than treating the root cause.  Here, AMT-130 offers a single treatment with potentially curative results, and with the commencement of clinical trials the initial results will be highly anticipated.


For more information please see the press release from uniQure

Vallès, A., M. M. Evers, A. Stam, M. Sogorb-Gonzalez, C. Brouwers, C. Vendrell-Tornero, S. Acar-Broekmans, L. Paerels, J. Klima, B. Bohuslavova, R. Pintauro, V. Fodale, A. Bresciani, R. Liscak, D. Urgosik, Z. Starek, M. Crha, B. Blits, H. Petry, Z. Ellederova, J. Motlik, S. van Deventer and P. Konstantinova (2021). “Widespread and sustained target engagement in Huntington’s disease minipigs upon intrastriatal microRNA-based gene therapy.” Science Translational Medicine 13(588): eabb8920.