Project: Regulated gene expression for Huntington's disease therapy

So far, treatments of chronic neurodegenerative diseases are only palliative not influencing ongoing underlying progressive pathology. Gene transfer into the brain is a promising technology for treatment of brain diseases, especially for monogenic orphan diseases like Huntington's Disease (HD) but also for idiopathic diseases like Parkinson´s and Alzheimer´s disease. Gene therapy is a technique for correcting defective or missing genes that otherwise cause a disease. This can be done by inserting a functional copy of the gene into the appropriate cells of the patient, to restore body function._x000D_Even though the first results of gene therapy are very promising, the danger lies in the fact that it may cause side effects due to its current nature of being irreversible. Thus, the ability to “turn on” expression of a therapeutic molecule when it is needed and to “turn off” this expression in case of unwanted effects would add considerably to the safety profile of any genetic therapy._x000D_HD is caused by a defect in the Huntingtin gene. As a consequence of this defect, mutated proteins are produced in the brain. These mutated proteins accumulate in the brain and destroy the neurons, causing loss of their functions. It has been shown by the groups participating in the current proposal that to prevent dying-off of the neurons, two actions can be taken: (1) prevent the production of the mutated Huntingtin protein (CHUV) and (2) stimulate the COtenance and survival of neurons (CHUV and UMG)._x000D__x000D_1. The production of the mutated Huntingtin protein can be prevented with RNA interference (RNAi). RNAi is a process within cells that decreases the activity of their genes. Two types of small RNA molecules – microRNA (miRNA) and short hairpin RNA (shRNA) – are central to RNAi. RNAs are the direct products of gene transcription, and these small RNAs can bind to other specific messenger RNA (mRNA) molecules and decrease their activity. Preventing the mRNA of the Huntingtin (Htt) gene to from producing the protein will result in a lower concentration of the disease-inducing gene and hence in a therapeutic effect._x000D_2. In the brain neurotrophic factors play a role in the COtenance and survival of neurons. Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent neurotrophic factors in the brain and has proven efficacy in several pre-clinical paradigms._x000D__x000D_In order to increase the chance for successful implementation of a regulatable genetic therapy for HD and thus of a marketable product, two strategies (regulated RNAi expression and regulated neurotrophin expression) will be followed and optimized. If one method fails, the other still might prove valuable. Possible toxic and off-target effects will be monitored throughout the project by Next Generation Sequencing (NGS) of small RNAs and transcriptome changes. Importantly, the developed products and procedures will be ready for clinical testing and of commercial interest also for treatment of several other neurodegenerative disorders such as Parkinson's disease, MSA, hearing loss._x000D__x000D_Besides developing these methods for HD, the consortium has to adapt uniQure's baculovirus production system in order to be able to generate rAAV in a GMP-compliant procedure to the DNA vector type. This system recently has been approved by the EMA for the production of Glybera, the first gene therapy drug in the Western world for treatment of lipoproteine lipase deficiency (LPLD). Moreover, the consortium plans to perform in vivo tests in HD animal models. The last step is to perform animal tests in rodents and non-human primates to get a more complete package ranging from proof-of-concept to safety studies._x000D__x000D_It is expected that this validation with external world-leading expertise will allow UniQure to optimize/increase the success rate in the field of CNS gene therapy and thereby saving significant costs. It will allow the company to produce better characterized and more reliable therapeutic candidates for further clinical development and potentially strategic Ping. In the case of the GDNF and RNAi, it will permit the company to validate their application in neurodegenerative diseases with an initial focus on Huntington’s disease. Furthermore, time-to-market is absolutely critical in this sector. Therefore, the time saved in accessing the scientific expertise directly through academic laboratory is invaluable. It allows the company to focus their efforts on aspects already mastered internally. Altogether, the costs of the project are the most cost effective way of attaining the objectives proposed and reduce the time-to-market.

Acronym HD-gene therapy (Reference Number: 7900)
Duration 01/06/2013 - 31/05/2016
Project Topic The use of highly active molecules for Huntington's Disease therapy requires regulation of gene expression to avoid toxicity. GeneSwitch-regulated GDNF and miHtt expression will be tested Safety and efficacy of AAV5-delivered molecules will be evaluated in rodent HD models and marmoset brains.
Network Eurostars
Call Eurostars Cut-Off 9

Project partner

Number Name Role Country
4 uniQure Biopharma B.V. Coordinator Netherlands
4 Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois) Partner Switzerland
4 University of Maria Curie-Sklodowska Partner Poland
4 University Medicine Goettingen Partner Germany