RPIB - Recherches Partenariales et Innovation Biomédicale

Neoglycoenzyme for lysosomal disease therapy – LysoProd

Submission summary

LysoProd project concerns the establishment of an experimental prototype for the production of a functionalized enzyme drug that can be transferred to an industrial level for the treatment of Pompe disease, a rare lysosomal storage disease. Studies and patents obtained by our academic teams UMR5247 (Partner 1, A. Morère), UPS3044 (Partner 2, M. Cérutti) and U845 (Partner 4, C. Caillaud) propose an original productive method to target lysosomes very effectively that is developed by NanoMedSyn (Partner 3, recently founded by M. Garcia and associates).
The development of therapeutic strategies to alleviate the 53 lysosomal storage disorders (LSD), most occurring in early infancy, constitutes a public health challenge. Today, enzyme replacement therapy (ERT) is the major therapeutic axis proposed for few LSDs but its application is impaired by a relative low efficacy and largely limited by its cost (€ 200K- 400K /year/patient). Nowadays, the recombinant enzymes used for ERT are synthesised in eukaryotic cells, which are the unique cells expressing the mannose 6-phosphate (M6P) signals required for lysosomal targeting. However, eukaryotic cells are expensive output systems and M6P signalling is often not optimal and further reduced in the bloodstream by enzymatic degradation.
LysoProd’s primary objective is to validate an innovative approach to lysosomal disorder therapy capitalizing on two innovative and proprietary technologies that overcome current barriers in the targeting of lysosomes:
• an original enzyme production in a baculovirus system
• an enzyme coupling with a synthetic derivative of M6P functionalized on aglycone position (AMFA), allowing optimal lysosomal targeting.
The proof of concept of the efficacy of the enzymes produced by this process was established in mouse models of two different lysosomal diseases, Hurler/Scheie disease (MPS I) and Pompe disease (GSD II). Recombinant enzymes functionalized by AMFA derivatives appeared weakly immunogenic and more efficient, than commercial enzymes.
The RPIB grant will accelerate the experimental development of the prototype enzyme on a first indication, Pompe disease and enable its technological transfer of the high scale production to expert companies.
The development of recombinant enzymes by the baculovirus production system and carbohydrate remodelling needs ability in several disciplinary fields. Partner 1 is expert in carbohydrate synthesis and will develop the synthesis and chemical characterization of AMFA for lectin targeting. Partner 2 is specialised in the baculovirus/insect cell system and will master the production of human recombinant enzyme, alpha-acid glucosidase (GAA). The high potent AMFA will be coupled to oligomannosidic chains of the recombinant enzyme by NanoMedSyn. The structure-activity analysis of these chemically-modified enzymes and their potential in preclinical ERT studies in primary fibroblasts of Pompe patients and in Pompe mouse model will be studied by partner 4 and by NanoMedSyn (partner 3). The combined know-how of the partners will allow the establishment of a neo-glycoenzyme prototype ready for industrial development.
The intellectual property of AMFA technology was found to be novel with an inventive step in view of the prior art by two International search reports. The free-to-operate of ERT for different LSD was also confirmed by consulting the patent database of the Swiss Federal Institute of Intellectual Property. The market of ERT for Pompe disease was estimated superior to €300 Million/year and the value of a new enzyme validated in clinical Phase II is €60-100 Million pending to the incidence of the disease. This program will strengthen the proof of concept of this technology and facilitate the access to significant private funding necessary for phase I/II clinical trials. Our final goal is the development of a new production platform of lysosomal enzymes for effective, cost-limited treatments of LSDs including orphan diseases.

Project coordination

Alain MORERE (Institut des Biomolécules Max Mousseron)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


UMR5247 Institut des Biomolécules Max Mousseron
UPS3044 Laboratoire Baculovirus et thérapie
NMS NanoMedSyn
INSERM U 845 Centre de recherche croissance et signalisation

Help of the ANR 473,903 euros
Beginning and duration of the scientific project: January 2014 - 24 Months

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