Decreasing ganglioside synthesis as a therapy for hereditary spastic paraplegia – TREATSPG11
Decreasing ganglioside synthesis as a therapy for hereditary spastic paraplegia
1. Proof of concept : downregulating GM3 synthase in vivo using a viral vector<br />2. Test therapeutic efficacy of antisense oligonucleotides (ASO) targeting GM3 synthase in a mouse model of SPG11<br />3. Preparing translation of preclinical proof of concept into clinical trial
Decreasing ganglioside synthesis as a therapy for hereditary spastic paraplegia
Hereditary spastic paraplegias (HSP) are a group of rare neurodegenerative diseases characterized by motor dysfunction, and also cognitive impairment in some severe forms of the disease. Currently, the only available treatments are symptomatic, and do not prevent or delay the disease progression. There is therefore a strong unmet need of treatment for this disease.<br />We have developed a mouse model of the complex and most frequent form of autosomal recessive HSP due to loss-of-function mutations in the SPG11 gene. In this model that reproduces the main symptoms observed in patients, we identified accumulation of gangliosides in lysosomes in the brain as a putative therapeutic target to prevent neurodegeneration. Our objective is thus to provide proof of concept for targeting deleterious lipid synthesis as a therapy for SPG11, and begin translational steps for the development of this therapy for patients. The strategy we selected to prevent accumulation of gangliosides is to downregulate the expression of GM3 synthase, an essential enzyme for the biosynthesis of gangliosides.
- Downregulation of GM3 synthase using either AAV-PHPeb viral vector allowing expression of a miRNA targeting GM3 synthase or antisense oligonucleotide (ASO) targeting the same enzyme
- Behavioral evaluation of mice injected by AAV-PHPeb or ASO
- Histological evaluation of mice injected by AAV-PHPeb or ASO
- Biochemical identification of peripheral biomarkers in mice injected with ASO
- Support for translation of program towards the clinic – investigate prevalent SPG11 patient population
1. Injection of an AAV-PHPeB allowing expression of miRNA targeting GM3 synthase:
- Prevented accumulation of gangliosides in neurons of cortex and cerebellum of Spg11 knockout mice at the age of 4 months
- Delayed the onset of motor and cognitive symptoms in Spg11 knockout mice
- Did not show any protective action at the age of 8 months, concurrent with reduced expression of transgene at this time point
2. We identified an ASO that efficiently downregulates GM3 synthase in mice. Behavioral and histological analyses are ongoing in Spg11 knockout mice
3. We identified neurofilament light chain as a biomarker of disease progression. We could not evaluate whether their levels change upon downregulation of GM3 synthase. We also performed an epidemiology study to estimate the prevalent patient population suffering from hereditary spastic paraplegia.
- Finalize the histological analysis of mice injected with AAV-PHPeB downregulating GM3 synthase
- Behavioral and histological analyses of wild type and Spg11 knockout mice injected with ASO
- Search for other biomarkers of disease progression and response to treatment
1 common article submitted for publication
Hereditary spastic paraplegias (HSP) are a group of rare neurodegenerative diseases characterized by motor dysfunction, and also cognitive impairment in some severe forms of the disease. Currently, the only available treatments are symptomatic, and do not prevent or delay the disease progression. There is therefore a strong unmet need of treatment for this disease.
We have developed a mouse model of the complex and most frequent form of autosomal recessive HSP due to mutation in the SPG11 gene. In this model that reproduces the main symptoms observed in patients, we identified accumulation of some lipids in lysosomes as a putative therapeutic target to prevent neurodegeneration. Our objective is thus to provide proof of concept for targeting deleterious lipid synthesis as a therapy for SPG11, and begin translational steps for the development of this therapy for patients.
To reach this objective, our specific aims are:
1. to provide a proof of concept that decreasing deleterious lipid synthesis prevents or slows down the progression of the symptoms in the Spg11-/- mouse model. This will be done by decreasing a key enzyme for synthesis of the target lipids in the brain of this mouse model (WP1);
2. to test a strategy that is appropriate for translation from preclinical proof-of-concept studies to clinical trials: we will design antisense oligonucleotides (ASO) targeting the enzyme downregulated in WP1 and test their therapeutic efficacy in the Spg11-/- mouse model (WP2).
3. To prepare the steps required to move towards a clinical trial, by elucidating the mechanisms underlying neurodegeneration in the Spg11-/- mouse and by identifying biomarkers of disease progression and response to treatment (WP3).
This project will thus provide proof-of-concept for the development of an ASO-based treatment for SPG11 patients by inhibiting the synthesis of some deleterious lipids. This participates in our long-term objective that aims at developing a treatment for SPG11 patients.
The project will be performed by a consortium composed of a team expert in the physiopathology of Spg11 and that identified the deleterious lipids as a putative therapeutic target (Institut du Cerveau et de la Moelle Epinière) and Dynacure, a small or medium enterprise, developing therapeutic strategies based on ASO technology. The combined expertise of the two partners will ensure the feasibility of the project and will strongly accelerate the switch from preclinical to clinical stage.
Project coordination
Frédéric DARIOS (ICM)
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.
Partnership
ICM ICM
DYNACURE
Ionis Pharmaceuticals
Help of the ANR 474,679 euros
Beginning and duration of the scientific project:
September 2019
- 36 Months
