Pharmacology of muscular dystrophies

Our research started in 2010 with the aim of developing innovative pharmacological approaches for the treatment of HGPS, a rare congenital disease characterized by accelerated aging in children. This syndrome is typically caused by a de novo mutation in the LMNA gene that encodes the major components of the nuclear lamina, the lamins A and C (for review Lo Cicero et al, Ageing Res Rev. 2015).

In HGPS, the LMNA mutation results in the production and accumulation of an abnormally farnesylated form of lamin A called progerin (for review Guilbert SM et al, Methods 2021). In 2010, in collaboration with Dr Nicolas Lévy, I-Stem pioneered the generation of several iPS cell lines carrying the C1804T mutation in LMNA to explore the potential of this unique biological resource. From 2010-2018 our group has successfully demonstrated that it was possible to use iPS cell derivatives to recapitulate key features of premature aging in bone (Blondel S 2014 Stem Cells Transl Med. 2014: Lo Cicero A, Sci Rep 2016 Retinoic), skin (Lo cicero et al Sci Rep 2018), and vascular tissues (Ribas J et al Small 2017; Pitrez PR et al ACS Biomater Sci Eng. 2018). We also identified new molecular mechanisms of HGPS, such as the role of miR-9 in the regulation of progerin expression in neurons (Nissan X et al., Cell Reports, 2012).

Finally during this period, we also identified several new drug candidates through hypothesis-driven research, such as the positive effect on LMNA alternative splicing of Metformin (Egesipe AL, NPJ Aging Mech Dis. 2016) and MG132 (Harhouri K, et al EMBO Mol Med.  2017) or by high-throughput screening as revealed with the identification of Mono-Aminopyrimidins (Blondel S et al Cell Death Dis 2016) or retinoids (Lo Cicero A, et al Sci Rep 2016).

Based on these findings, since 2018, we have pursued our research activity on HGPS in different directions in collaboration with the groups of Nicolas Lévy, Antoine Muchir, Claudia Cavadas and Lino Ferreira identifying pathological mechanisms causing vascular aging in HGPS (Ribas J, et al, Small 2017; Estronca L et al, ACS Biomater Sci Eng. 2018) or new therapetuical options targeting MMP13 (Pitrez PR et al, Nat Commun. 2020) or NAD metabolism (Cardoso et al, submitted). More recently, we have initiated an innovative AI based approach targeting progerin with PROTACs with the Belgium company Kantify.

In September 2015, in collaboration with the group of Isabelle Richard at Genethon, we extended our research on Limb Girdle Muscular Dystrophies (LGMDs).

LGMDs are part of the larger group of progressive muscular dystrophies that progressively affect muscles throughout the life of the patients. LGMDs were first described in 1954 and are mainly characterized by the impairment of the hip and shoulder muscles, high creatine kinase (CK) levels, and muscle degeneration with exacerbated fibrosis and inflammation. To date, the group includes pathologies with mutations in 33 different genes, mostly affecting structural or secondary components of the muscle fiber. The age of onset is highly variable and disease severity is very heterogeneous. Currently, there is no specific treatment available for any LGMD, even if gene therapy and exon skipping strategies are being investigated for some of them.

In our group, we are interested in using iPS-derived myoblasts and other cellular models to identify pharmacological treatments for several LGMDs by high throughput screening or drug repurposing. Among the large spectrum of LGMDs, we have a particular interest in LGMD R3 (alpha sarcoglycan), LGMD R5 (gamma sarcoglycan), LGMD R2 (Dysferlin) and LGMD R9 (FKRP). Recently, team’s effort for the LGMD R3 program has shed light on a the potential repurposing of givinostat for the disease (Hoch et al 2019 Scientific reports ; Hoch et al 2022 Frontiers in pharmacology).

Glycogen storage diseases (GSD) are rare autosomal recessive disorders caused by mutations in genes encoding individual enzymes of the glycogen metabolism pathway. Among them, glycogen storage disease type III (GSDIII; incidence: 1/100 000) is caused by mutations in the AGL gene encoding the glycogen debranching enzyme (GDE) and leads to the accumulation of cytosolic glycogen in the whole body. Although GDE is expressed in all the tissues, the disease manifestation is primarily due to its absence in liver and muscles. During childhood, the disease is mainly metabolic, with hepatomegaly and severe fasting hypoglycemia. In the adulthood, the metabolic disease becomes less prominent and a generalized muscle weakness appears. To date, no treatment is available for GSDIII. Patients follow strict diet regimens to avoid recurrent hypoglycemia.

Started in 2020 in collaboration with Giuseppe Ronzitti‘s group at Généthon this program was recently awarded by an ANR JCJC, a grant from the Foundation Maladies Rares and the support of the Association Francophone des Glycogénoses. Led by Lucile Hoch this program aims to use patients derived pluripotent stem cells to understand the molecular mechanisms involved in the muscular pathophysiology of the disease and identify an efficient pharmacological treatment to clear glycogen accumulation in muscles.