Our Pipeline
At Atamyo, we work on the development of novel approaches to treat different forms of limb-girdle muscular dystrophies (LGMD), gene-related disabling diseases characterized by a predominant impairment of muscles of the hip and shoulder areas.
We use our expertise in gene therapy and muscular dystrophies to find new approaches for gene replacement. Our goal is to design the best delivery system for a particular disorder, in order to decrease side effects and improve the restoration of a normal physiological function for patients. Atamyo’s therapeutic strategies are based on modified adeno-associated virus (AAV). In collaboration with Genethon's research teams, we design new capsids, promoters, transgenes and regulation elements that will increase power, specificity and safety of future treatments.
Currently, our pipeline focuses on 5 different LGMD subtypes:
LGMD-R9/LGMD2i or deficiencies in the protein FKRP
LGMD-R9 is a recessive autosomal dystrophy caused by mutation in the fukutin related protein (FKRP) gene. FKRP is a ribitol-5-phosphatase transferase that participates in α-dystroglycan glycosylation to ensure matrix-anchoring of the muscle fiber. This subtype is one of the most frequent recessive LGMD in Europe. The onset of the disease occurs from the first to the third decade of life, with symptoms that vary largely in severity and can be as severe as what is observed in Duchenne Muscular Dystrophy (DMD). Most of patients suffer from respiratory impairment and a cardiac involvement is also possible, which may lead to heart failure and death, but with no direct correlation to the severity of the skeletal muscle phenotype.
LGMD-R5/LGMD2C or deficiencies in γ-sarcoglycans
LGMD-R3 and R5 are linked to autosomal recessive mutations in α- and γ-sarcoglycans, respectively. Sarcoglycans are a family of transmembrane proteins that are involved in the connection between the internal cytoskeleton and extracellular matrix. In muscles, they are part of the dystrophin glycoprotein complex and prevent sarcolemmal damage during muscle contractions. These 2 subtypes of LGMD share a childhood onset with typical symptoms of the disease involving progressive weakness and atrophy of scapular and pelvic muscles. The prognosis is similar in both disease forms and results in difficulties of movement and reduced quality of life. While for LGMD-R3, cardiac and respiratory symptoms are rare, in LGMD-R5, there is a more frequent involvement of both the heart and diaphragm. A feature, often present in LGMD-R3, is the hypercontraction of the Achille’s tendon leading to a peculiar tiptoe gait pattern.
LGMD-R1/LGMD2A or Calpainopathy
Also known as calpainopathy, LGMD-R1 first symptoms appear in childhood or early adulthood. This LGMD subtype is caused by autosomal recessive mutations in the CAPN3 gene, which encodes for calpain-3, a skeletal muscle-specific calcium-activated cysteine protease. Patients affected by this condition usually experience symmetrical weakness in their pelvis, upper and lower limbs, causing joint stiffness, difficulties in walking, posture abnormalities and scoliosis. The severity of the symptoms often forces the patients to the use of a wheelchair.
LGMD-R2/LGMD2B or Dysferlinopathy
LGMD-R2 is characterized by mutations in the dysferlin gene, usually presenting with a late teenage onset. Dysferlin is expressed mainly in skeletal muscle, heart and macrophages. This protein is involved in a process called cell membrane repair, which is a protective mechanism to reseal membrane disruption, maintaining homeostasis and preventing cell death. This form of LGMD presents with a slow progression of proximal weakness and atrophy of shoulder and pelvic muscles. Typically, there is no involvement of heart or respiratory muscles. Calves pseudohypertrophy and highly elevated levels of serum creatine kinase are frequent in LGMD-R2 patients.
LGMD-R3/LGMD2D or deficiency in α-sarcoglycans
LGMD-R3 and R5 are linked to autosomal recessive mutations in α- and γ-sarcoglycans, respectively Sarcoglycans are a family of transmembrane proteins that are involved in the connection between the internal cytoskeleton and extracellular matrix. In muscles, they are part of the dystrophin glycoprotein complex and prevent sarcolemmal damage during muscle contractions. These 2 subtypes of LGMD share a childhood onset with typical symptoms of the disease involving progressive weakness and atrophy of scapular and pelvic muscles. The prognosis is similar in both disease forms and results in difficulties of movement and reduced quality of life. While for LGMD-R3, cardiac and respiratory symptoms are rare, in LGMD-R5, there is a more frequent involvement of both the heart and diaphragm. A feature, often present in LGMD-R3, is the hypercontraction of the Achille’s tendon leading to a peculiar tiptoe gait pattern.