Gene therapy
for hereditary diseases

Dysferlinopathies are rare inherited muscular dystrophies. They are caused by mutations in the DYSF gene, which leave muscle fibers with almost no dysferlin protein. Dysferlin helps repair the muscle cell membrane after the microdamage that occurs during normal physical activity. Without dysferlin, muscle fibers gradually break down and are replaced by connective and fat tissue.

The first signs of the disease usually appear in late adolescence or young adulthood. In limb-girdle muscular dystrophy R2 (LGMD R2), the muscles of the pelvic and shoulder girdles weaken first: running, climbing stairs and getting up from a chair become difficult. In Miyoshi myopathy, the calf muscles are affected first, and the person can no longer stand on tiptoe. The disease progresses slowly: on average, a cane is needed 13–16 years after symptom onset, and a wheelchair after 21–23 years. A characteristic laboratory finding is a blood creatine kinase (CK) level that is usually 10–100 times above normal. The heart is rarely affected. Because of inflammatory changes in muscle tissue, the disease is often mistaken for polymyositis.

Inheritance is autosomal recessive: a person develops the disease after inheriting an altered copy of the DYSF gene from each parent. The parents are usually healthy carriers, and in such a family the chance of having an affected child is 25% with each pregnancy. The diagnosis is confirmed by genetic testing of the DYSF gene. The exact prevalence of dysferlinopathies is unknown; by minimum estimates, about 1,000 people in Russia live with this diagnosis.

GT DF 102 uses two vectors based on adeno-associated virus (AAV) to deliver a functional copy of the DYSF gene to skeletal muscles. The dysferlin gene is too large for a single AAV vector, so its coding sequence is split into two parts, each carried by its own vector. The drug is designed so that in a muscle cell that receives both vectors, the two parts combine into a full-length gene and the cell can produce dysferlin. Gene activity is controlled by regulatory elements that are active in muscle tissue.

The route of administration and the dose will be determined based on the results of preclinical studies.

Proof-of-concept studies in cell cultures and model mice have been completed. The preclinical stage is now under way: studies of the drug's safety and biodistribution, which are required to obtain permission for a clinical trial.

After the preclinical stage is completed, the documents will be submitted to the Ministry of Health of Russia. The first clinical trial will focus primarily on the safety and tolerability of the drug and on dose selection. Patients who meet the inclusion criteria will be able to take part at medical centers authorized to conduct the trial.

We will publish the enrollment start dates, inclusion criteria and the list of study sites on this page.

Dysferlinopathy is a rare inherited muscle disease caused by mutations in the DYSF gene. This gene encodes dysferlin, a protein involved in repairing the muscle fiber membrane after damage. Without it, the fibers gradually break down and are replaced by fat and connective tissue.

The first symptoms usually appear between the ages of 15 and 30: weakness in the legs and difficulty running, climbing stairs and walking on tiptoe. The main forms are limb-girdle muscular dystrophy R2 (formerly 2B) and Miyoshi myopathy. A characteristic laboratory finding is a blood creatine kinase level elevated tens of times. Because of this, the disease is often mistaken for polymyositis, and hormone therapy is prescribed in error. The disease progresses slowly; in most cases the heart and respiratory muscles are only mildly affected.

The inheritance pattern is autosomal recessive. The disease develops if a person inherits an altered copy of the gene from each parent. The parents are usually healthy carriers. For a couple of carriers, the chance of having an affected child is 25% with each pregnancy. A patient's children will be carriers and will develop the disease only if the other parent is also a carrier.

Gene therapy targets the cause of the disease: a working copy of the gene is delivered to muscle cells so that they start producing the missing protein again. Delivery uses vectors based on adeno-associated virus, a viral shell that cannot cause infection.

The DYSF gene is large and does not fit entirely into a single vector of this kind, so developers use special technological solutions, such as delivering the gene in two parts. The expected effect is to slow or stop disease progression. The therapy cannot restore muscle tissue that has already been lost. There are currently no registered gene therapy drugs for dysferlinopathy in any country.

The drug candidate is at the preclinical stage: its safety, reproducibility and effect in disease models are being studied. Studies in humans can begin only after the preclinical program is completed, the drug is manufactured to quality standards and permission is obtained from the regulator.

Eligibility criteria will be approved together with the study protocol. Based on international practice, a genetically confirmed diagnosis will be required. Age, functional status, comorbidities and the presence of antibodies to the viral vector will also be taken into account.

What you can do now: confirm the diagnosis genetically and apply to the Dysferum patient registry, which is building a Russian cohort for future studies. Participation in clinical trials is always free of charge. An offer to pay for enrollment in a trial is a sign of fraud.

The main method is next-generation sequencing: a neuromuscular disease gene panel or exome sequencing. The diagnosis is considered confirmed if two pathogenic variants are found in the DYSF gene. It is advisable to test the parents as well, to make sure that one variant was inherited from each of them.

If only one variant or a variant of uncertain significance is found, the doctor may order additional tests. These include a search for large deletions and duplications and analysis of dysferlin protein in blood monocytes or in a muscle biopsy. A referral is given by a neurologist or a geneticist.

ANO Dysferum (dysferum.com) is an organization founded by a patient with dysferlinopathy. It maintains a patient registry and offers three areas of support: specialist consultations, genetic assistance and legal navigation, including registration of disability status and assistive devices. Contact: info@dysferum.com.

i-Mio Project (i-mio.org) is an interregional organization that helps people with rare genetic neuromuscular diseases. It provides legal support, publishes translations of scientific materials, and runs a forum and a map of neuromuscular medical facilities.