Gaucher is a rare disease with high unmet clinical needs that we aim to treat with gene therapy.
Gaucher disease is characterised by the deposition of glucocerebroside in cells of the macrophage/monocyte system caused by a mutation to the GBA1 gene leading to impaired production of the enzyme beta-glucocerebrosidase (GCase). The accumulation of glucocerebroside results in varying clinical features, including enlargement of the liver and spleen (hepatosplenomegaly), a low number of red blood cells (anemia), easy bruising caused by a decrease in blood platelets (thrombocytopenia), lung disease, and bone abnormalities such as bone pain, fractures and arthritis. In some forms of the disease there are neurological symptoms such as muscle rigidity, loss of movement, seizures, cognitive impairment, and vision problems.
Gaucher disease has an incidence of approximately 1 in 40,000 to 1 in 60,000 of all live births; but a higher incidence of 1 in 800 in Ashkenazi Jews. There are three main types of Gaucher disease; Type 1, 2, and 3. Freeline is targeting type one, the most common (90% of all cases) variant. This form of Gaucher disease does not typically involve the brain and spinal cord. In contrast, Type 2 and 3 forms commonly have neurological manifestations that may be difficult to treat or reverse.
Standard treatment and unmet needs
Standard treatments for Gaucher disease are enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). ERT is administered via intravenous infusion biweekly and serves as temporary replacement for the missing/dysfunctional enzymes exhibited by the disease. SRT is taken orally two to three times per day and acts by inhibiting the metabolic pathway of the missing/dysfunctional enzyme to reduce the load on the enzyme and the accumulation of glycosphingolipids. ERT and SRT benefit people living with Gaucher disease, however cyclical symptoms and the inability to address certain symptomatology limit the effectiveness of these treatments. A patient’s quality of life is also impacted through the necessity for weekly or bi-weekly infusions and the manifestation of symptoms.
Gene therapy and Gaucher Disease
Gene therapy is being investigated in preclinical studies for its ability to treat and provide a functional cure for Gaucher disease. The therapy works by delivering a GBA1 gene to the liver to produce the missing enzyme, glucocerebrosidase (GCase). Once GCase is expressed by the liver, released to the circulation and taken up by somatic cells throughout the body it will metabolise glucocerebroside in lysosomes. Replacement of the GBA1 gene prevents the build-up of glucocerebroside and stops the progression of disease, hopefully reversing the effects of this debilitating illness.