Science

About Gene Therapy

Our foundation is hope

Gene therapies are transformative medicines that hold promise for treating diverse, genetically-driven diseases. Genetic diseases are caused by alterations in genes that result in the defective function or complete absence of important proteins in cells. Gene therapies can help to correct these defects by replacing or modifying the mutated gene(s). The essential components of a gene therapy are:

Gene therapies commonly use viral vectors to transport functional versions of a gene (or gene modifiers) into cells. Viral vectors are engineered viruses that can infect cells and deliver the functional gene without causing diseases themselves. One type of virus used for this purpose are adeno-associated viruses (AAVs), which have been proven to be safe and efficient delivery vehicles for gene therapy. The specific choice of viral vector can influence where in the body the gene therapy has its therapeutic effect.

Genes (or gene modifiers) are the “payloads” of a gene therapy, helping to correct the underlying genetic defect at a molecular level. Genetic constructs are packaged into viral vectors during the manufacturing process and delivered, by those vectors, into the nucleus of cells. There, these genes are expressed into proteins that have the desired therapeutic effect: usually either replacing or somehow repairing, a defective protein. The design of the genetic construct is a critical factor in determining when, where and how well a gene therapy will work.

The selection of the delivery method for a gene therapy is just as important as what viral vector or payload is used. This is because not all cells necessarily need to receive the therapy, and there may in fact be reasons to avoid whole-body exposure. The delivery method is usually tailored to the disease. For example, a musculoskeletal disease may require an intravenous injection to allow viral vectors to access all cells in the body, whereas a central nervous system disorder might need a direct injection of vector into the brain.
Science

Krabbe Disease - FBX-101Our foundation is hope

About Krabbe Disease

Krabbe disease is a rare, pediatric leukodystrophy affecting about 1 in 100,000 people in the U.S. and is inherited in an autosomal recessive manner. Krabbe disease is caused by loss-of-function mutations in the galactosylceramidase (GALC) gene, a lysosomal enzyme responsible for the breakdown of certain types of lipids such as psychosine. Without functional GALC, psychosine accumulates to toxic levels in cells. The psychosine toxicity is most severe in the protective cells surrounding the nerves in the brain and throughout the body (peripheral nervous system), eventually leading to the death of these cells. The progressive neuronal cell death manifest over the course of the disease: initially presenting as mental and physical delays in development, muscle weakness and irritability and advancing rapidly to vision and hearing loss and difficulty swallowing and breathing. Early onset, “Early Infantile”, Krabbe cases usually results in death by age 2, while later onset “Late Infantile” cases have a more variable course of progressive decline1. There is currently no cure for either form of Krabbe disease. 

The current standard of care for early infantile Krabbe disease, hematopoietic stem cell transplant (HSCT), was pioneered by Dr. Maria Escolar2. After HSCT, symptoms of disease have been shown to stabilize by neurological assessment, and survival has improved through correction of the GALC deficiency in the brain. However, HSCT does not effectively correct the GALC deficiency in the peripheral nervous system and as pediatric patients grow, they will progressively lose motor and sensory skills eventually resulting in death3.

About FBX-101

We are developing FBX-101 to treat infantile Krabbe disease, a severe and debilitating disorder caused by mutations in the galactosyceramidase (GALC) gene. FBX-101 is a combination adeno-associated viral (AAV) gene therapy and umbilical cord blood transplant approach that delivers GALC to cells in both the central and peripheral nervous system. FBX-101 has been shown to functionally correct the central and peripheral neuropathy and correct the behavioral impairments associated with Krabbe disease in animal models, and to drastically improve the lifespan of treated animals4. The FBX-101 combination treatment will be administered by intravenous infusion and has the potential to overcome some of the immunological safety challenges of traditional AAV gene therapies.

Refrences

1. Bascou, N., A. DeRenzo, M. D. Poe, and M. L. Escolar. 2018. 'A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life', Orphanet J Rare Dis, 13: 126.

2. Escolar, M. L., M. D. Poe, J. M. Provenzale, K. C. Richards, J. Allison, S. Wood, D. A. Wenger, D. Pietryga, D. Wall, M. Champagne, R. Morse, W. Krivit, and J. Kurtzberg. 2005. 'Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease', N Engl J Med, 352: 2069-81.

3. Wright, M. D., M. D. Poe, A. DeRenzo, S. Haldal, and M. L. Escolar. 2017. 'Developmental outcomes of cord blood transplantation for Krabbe disease: A 15-year study', Neurology, 89: 1365-72.

4, Rafi MA, Rao HZ, Luzi P, et al. Long-term improvements in lifespan and pathology in CNS and PNS after BMT plus one intravenous injection of AAVrh10-GALC in twitcher mice. Mol Ther 2015; 23:1681–1690.