The primary cause of FA is a triplet repeat mutation in the FXN gene, which codes for the frataxin protein
Frataxin is a mitochondrial iron-binding protein involved in iron homeostasis. Iron is critical for many essential cellular processes, including energy production. FA is autosomal recessive disorder caused by a defect in both frataxin genes, most commonly due to GAA repeat expansions. This results in abnormally low levels of the frataxin protein and accumulation of intracellular iron. This excess of iron in the heart and brain cells of FA patients promotes the production of toxic reactive oxygen species and leads to mitochondrial damage. This damage ultimately leads to progressive nervous system degeneration, movement problems, and cardiac dysfunction.
Genetics of FA
An increased number of GAA repeats between exon 1 and 2 of the FXN gene cause the disease and are associated with disease severity. Normal FXN has GAA repeat levels ranging from 1 to 43. Mutated FXN has GAA repeat levels ranging from 44 to 1,700.
The following factors contribute to making FA a natural candidate for gene therapy treatment:
Mutations in both copies of the frataxin gene are the cause of disease
Onset and progression of disease directly related to the amount of frataxin protein expressed in cells
Carriers of one normal and one mutated copy of the frataxin gene are clinically normal
All patients express some level of frataxin, thus will not mount an immune response to the therapeutic protein
Delivery of gene therapy to one or more impacted tissues will provide clinical benefit to patients
Proof of concept in animal models suggests viability of gene therapy for treating FA
AVB-202-TT for the treatment of FA:Solid's approach is to target both the neurologic and cardiac impairments experienced by patients with FA.
The gene therapy development candidate AVB-202-TT is designed with a transgene encoding full length frataxin protein packaged into an AAV9 capsid and under control of a universal promoter designed to drive expression of frataxin in the target tissues of disease, especially those of the central nervous system and heart.
We believe that the construct design, along with the planned dual route of administration, provides AVB-202-TT with the potential to be a best-in-class therapy for the treatment of FA.