Friedreich’s ataxia (FA) is a rare, inherited progressive genetic neuromuscular disease with high unmet medical need
FA affects the nerves and spinal cord, causing loss of control of body movements (ataxia)
A person with FA
Will usually need a wheelchair within 10 to 20 years of symptoms beginning
May be completely incapacitated in later stages of the disease
May have a shortened life span
Mortality in FA is most commonly due to cardiac complications
59%of FA deaths are from cardiac dysfunction
Only symptomatic treatment options are available, with none addressing the underlying cause of the disease—the defective frataxin gene
FA is the
most common hereditary ataxia
Males and females
are equally affected
One in every 40,000 to 50,000 people have FA
Approximately 9,000 patients
in the United States and ~26,000 patients in the European Union are affected
FA is a multisystem disease
Cardiac
Hypertrophic and dilated cardiomyopathy, arrhythmia, and mortality
Skeletal abnormalities
Scoliosis and pes cavus
Hearing loss
Auditory neuropathy/dyssynchrony and vestibular dysfunction
Endocrine
Diabetes, impaired fasting glucose, and impaired glucose tolerance
Vision
Nystagmus and oculomotor disturbances
Fatigue
Nearly all patients experience significant fatigue that impacts quality of life
FA also shows progressive neurological symptoms
LOSS of balance and coordination
• Progressive gait and balance instability
• Impaired coordination affecting mobility
• Loss of reflexes
• Dysarthria (slurred speech)
LOSS of sensation in the arms and legs
LOSS of vision and hearing
Living with FA
Frataxin
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. However, too little or too much iron can be harmful
The frataxin deficiency associated with FA disrupts iron regulation and mitochondrial function
As a result, cells in the heart and brain accumulate iron, which promotes the production of reactive oxygen species and leads to mitochondrial damage
Genetics of FA
An increased number of GAA repeats between exon 1 and 2 of the FXN gene are implicated with the cause and severity of the disease
The FXN gene is located
on chromosome 9q13-q21.1
Normal FXN has GAA repeat levels ranging from 1 to 43
Mutated FXN has GAA repeat levels ranging from 44 to 1,700
FA is a natural candidate for gene transfer therapy
These factors contribute to making FA a natural candidate for gene therapy treatment
Recessive disease is caused by a single gene
Phenotype is directly related to the amount of frataxin
Carriers are clinically unaffected even with reduced frataxin levels
All patients express some frataxin and no aberrant protein, so the immune system recognizes frataxin as self
Targeting of one or more affected organs will be clinically meaningful
Proof of concept in animal models suggests viability of therapy
AavantiBio’s distinctive approach is to specifically target both the neurological and the cardiac impairments caused by FA
AVB-202 for the treatment of FA
We optimized our gene transfer therapy construct to target the genetic root cause of FA in the tissues most impacted
AVB-202 is being developed with a transgene to encode full-length frataxin protein (210 amino acids) packaged into an AAV9 capsid under the control of a promoter specifically designed to drive expression in neurons and cardiac cells and target the neurological and cardiac manifestations of FA
The AVB-202 construct combined with a dual route of administration and our novel immunomodulatory strategy optimizes the safety, efficacy, and potential for AVB-202 to be best in class in FA
References
1. Cnop M, et al. J Neurochem. 2013;126(Suppl 1):94-102. 2. Cook A, Giunti P. Br Med Bull. 2017;124(1):19-30. 3. Dürr A, et al. N Engl J Med. 1996;335(16):1169-1175. 4. European Medicines Agency. EU/3/18/2037: Public summary of opinion on orphan designation: Omaveloxolone for treatment of Friedreich’s ataxia. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3182037. Accessed December 16, 2020. 5. Koeppen AH. J Neurol Sci. 2011;303(1-2):1-12. 6. Llorens JV, et al. Front Neurosci. 2019;13:75. 7. National Institute of Neurological Disorders and Stroke. Friedreich’s Ataxia Fact Sheet. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Friedreichs-Ataxia-Fact-Sheet. Accessed December 14, 2020. 8. National Organization for Rare Disorders. Friedreich’s Ataxia. https://rarediseases.org/rare-diseases/friedreichs-ataxia/. Accessed November 4, 2020. 9. Parkinson MH, et al. J Neurochem. 2013;126(Suppl 1):103-117. 10. Ruano L, et al. Neuroepidemiology. 2014;42(3):174-183. 11. Sandi C, et al. Front Genet. 2014;5:165. 12. Santos R, et al. Antioxid Redox Signal. 2010;13(5):651-690. 13. Schmucker S, Puccio H. Hum Mol Genet. 2010;19(R1):R103-R110. 14. Tsou AY, et al. J Neurol Sci. 2011;307(1-2):46-49.
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