AAVantgarde has two proprietary AAV-based large gene delivery platforms. The first leveraging DNA recombination, named dual hybrid; and the second, a protein trans-splicing, named AAV intein. The company is validating the platforms in two lead programs in Ophthalmology with a high unmet need: Usher Syndrome Type 1B associated retinitis pigmentosa (Usher1B), using the dual hybrid platform; and Stargardt disease, using our AAV intein-mediated platform.
AAV gene therapy has been limited by transgene capacity, and the Company’s platforms enable delivery of large genes to tissue and cells in vivo; something that could be extended into many different disease areas.
- Disease Summary: USH1B is the most prevalent form of Usher type 1 and is an autosomal recessive genetic disorder due to mutations in the MYO7A gene characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP) that results in loss of night vision (by pre-pubertal age) and of side (peripheral) vision (severe by midlife).
- Prevalence: USH1B affects approximately 1:50,000 people.
- Unmet need: With the progressive loss of vision and no existing treatment options, USH1B's ocular manifestations represent a significant unmet need.
MYO7A gene mutations cause USH1B syndrome characterized by rod & cone degeneration
In the retina, MYO7A has been detected in the retinal pigment epithelium (RPE) and the photoreceptor cells. The majority of the protein is found in the RPE, where it localizes in the apical region (Hasson et al. 1995; Liu et al. 1997). In the photoreceptors, MYO7A is localized to the connecting cilium and periciliary region (Liu et al. 1997; Williams 2008).
MYO7A has been shown to be a functional actin-based motor (Udovichenko et al. 2002). The most obvious defect due to MYO7A deficiency is mislocalization of melanosomes in the RPE (Liu et al. 1998). Without MYO7A, the melanosomes are unable to move along actin filaments, and are thus absent from the apical RPE (Futter et al. 2004; Gibbs et al. 2004; Klomp et al. 2007; Lopes et al. 2007). The consequences of mislocalized melanosomes are not clear and might result in abnormal light absorption.
MYO7A also participates in the transport of rhodopsin from rod inner to outer segments (Dhooge P., et. al. 2020). MYO7A deficiency causes a delayed transport of rhodopsin through the connecting cilium, which negatively impacts on light conversion into electrical signal.
Both melanosomes and rhodopsin transport and proper localization are necessary for normal vision.
Dual hybrid AAV8 vectors improve the retinal phenotype in a mouse model of USH1B
- Disease Summary: STGD is the most prevalent inherited macular dystrophy and is an autosomal recessive genetic disorder due to mutations in the ABCA4 gene characterized by progressive loss of central vision starting from childhood or adolescence, leading to profound vision loss. It is the most common form of inherited juvenile macular degeneration.
- Prevalence: STGD disease affects approximately 1:6,500 people.
- Unmet need: high unmet need as there are no therapies currently available.
ABCA4 gene mutations cause STGD disease, characterized by degeneration of photoreceptors in the macula
ABCA4 is preferentially expressed in photoreceptors. Mutations in the ABCA4 gene lead to accumulation of toxic lipofuscin, a non-degradable visual pigment derivative. Lipofuscin accumulation leads to cell atrophy and vision loss observed in the macula of Stargardt patients.