SCIENCE

Progressing innovative gene therapies to treat neurodegenerative disease

PIPELINE

We are building a pipeline of transformative investigational therapies for neurodegenerative diseases of significant unmet medical need. Our gene therapies target the genetic drivers, modifiers, or pathways of monogenic and complex neurodegenerative diseases. Our neuroanatomy-led approach to viral vector distribution seeks to deliver our therapies to the right place to maximise their potential.

AVB-101

AVB-101 is an investigational, one-time, adeno-associated virus (AAV) gene therapy for patients with Frontotemporal Dementia (FTD) with mutations in the Progranulin (GRN) gene. AVB-101 is designed to slow or arrest disease progression by delivering a functional copy of the GRN gene throughout the central nervous system to restore normal progranulin levels. AVB-101 is administered intrathalamically to facilitate transport of the viral vector and the progranulin protein by exploiting the neuronal networks of the brain to maximise biodistribution.

FRONTOTEMPORAL DEMENTIA

Frontotemporal dementia (FTD) is one of most common forms of dementia in individuals under the age of 65 (second after Alzheimer’s disease). It is characterized by a rapid decline in behavior, executive function and/or language with an average of onset in the mid-50s. Patients experience a change in personality, apathy, loss of empathy, inappropriate social behavior, and disinhibition. Unfortunately, with time, patients require significant supportive care and survive seven to ten years after disease onset. Currently there are no approved medicines for the treatment of frontotemporal dementia.

FTD predominantly affects the frontal and temporal cortices, but with time spreads to other cortical and sub-cortical structures.

Accumulation of protein inclusions of either microtubule associated protein tau (MAPT) or transactive response DNA-binding protein 43 (TDP-43) in neurons and glia characterize FTD cellular pathology. Approximately 30-40% of FTD cases are familial and linked to autosomal dominant mutations in three genes; GRN (progranulin), MAPT (microtubule-associated protein tau), and a GGGGCC hexanucleotide repeat expansion in C9orf72 (chromosome 9 open reading frame 72).

FTD affects 50,000 to 60,000 patients in the U.S. and over 100,000 in the E.U.

AMYOTROPHIC LATERAL SCLEROSIS (or MOTOR NEURON DISEASE)

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig’s disease is a devastating neurodegenerative disease characterized by degeneration of upper and lower motor neurons in the brain and spinal cord, leading to progressive paralysis and death. Unfortunately, patients survive on average 2 – 5 years after their diagnosis.

ALS is the most common adult motor neuron disease, with more than 15,000 patients diagnosed with ALS every year in the US and EU.

ALS and FTD are thought to represent a broad neurodegenerative disease spectrum, displaying significant overlap in genetic drivers, disease mechanisms and pathologies.

REFERENCES

GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 May;18(5):459-480.

Boxer AL, Miller BL. Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord. 2005 Oct-Dec;19 Suppl 1:S3-6

Olney NT, Spina S, Miller BL. Frontotemporal Dementia. Neurol Clin. 2017 May;35(2):339-37

Hogan DB, Jetté N, Fiest KM, Roberts JI, Pearson D, Smith EE, Roach P, Kirk A, Pringsheim T, Maxwell CJ. The Prevalence and Incidence of Frontotemporal Dementia: a Systematic Review. Can J Neurol Sci. 2016 Apr;43 Suppl 1:S96-S109

Rohrer JD, Guerreiro R, Vandrovcova J, Uphill J, Reiman D, Beck J, Isaacs AM, Authier A, Ferrari R, Fox NC, Mackenzie IR, Warren JD, de Silva R, Holton J, Revesz T, Hardy J, Mead S, Rossor MN. The heritability and genetics of frontotemporal lobar degeneration. Neurology. 2009 Nov 3;73(18):1451-6

Abramzon YA, Fratta P, Traynor BJ, Chia R. The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Front Neurosci. 2020 Feb 5;14:42

Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017 Jul;88(7):540-549

REFERENCES

Boxer AL, Miller BL. Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord. 2005 Oct-Dec;19 Suppl 1:S3-6

Olney NT, Spina S, Miller BL. Frontotemporal Dementia. Neurol Clin. 2017 May;35(2):339-37

Abramzon YA, Fratta P, Traynor BJ, Chia R. The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Front Neurosci. 2020 Feb 5;14:42

Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017 Jul;88(7):540-549