Voyager Therapeutics, Inc. (NASDAQ:VYGR),a clinical-stage gene therapy company developing life-changing treatments for severe diseases of the central nervous system (CNS), today announced the publication of new preclinical data highlighting markedly reduced tau pathology including neurofibrillary tangles and neurodegeneration following treatment with a single dose of an adeno-associated virus (AAV) vector designed to administer a tau monoclonal antibody, PHF1, to the hippocampus of mutant tau transgenic mice. Scientists at Voyager, including Wencheng Liu, Ph.D., and Steven Paul, M.D., president and chief executive officer of Voyager, working in collaboration with colleagues at Weill Cornell Medical College, carried out the study and published the results in a recent issue of the Journal of Neuroscience1.
"Using AAV vectors to deliver monoclonal antibodies directly to the brain represents an innovative approach to potentially treating various neurodegenerative disorders, such as frontotemporal dementia, progressive supranuclear palsy, or Alzheimer's disease, compared with systemically infusing repeated, high doses of antibodies, very little of which actually crosses the blood-brain barrier," said Steven Paul, M.D., president and chief executive officer of Voyager. "With the misfolded pathological tau protein implicated in the progression of several neurodegenerative diseases, we demonstrated that a single injection of an AAV vector to deliver an anti-tau antibody resulted in very high antibody expression in hippocampal and cortical neurons and reduced tau pathology by up to 90% in a robust tauopathy animal model as compared to 40-50% reductions in tau pathology reported by others using weekly, systemic infusions of anti-tau antibodies for several months. One of our ongoing efforts at Voyager, VY-TAU01, employs a similar approach and we are excited to continue to develop this program directed against tau, as well as to explore this approach with other antibodies directed at other misfolded proteins implicated in neurodegenerative disorders."
About the Study and Voyager's Monoclonal Antibody VY-TAU01 Program
In healthy individuals, tau is an abundant soluble cytoplasmic protein that binds to microtubules to promote microtubule stability and function.2,3 In Alzheimer's disease (AD) and other tauopathies, tau aggregates and becomes hyper-phosphorylated, forming insoluble tau-containing neurofibrillary tangles (NFTs).4,5 The progressive spread of tau pathology along distinct anatomical pathways in the brain closely correlates with disease progression and severity in a number of tauopathies, including AD, frontotemporal lobar degeneration (FTD), Pick's disease, progressive supranuclear palsy (PSP), and corticobasal degeneration. Because the extent of tau pathology in AD and other tauopathies closely correlates with the severity of neurodegeneration, synapse loss, and cognitive deficits, attempts to prevent, reduce, or slow the development of tau pathology have become prominent therapeutic strategies for AD and related tauopathies.6,7,8
In previous preclinical studies, despite high, weekly or biweekly infusions of anti-tau monoclonal antibodies (20-45 mg/kg weekly cumulative dose) administered for 3-6 months, only very low levels of antibody reach the brain parenchyma from the systemic circulation resulting in modestly reduced tau pathology of ~40-50%.9,10,11 This incomplete and modest reduction in tau pathology following treatment with very high and frequent systemic doses of these antibodies may pose therapeutic challenges in humans with various tauopathies.
To address these limitations, investigators in this study injected an AAV vector containing a tau monoclonal antibody, PHF1, previously shown to reduce tau pathology following passive immunization.9,11 Stereotactic injections administered bilaterally were administered to the hippocampus of a mutant tau transgenic P301S mouse tauopathy model that develops severe age-dependent tau pathology and neurodegeneration. A single, intracerebral dose of the AAVrh.10-vectored PHF1 antibody resulted in ~50-fold higher level of PHF1 antibody measured in the brain than that observed following a single systemic dose of t...
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