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Voyager Therapeutics Announces New Data in Multiple Presentations at the American Society of Gene and Cell Therapy 2019 Annual Meeting
Voyager’s vectorized antibody program directed against tau demonstrates antibody distribution and expression levels in specific cell types that further facilitate studies with a vectorized antibody in animal models of disease
New TRACER™ system enables the rapid discovery of novel AAV capsids with the potential to penetrate the blood-brain barrier for cell-specific transduction after IV administration
Preclinical updates with VY-SOD102 for ALS-SOD1 support the potential benefit of suppressing SOD1 with a one-time intraparenchymal administration
“One of the major limitations of biologic therapies for the treatment of severe neurodegenerative diseases is the ability of those therapies to cross the blood-brain barrier,” said
Vectorized antibodies directed against tau for the treatment of Alzheimer’s disease
The use of therapeutic antibodies targeting various forms of tau to prevent, reduce, or slow the development of tau pathology is an important potential therapeutic strategy for Alzheimer’s disease and other tauopathies. Because of the blood-brain barrier, only very low levels of antibody distribute to the brain from the systemic circulation after passive immunization, resulting in modestly reduced tau pathology in animal models.
Voyager’s vectorized antibody approach aims to circumvent this limitation by delivering, with a potential one-time intravenous (IV) administration, the genes that encode for the production of therapeutic antibodies utilizing Voyager’s novel blood-brain barrier penetrant AAV capsids. This approach could potentially result in higher levels of therapeutic antibodies in the brain compared with current systemic administration of antibodies.
Oral presentation title: “Cell Specific Transduction of a Vectorized Anti-Tau Antibody Using IV Dosing of a Blood Brain Barrier Penetrant AAV Capsid in Mice”
- In this study, a vectorized antibody consisting of a novel capsid, VOY101, and transgenes encoding an anti-tau antibody and either a cell-specific or ubiquitous promoter was delivered to C57BI/6J wild-type mice.
- This one-time IV administration of the vectorized antibody resulted in high anti-tau antibody distribution in the brain, particularly in the hippocampus, cortex and thalamus, four-weeks post dosing. Specifically, IV dosing using the VOY101 capsid and cell type-specific promoters resulted in anti-tau antibody expression in neurons and astrocytes at levels similar to those achieved with ubiquitous promoters.
- In a previous study conducted by Voyager, anti-tau antibody expression levels in the mouse central nervous system (CNS) after IV dosing of a vectorized antibody with a ubiquitous promoter were at least fifteen-fold higher than levels achieved with passive immunization.
- Results from the current study facilitate the evaluation of cell type-specific versus ubiquitous anti-tau antibody expression on efficacy in animal models of Alzheimer’s disease to help define the target profile for a therapeutic vectorized antibody.
Voyager’s TRACER System for Discovering Novel Gene Therapy Capsids
Robust delivery across the blood-brain barrier is one of the major limitations of current AAV gene therapies for CNS diseases. To address this, Voyager is discovering and developing novel AAV capsids that cross the blood-brain barrier after IV administration with improved transduction of the brain and spinal cord and enhanced cellular specificity. As part of that effort, Voyager scientists have developed a proprietary system called TRACER (Tropism Redirection of AAV by Cell Type-Specific Expression of RNA) to facilitate the selection of AAV capsids with blood-brain barrier crossing and cell-specific transduction properties for particular therapeutic applications.
Oral presentation title: “Targeted In Vivo Bio-Panning of AAV Capsid Libraries Using Cell Type-Specific RNA Expression”
- Voyager’s TRACER system is a broadly-applicable, functional RNA-based AAV capsid screening platform that allows for rapid in vivo evolution of AAV capsids with cell-specific transduction properties in wild-type animals.
- Results presented at this year’s ASGCT provide in vivo proof-of-concept for the TRACER system using libraries under the control of either the neuron-specific synapsin (SYN) promoter or the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter to apply selective pressure for capsid variants that transduce the cell type of interest.
- Multiple capsid variants were identified with up to 1,000-fold improvement of CNS transduction in the mouse over AAV9 following IV administration after three rounds of selection. Voyager scientists are applying the TRACER system towards selecting AAV capsids with improved blood-brain barrier penetrant properties in the non-human primate.
VY-SOD102 for SOD1 ALS
VY-SOD102 is composed of an AAV capsid and a proprietary transgene that harnesses the RNA interference pathway to selectively knock down, or lower, levels of SOD1 mRNA in order to reduce levels of toxic, mutant SOD1 protein in the spinal cord. VY-SOD102 is administered by a novel delivery paradigm comprising a one-time infusion after laminectomy to the cervical region of the spinal cord. Preclinical data previously reported included extensive reductions of SOD1 mRNA throughout the spinal cord of the Göttingen mini-pig, which has a spinal cord similar in length and diameter to the human spinal cord. This novel delivery approach with VY-SOD102 reduced SOD1 mRNA in the spinal cord on average by 70% and 50% in the cervical and thoracic regions, respectively, both regions critical for respiratory function, and by 22% in the lumbar region.
Oral presentation title: “Intraparenchymal Spinal Cord Delivery of AAV Gene Therapy Provides Robust SOD1 Knockdown in Large Mammal Spinal Cord for the Treatment of SOD1-ALS”
- New data at this year’s ASGCT demonstrated functional improvement and extended survival in a transgenic mouse model of ALS-SOD1.
- In G93A mice, intra-lumbar injections of VY-SOD102 delayed median disease onset, reduced median disease duration, and improved survival compared with vehicle control. Improvements in disease onset, disease duration and survival were also accompanied by improved hindlimb function as measured by delay to complete hindlimb paralysis compared with vehicle control.
- These efficacy and pharmacology studies in the G93A mouse model of ALS-SOD1 and Göttingen mini-pigs, respectively, support the use of VY-SOD102 with intraparenchymal spinal cord delivery as a novel approach for the treatment of ALS-SOD1.
- Preclinical pharmacology and toxicology studies are underway to support the potential filing of an investigational new drug (IND) application later this year.
This press release contains forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as “may,” “might,” “will,” “would,” “should,” “expect,” “plan,” “anticipate,” “believe,” “estimate,” “undoubtedly,” “project,” “intend,” “future,” “potential,” or “continue,” and other similar expressions are intended to identify forward-looking statements. For example, all statements Voyager makes regarding the initiation, timing, progress, activities, goals and reporting of results of its preclinical programs and clinical trials and its research and development programs, the potential benefits and future operation of the collaboration agreements with Sanofi Genzyme,
Vice President of Corporate Affairs, Communications and Investor Relations