Gene Therapy for Inherited Genetic Disease

A wide range of inherited genetic disorders could potentially be cured based on long term genetic correction/replacement of defective gene. This key requirement for long term gene expression is currently being addressed by a limited repertoire of integrative gene transfer vectors. In selective instances, gene therapy cures have been achieved in humans. These dramatic gene therapy successes have catalyzed strong interest and investment by Big Pharm.

Gene Therapy Vectors for Long Term Correction

Current Approaches

Successful gene therapy interventions have employed integrative vectors such as AAV and lentivirus. These vectors have significant commercial disadvantages vis-à-vis upscaling and production. In addition, the potential for random integration in host chromosome represents a major safety concern.

A New Paradigm

Adenovirus has useful properties regarding upscale and production commensurate with pharmacologic manufacture. Adenovirus is a well characterized viral vector with established safety profile in humans. Adenovirus co-delivery of therapeutic gene and CRISPR/Cas9 allows targeted integration at safe harbor loci in host chromosome.

Gene Therapy for Inherited Genetic Disease

Target Product Profile: Adenoviral Vector to Accomplish Long-Term Correction of Inherited Alpha1-Antitrypsin Deficiency Lung Disease

Inherited deficiency of serum anti-protease alpha1-antitrypsin (AAT) is associated with premature emphysema/death. A range of commercial AAT protein replacement products have been developed for AAT deficiency lung disease. AAT deficiency considered ideal gene therapy target, however, current strategies have not achieved adequate AAT serum levels or duration

Unique Advantage

Adenovirus Can Achieve Greatly Augmented Serum Levels AAT

Clinical studies have defined key threshold level of serum AAT to realize effective lung protection. AAV vector strategies evaluated to date have not achieved corrective levels of serum AAT. Adenovirus achieves unparalleled in vivo gene delivery to accomplish effective AAT levels.

Adenovirus-CRISPR/Cas9 Can Achieve Targeted Integration of Therapeutic Gene at Safe Harbor Locus

Available vectors for AAT gene therapy integrate therapeutic gene in host chromosome in random manner. Ad-mediated co-delivery of CRISPR/Cas allows integration of therapeutic gene at defined “safe harbor” in host chromosome. This strategy provides greatly improved margin of safety.

Technology Validation

AAT Gene Therapy – Developmental Plan

Lead indication – AAT deficiency lung disease.Established precedents – human clinical gene therapy trials for AAT deficiency lung disease with AAV. PI’s established credentials in leveraged NIH/FDA support for translational development. PI’s established credentials in successful translational development novel adenoviral agents.

Precision Virologics, Inc. – Intellectual Property

  • “In vivo editing with adenoviral vectors”
  • PCT filed May 2017
  • National phase planned November 2018

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