Our approach to genetic medicines

Genetic medicines offer the potential for transformative results

Passage Bio is exploring genetic medicines that work by delivering functional therapeutic genes to patients with diseases where genes are mutated, nonfunctional, or missing. Genetic drug development is especially difficult for neurodegenerative disorders due to challenges in crossing the blood-brain barrier and the potential off-target effects. Our current clinical program utilizes therapies delivered directly to the cerebrospinal fluid (CSF)—a powerful method with the potential for long-term correction of neurodegenerative diseases with a single treatment.

Adeno-associated viruses (AAVs) are the leading platform for gene delivery in the treatment of a variety of neurodegenerative diseases

Remove existing AAV DNA

Therapeutic recombinant AAV (rAAV) vectors are made by first removing all AAV protein coding sequences

Add functional gene expression cassette

This cassette contains the functional therapeutic gene, as well as the regulatory elements necessary for that gene to be expressed

Vector delivers the gene to the target cell nucleus

The functional therapeutic gene is introduced into the target cells

Functional gene is expressed

Once delivered, the new gene may confer stable expression of the new protein, offering effective, long-term disease treatment

In neurodegenerative diseases, we believe AAV-based genetic medicines*:

  • Show promise in hard-to-target organs like the brain
  • Have the ability to penetrate non-dividing or slowly dividing cells like neurons
  • Potentially offer long-term disease treatment with a single administration
  • Likely provide the additional benefit of avoiding neutralizing antibodies (nAbs) when directly administered tothe central nervous system (CNS). nAbs are produced by the body as an immune response from previous exposures to naturally-occurring AAVs and can impede the efficacy of AAV vectors

*There are risks associated with AAV-based therapies.

Passage Bio is dedicated to addressing the underlying pathology of genetically-driven neurodegenerative diseases

upliFT-D icon

upliFT-D is a clinical trial for people that have frontotemporal dementia caused by a mutation in the GRN gene (FTD-GRN). This potential genetic medicine is intended to deliver a functional GRN gene to elevate levels of progranulin (PGRN) in the brain.

Genetic medicine delivery utilizing intra-cisterna magna (ICM) administration

We are using ICM administration for our ongoing clinical development programs to directly target the CNS

In ICM administration:

  • AAVs are delivered directly to the CSF via injection into the cisterna magna, an area outside of the brain near the base of the skull between the cerebellum and medulla
  • There is potential for broad distribution of the therapy throughout the CNS
  • Direct delivery into the CSF reduces the vector doses needed for transgene expression in relevant CNS regions, and lowers the potential for immune response
  • Neuroimaging allows for precise delivery
An arrow pointing towards the ICM