OUR VIEWS Ideas & Insights

Our second wave: How tag technology is driving exciting preclinical results in Pompe disease research

Senior Director, Gene Therapy

Niek van Til, Ph.D. | Senior Director, Gene Therapy

At AVROBIO, we’ve been highly strategic in selecting our second wave of programs for our leading lentiviral gene therapy pipeline. We’re targeting three devastating lysosomal disorders in this next wave – Pompe disease, Hunter syndrome and Gaucher disease type 3 – each of which impacts multiple organ systems throughout the body and is marked by severe cognitive or neurological symptoms that are untouched by current treatments.

We believe our investigational lentiviral gene therapies have the potential to deliver a comprehensive, single-dose treatment that would leap forward care. Why? Because we carefully select diseases that have the potential to be helped by the features of lentiviral gene therapy. In these diseases, we believe what’s required is lifelong, durable delivery of an active protein throughout the body, including the brain and spinal cord.

One reason we’re confident in our potential to address these specific indications is our proprietary tag technology. Tags aid in the uptake of the therapeutic protein not just into target tissues, but also the lysosomes of target cells. They serve as “first-class tickets” with the potential to reach key tissues that are otherwise hard to access, such as muscle and the central nervous system (CNS).

At this month’s WORLDSymposium™ 2021, a leading annual scientific meeting dedicated to lysosomal disorders, I presented preclinical research from our Pompe disease investigational lentiviral gene therapy program. Pompe disease is a rare, progressive and often fatal neuromuscular disorder that is caused by mutations in the acid alpha-glucosidase gene, which results in deficient enzyme activity and leads to accumulation of glycogen in tissues and organs, predominantly in muscles.

These preclinical data suggest our tag technology may allow us to address diseases like Pompe that we believe are otherwise beyond the reach of existing conventional gene therapies. In the below graph, we highlight the stark difference in the performance of our “tagged” gene therapy compared to a “non-tagged” gene therapy in infantile-onset Pompe disease mice. Four months after infusion, our tagged gene therapy reduced glycogen accumulation in the brain by more than 99%.

Preclinical Data: Glycogen Reduction in the Brain

LV GT: Lentiviral Gene Therapy w/o GILT tag; GILT: Glycosylation-Independent Lysosomal Targeting; PAS: Periodic Acid-Schiff; IHC: Immunohistochemistry

The tags also appear to effectively deliver active protein – and therefore reduce toxic substrate – in organs beyond the brain. Again, our preclinical research showed that, in a Pompe mouse model, our investigational GILT-tagged gene therapy reduced glycogen accumulation by more than 97 to 99 percent in tissues including the spinal cord, heart and diaphragm, and by more than 85 percent in the skeletal muscle. What gets me excited here is that the one-two punch of lentiviral gene therapy with a tag engineered into the construct allows us to target diseases that we believe are otherwise not amenable to standard gene therapy approaches.

While still early, these preclinical data support our belief in the potential of our tag technology. We have an incredible sense of urgency because Pompe disease patients and the broader lysosomal disorder community don’t have time to wait for better treatment options, and we’re committed to meeting this challenge with help from our tag technology and other tools in our plato® gene therapy toolbox.