Gene Replacement Therapy

Most of us have heard the word "gene", but what exactly does it mean?  Genes are the fundamental units of heredity that carry instructions for how our bodies grow, function, and maintain health. We are made of genes and collectively they make us what we are. Half of your genes come from your mother, and the other half come from your father. 

Genes serve a variety of important roles in the body:  

• Some genes produce proteins that form the physical structures of the body—like skin, bones, blood, and organs.

• Others create proteins that tell the body what to do—such as flexing a muscle, growing hair, or digesting food.

• Many genes play indirect roles, such as supporting the immune system, helping blood circulate, or regulating chemical signals.

• Genes also influence traits that make us unique, like eye color, hair texture, skin tone, and even aspects of personality.

In short, genes are the body’s blueprint. When they work as expected, everything functions smoothly. But when a gene is missing or doesn’t function properly, it can lead to serious health conditions.

Gene therapy is a breakthrough approach to treating diseases caused by faulty or missing genes. Some conditions, like Aspartylglucosaminuria (AGU), are present from birth because a gene doesn’t function correctly. Others may arise later in life due to genetic mutations or changes in gene activity. When this happens, the body may not produce essential proteins or enzymes, leading to serious and progressive health problems.

Gene therapy addresses the root cause by delivering a working copy of the gene into the patient’s cells. Once inside, the new gene begins producing the necessary protein or enzyme, potentially restoring lost function and slowing—or even reversing—the disease.

To deliver the gene, scientists use a tool called a vector—often a harmless virus that has been genetically modified to carry the therapeutic gene. For our AGU gene therapy, we use AAV9 (adeno-associated virus serotype 9), one of the most advanced and trusted delivery vectors in the field.

AAV9 has emerged as a leading vector for gene therapy, particularly for diseases that affect the brain and body. It offers several advantages:

• Crosses the Blood-Brain Barrier: AAV9 can reach cells in the central nervous system, which is crucial for treating neurological conditions like AGU.

• Systemic Reach: It also delivers the gene to multiple organs and tissues throughout the body, helping address the disease systemically.

• Long-Term Expression: AAV9 provides stable, long-lasting expression of the gene—often from a single dose.

• Favorable Safety Profile: AAV9 has a low risk of triggering a strong immune response, making it well-suited for clinical use.

AAV9 has already been used successfully in several approved gene therapies, demonstrating its safety and effectiveness:

Zolgensma® (onasemnogene abeparvovec)

• Indication: Spinal Muscular Atrophy (SMA)

• Approval: FDA-approved in 2019

• How it works: Delivers a working copy of the SMN1 gene using AAV9 to restore motor neuron function and prevent progressive muscle weakness in infants.

• Significance: One-time intravenous infusion with life-changing results in a previously fatal condition.

Clinical Trials in Rett Syndrome, Giant Axonal Neuropathy, and Batten Disease

• AAV9 is being used in numerous investigational therapies targeting neurological and lysosomal storage disorders. These trials are showing promise in slowing disease progression and improving quality of life.

Children with AGU lack a functional AGA gene, which prevents their cells from making an essential enzyme that clears cellular waste. Without this enzyme, waste builds up—especially in the brain—causing progressive damage.

Our therapy uses AAV9 to deliver a codon-optimized version of the AGA gene directly to the patient’s cells. This enables the production of the missing enzyme, with the goal of halting the disease’s progression and preserving cognitive and physical function.

Developing gene therapy takes years of work and significant funding. While progressing toward clinical trials, we also supported the development of chaperone therapy, which helps stabilize the remaining enzyme in AGU patients. This has helped slow the disease and keep children healthier as we prepare for the next stage in treatment.