Can Gene Therapy Treat Tay-Sachs Disease?

Tay-Sachs disease is a rare genetic disorder that progressively destroys nerve cells in the brain and spinal cord, with its most severe form affecting infants. As symptoms appear in early infancy and lead to a rapid decline in health, the condition is particularly devastating. Gene therapy has emerged as a promising avenue of research, offering the potential to treat the root cause of Tay-Sachs. This approach seeks to correct the genetic defect responsible for the disease.

Understanding Tay-Sachs Disease

Tay-Sachs disease is an inherited lysosomal storage disorder stemming from mutations in the HEXA gene on chromosome 15. This gene holds the instructions for making part of an enzyme called beta-hexosaminidase A. Without a functional version of this enzyme, the body cannot break down a fatty substance known as GM2 ganglioside.

The accumulation of GM2 ganglioside to toxic levels occurs primarily in the neurons of the brain and spinal cord. This buildup leads to the progressive destruction of these nerve cells, which drives the disease’s severe symptoms.

In the most common infantile form, a baby may appear to develop normally for the first few months before symptoms emerge. Parents might first notice an exaggerated startle response to noise, followed by a loss of motor skills, muscle weakness, and floppiness.

As the disease advances, children may experience seizures, difficulty swallowing, and a loss of vision and hearing. A characteristic sign is a cherry-red spot in the back of the eyes. Currently, there is no cure, and medical care focuses on palliative support to manage symptoms.

Gene Therapy: A Primer

Gene therapy is a medical approach that treats or prevents disease by addressing the underlying genetic problem. Its goal is to correct a faulty gene by replacing it with a healthy copy, inactivating it, or adding a new gene to the body.

Delivering new genetic material into cells relies on a carrier, known as a vector. Viruses like adeno-associated viruses (AAVs) are often used because of their ability to enter cells. In the lab, these viruses are modified to remove their own genes and are loaded with the therapeutic human gene.

Gene therapy can be administered through an in vivo approach, where the vector is injected directly into the patient. An alternative ex vivo method involves removing a patient’s cells, modifying them in a lab, and then returning the treated cells to the patient.

Targeting Tay-Sachs with Gene Therapy

The strategy for applying gene therapy to Tay-Sachs is to provide the body with a functional copy of the HEXA gene. This enables affected neurons in the central nervous system (CNS) to produce the missing beta-hexosaminidase A enzyme. Restoring enzyme function would allow cells to break down the harmful GM2 ganglioside, potentially halting the disease’s neurodegeneration.

A hurdle in treating neurological disorders is the blood-brain barrier, which prevents many substances from entering the brain. To overcome this, researchers use specific AAV vectors, like AAV9, that can cross this barrier and deliver genes to neurons throughout the brain and spinal cord.

Administration of the vector is a key part of the strategy. One method is a one-time intravenous (IV) infusion, allowing the vector to circulate and reach the CNS. Another approach is direct delivery via an intrathecal injection into the spinal canal or an intracerebroventricular injection into the brain’s ventricles.

Current Research and Clinical Trials

Preclinical research in animal models was foundational to developing a gene therapy for Tay-Sachs. These studies showed that delivering a functional HEXA gene could increase enzyme levels, reduce GM2 ganglioside storage, and improve neurological function and survival. These results paved the way for human clinical trials.

Several early-phase clinical trials are now underway to evaluate the safety and efficacy of this approach in children. These Phase I or I/II trials focus on assessing safety and determining the correct dosage. Sponsoring institutions include academic medical centers and biotechnology companies.

The trials enroll children with infantile and sometimes juvenile-onset forms of the disease. Researchers monitor participants for adverse effects and measure biological markers, such as beta-hexosaminidase A enzyme activity in the blood and cerebrospinal fluid. This indicates if the delivered gene is working as intended.

Investigators also track brain imaging changes and assess developmental progress over time. Preliminary reports suggest the therapy is well-tolerated and can increase enzyme production, leading to some positive clinical outcomes. More data is needed to understand the long-term effects of this active area of investigation.

Key Considerations in Therapeutic Development

Developing a gene therapy for Tay-Sachs involves several considerations:

• Achieving sufficient delivery of the gene vector throughout the central nervous system to ensure enough neurons produce the enzyme.
• Managing potential immune system reactions to the AAV vector or the new beta-hexosaminidase A enzyme.
• Confirming the long-term durability of the treatment, so the gene continues to express the enzyme for years.
• Determining the optimal time to intervene, especially in the rapidly progressing infantile form of the disease.
• Overcoming the intricate manufacturing process for clinical-grade vectors and scaling production to meet future demand.