Fusion Protein Strategy Creates Trojan Horse for Future Batten Disease Treatment

Those afflicted with lysosomal storage disorders such as Batten disease may benefit from a clever new treatment strategy one day.

A recent study has demonstrated how to turn a certain antibody into a so-called Trojan horse for ferrying healthy enzymes missing in these disorders across the blood-brain barrier. This technique could be an important step toward better therapies for Batten disease and other related illnesses.

The study, “Bi-functional IgG-lysosomal enzyme fusion proteins for brain drug delivery,” was published recently in the journal Nature.

Also known as neuronal ceroid lipofuscinosis (CLN), Batten disease is a group of rare inherited neurological disorders. They can cause vision loss, progressive motor and cognitive decline, and seizures.

Batten disease is caused by mutations in genes that provide instructions for making lysosomal enzymes, which normally remove cellular waste products. In the case of Batten disease, these waste products accumulate to toxic levels within nerve cells inside the brain.

Lysosomal enzyme disorders often are treated via enzyme replacement therapy (ERT). ERT replaces malfunctioning or absent enzymes by injecting healthy synthetic ones into a patient’s bloodstream.

The enzymes needed to treat Batten and related diseases, however, do not cross the blood-brain barrier (BBB) — a semipermeable membrane that protects the brain from the outside environment. The BBB is a major obstacle for the efficient delivery of certain therapeutics that need to reach the brain and central nervous system.

This severely limits the usefulness of ERT in treating these illnesses. The BBB is highly selective and allows passage of only certain molecules that are recognized by proteins embedded along its surface, akin to locked doors awaiting the right key.

Researchers from Armagen, a biotechnology company dedicated to neurological disorders, created fusion proteins composed of an IgG antibody domain — which crosses the BBB via the insulin receptor — and the active component of palmitoylthioesterase-1 (PPT1), which is mutated in cases of infantile Batten disease, also known as CLN1.

Fusion enzymes have been used to cross the BBB before, but no current fusion enzyme therapy exists to treat Batten disease.

In addition to crossing the BBB, replacement enzymes must remain active and avoid triggering an immune response. The study used a long and flexible amino acid chain to link the two parts of the fusion protein. Of note, amino acids are the building blocks of proteins.

This enabled each part of the fusion to function freely, without interfering with each other. Past efforts had resulted in trade-offs between enzyme activity and access across the BBB. Preliminary results suggest that the current strategy will avoid such a trade-off.

In the past, long synthetic amino acid chains, like that used in this study, have sometimes triggered an immune response. The ArmaGen group expects to avoid this risk by selecting the amino acid chain from an existing human sequence.

Along with the PPT1 enzyme that is mutated in cases of CLN1, the group also made fusion proteins with enzymes relevant to Tay-Sachs disease, Niemann Pick disease type A, and GM1 gangliosidosis. All fusions showed the same potential for crossing the BBB and conserving enzyme activity.

The study shows that several different lysosomal enzymes can be engineered to cross the BBB and remain active. This Trojan horse strategy may make ERT a successful means for treating those suffering from lysosomal storage disorders.