Gene Therapy

Batten disease, also known as neuronal ceroid lipofuscinoses (NCL) is a rare inherited neurodegenerative disorder. The disease affects lysosomes, small compartments in the cell that degrade components that are no longer needed.

There is no cure for Batten disease and treatments available focus on symptom relief.

Gene therapy is a therapeutic approach that is being researched for several genetic conditions,  including Batten disease.

How gene therapy for Batten disease works

Batten disease is an autosomal recessive disorder. This means it only develops if a person inherits two copies of a faulty gene causing the disease, one from each parent. Most gene mutations in Batten disease result in the production of non-functional proteins, or proteins with decreased function.

The idea of gene therapy is to deliver an intact, healthy version of the mutated gene to cells to restore normal function. Viruses are specialized in delivering their genetic material to a cell and in forcing the cell to make the proteins based on the genetic information the virus carries. Gene therapy makes use of the viral capacity to deliver genes into a cell. The virus is not harmful to the body because all its disease-causing parts are removed and replaced by a gene that has a therapeutic effect.

In Batten disease, lentiviral and adeno-associated viral (AAV) particles are commonly used. The genetic material of AAVs is delivered into the nucleus of the cell, where it is used to make proteins like any other active gene in the cell. It does not, however, integrate into the cell’s DNA, which means that genes delivered by AAVs are not replicated before the cell divides. In Batten disease, AAVs are commonly delivered into non-dividing neurons of the central nervous system (CNS). As a result, the delivered gene is maintained for a relatively long time, and frequent injections are not necessary.

Most of the lysosomal enzymes that are mutated in Batten disease are soluble proteins. Soluble proteins can be secreted by cells and taken up by neighboring cells. This facilitates gene therapy because even a small number of cells that receive the virally delivered gene will pass the gene product onto many other cells. This also reduces the number of injections necessary to deliver the therapeutic gene.

Genes that encode for transmembrane proteins, which are proteins that are anchored to the cell membrane, also sometimes can be mutated in Batten disease. Transmembrane proteins are not soluble, and gene therapy for these is more challenging. It is possible, but the therapeutic gene needs to be delivered to a much larger number of cells.

Gene therapy in clinical trials for Batten disease

A Phase 1 clinical trial (NCT00151216) is assessing the safety of delivering the TPP1 gene, which is mutated in a form of Batten disease known as CLN2 disease, to 10 patients. The trial is active, but no longer recruiting participants. Results so far have shown that neurological decline was reduced in patients who received the gene therapy compared to controls, suggesting that the approach has the potential to delay disease progression in Batten disease.

A Phase 1/2, non-randomized, open-label clinical trial (NCT01414985) at the Weill Cornell Medical College in New York is assessing the effect of gene therapy in eight children with late infantile Batten disease. The trial is expected to be completed in December 2022.

Another Phase 1, non-randomized, open-label trial (NCT01161576) is assessing the safety of a gene transfer vector called Rh.10 in 25 children with late infantile Batten disease. The study is expected to be completed in August 2032.

A Phase 1/2 clinical trial (NCT02725580) is currently recruiting patients with late infantile Batten disease carrying a mutation in the CLN6 gene. The study will take place at Nationwide Children’s Hospital in Ohio. Participants will receive a single dose of AAV carrying the healthy CLN6 gene, and will be monitored for two years.

The pharmaceutical company Abeona Therapeutics is developing two additional gene therapy approaches to treat Batten disease. ABO-202 is designed to treat a type of Batten disease called CLN1 disease and ABO-201 is designed to treat CLN3 disease. These gene therapies are still in early stages of development and not yet in clinical trial stage. However, they both received orphan drug designation from the U.S. Food and Drug Administration (FDA), which will speed their clinical development.

Drawbacks of gene therapy

A significant problem with viral gene delivery is the patients’ immune response, which attacks the virus carrying the healthy copy of the gene, as it is foreign to the body. This can lead to reduced gene delivery and can cause negative effects. The immune system also can target the newly made protein that the healthy gene encodes for since the body has never encountered such a protein before.

Another problem is gene delivery into the brain. The blood-brain barrier regulates the entry of substances into the brain, and viral vectors have to be injected directly into the brain. Because of the large size of the brain, injections at multiple sites are necessary. But repeated injections into the brain can cause damage. Mannitol, a sugar alcohol, disrupts the blood-brain barrier. After mannitol administration in mice, viral vectors have been successfully delivered by injection into arteries leading to the brain. This approach could be an option to increase the effectiveness of gene therapy, but needs further research.


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