New Insights into Batten Disease Help Inform Treatments Under Development, Review Says

Ana Pena, PhD avatar

by Ana Pena, PhD |

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gene therapy trial update

New research has deepened the understanding of the underlying causes of Batten disease, including organs and cell types affected as well as crucial molecular mechanisms, which can help the design of novel therapies, a review study reports.

Researchers believe these new insights will be key to inform the targeting, timing, and strategies for future treatments.

The study, “Pathomechanisms in the neuronal ceroid lipofuscinoses,” was published in the journal Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease.

Batten disease, also known as neuronal ceroid lipofuscinoses (NCLs), is a group of inherited neurodegenerative disorders that share certain clinical symptoms. The various forms of the disease are caused by different mutations and distinguished in part by the age at which symptoms appear.

All are lysosomal storage disorders (LSDs) characterized by the abnormal accumulation of fatty substances, known as ceroid and lipofuscin, inside cells in compartments called lysosomes, which are responsible for breaking down and recycling cell materials.

This buildup is particularly toxic to nerve cells (neurons) and leads to progressive deterioration of the brain, even though other tissues can also be affected.

Novel clinical and preclinical findings have deepened scientists’ understanding of what causes Batten disease and how these disorders progress over time.

The study reviews these insights, which could facilitate the development of new treatments that target each disease type.

Other organs can be affected, in addition to the brain

Major advances have been made in therapies targeting the central nervous system, or CNS (comprising the brain and spinal cord), but NCLs should be considered diseases “that can affect multiple organ systems, and not just the brain as has been the traditional view,” the researchers wrote.

Evidence shows that multiple organs can be affected, with disease spreading to other body regions depending on disease type. Mapping all the tissues affected will be important to refine therapeutic delivery and timing, the researchers said.

Shrinkage, or atrophy, of the brain, accompanied by enlargement of the lateral ventricles (cavities within the brain filled with cerebrospinal fluid) is a common finding in Batten disease. But as the proteins affected in Batten disease are widely expressed in various tissues and cell types, it is likely that other organs are also affected by these disorders.

Observations in animal models and patients, for instance, suggest that the spine, as well as vision, the heart, and the bowel, are likely affected in multiple NCLs.

Identifying and targeting all organs and tissues involved, which so far have been overlooked, is important and could provide added benefit to treatment approaches for Batten disease, the scientists said.

Some cell types are more susceptible to Batten disease

Specific populations of neurons are more vulnerable to Batten disease. Early in the disease, interneurons — neurons that connect sensory and motor neurons within the CNS — are lost in several regions in the brain. Moreover, a type of neuron involved in controlling motor movement, called Purkinje cells, also seem to be particularly vulnerable.

While the reasons for this are still unclear, the unique biological and electrical properties of these neurons and their greater dependence on lysosomes could explain why they are more vulnerable to Batten disease.

Researchers have also been reconsidering the role played by glial cells, which are cells of the nervous system that provide protection and support to neurons.

Although Batten disease has been considered a disease of neurons, the abnormal accumulation of fatty and proteic substances that mark these disorders occurs in various cell types across the body, in addition to the nervous system.

A growing body of evidence suggests that the activation of astrocytes and microglia — two types of glial cells — precedes and more accurately predicts where neuronal loss is going to occur, when compared to the actual measurement of fatty material accumulation.

In cell models of CLN1 (known as infantile Batten disease) and CLN3 (known as juvenile Batten disease), astrocytes and microglia were seen to cause neuronal loss, which suggests that they have an important role in the development of Batten disease.

There is also evidence for an antibody-mediated immune response in Batten disease, with a possible autoimmune component — a harmful immune response that attacks the body’s own tissues — especially in CLN3.

Other cellular defects may contribute to disease development

In addition to their role in degrading cell waste, lysosomes are involved in other processes such as sensing nutrients and balancing the levels of calcium and metals, as well as the transport and communication between nerve cells.

Likely related to that is the fact that various Batten disease models are characterized by synaptic dysfunction — a malfunction of the synapse, or the junctions between two nerve cells that allow them to communicate.

Other cellular pathways linked to lysosomes — including autophagy (the “self-eating” waste disposal system of cells) and gene activation routes — may also be abnormal in Batten disease and contribute to its development.

This information sheds light on potential mechanisms by which NCL mutations may lead to disease, beyond the role of lysosomes.

Treatment candidates being explored

Various investigational therapies have gone through preclinical tests, including immunomodulatory agents, modulators of lysosomal function, agents that mimic the deficient enzyme in a particular NCL, and inhibitors of glutamate receptor (cell receptors important for transmitting signals between neurons). All these approaches have had “varying degrees of success,” the review stated.

Some medicines have been tested in patients, such as the immunosuppressive agent mycophenolate mofetil, sold under the brand name CellCept, which was evaluated in a Phase 2 study for CLN3 (NCT01399047).

Cystagon, a molecule that mimics PPT1 (the protein deficient in CLN1), has also been clinically tested in a Phase 4 clinical trial (NCT00028262). However, the benefits of both treatments have been only modest in patients.

“This has further highlighted the importance of targeting [disease mechanisms] that are specific to each form of the disease,” the researchers wrote.

They believe that targeting the known common defects in neuroinflammation and autophagy may help to develop add-on therapies “that could greatly improve the therapeutic efficacy as compared to single-therapy strategies.”

Moreover, the discovery of disease manifestations at unexpected sites within or outside the CNS “will necessitate the development of therapies that can be targeted to these tissues successfully,” the researchers wrote.

Defining the timing of disease in these different tissues, in relation to events in the CNS, will provide important information about effective therapeutic windows and is currently informing the design of various gene therapy clinical trials.

These include ongoing Phase 1/2 clinical trials at the Nationwide Children’s Hospital, in Ohio, testing Amicus Therapeutics‘ gene therapies: AAV-CLN6 for CLN6 disease (NCT02725580) and AAV9-CLN3 for CLN3 (NCT03770572).

To evaluate a gene therapy for CLN2, safety and efficacy studies (NCT00151216, NCT01414985, and NCT01161576) are being conducted at Weill Cornell Medical College in New York.