Could Batten’s disease be cured by supplementing a drug which promotes lipolysis, since it is caused by an accumulation of lipids in brain?
Batten disease (neuronal ceroid lipofuscinosis, NCS) is a group of diseases caused by errors in the genes encoding for various lysosomal enzymes, which break down or recycle many intracellular substances.
This is taken from the National Institute of Neurological Disorders and Stroke:
Batten disease is an inherited genetic disorder that appears to affect the function of tiny bodies within cells called lysosomes. Lysosomes are the “recycle bin” of the cell and regularly break down waste, proteins, and naturally occurring fatty compounds called lipids into smaller components that can be discarded out of the cell or recycled. Lipids include fatty acids, oils, waxes, and sterols. In Batten disease/NCLs, the mutated genes do not produce the proper amounts of proteins important for lysosomal function. Each gene (representing a form of the disease) provides information for a specific protein that is in turn, defective and not produced. These proteins are needed for brain cells (neurons) and other cells to work efficiently. The lack of a functional protein causes the abnormal buildup of “junk” material in the lysosomes—as well as the abnormal buildup of the residue called lipofuscin that occurs naturally as part of the lysosomal breakdown of lipids. It is not known whether the lipofuscin itself is toxic or if the buildup is a marker of impaired lysosomal function.
So it is not currently known whether the lipofuscin buildup is toxic, or if the clinical features are caused by the lysosomal dysfunction. It may be a complex combination of the two, which is why promoting lipolysis alone may not be beneficial.
What are the therapeutic options?
The current mainstay of therapy is symptomatic management, such as typical anti-epileptic drugs to control seizures.
The only specific treatment available for neuronal ceroid lipofuscinoses (NCLs) is cerliponase alfa (Brineura) for neuronal ceroid lipofuscinosis type 2 (CLN2, also known as tripeptidyl peptidase 1 [TPP1] deficiency).
This is a proenzyme, which is metabolised you an active enzyme that performs the function of the deficient enzyme.
There are several other possible therapeutic targets under research.
One protein of interest is granulin. It is produced from progranulin, which is encoded by the GRN gene. Interestingly, heterozygous mutations are associated with Frontotemporal Dementia, while homozygous mutations are associated with NCS.
This review paper gives a detailed analysis of the current understanding of the many roles of progranulin in embryogenesis, tumorigenesis, inflammation, wound repair, neurodegeneration and lysosome function. It summarises the role of progranulin as a possible therapeutic option, which could be implemented using gene therapy.
This research paper shows that gene therapy to replace deficient progranulin can help improve some of the clinical features, but the research was conducted on mice and not humans.
In summary, the pathogenesis of NCS and associated disorders are complex. Treatment is more complex than simply trying to break down the accumulating lipofuscin. Instead, replacing the deficient enzyme would restore the lost function, instead of just removing the byproduct.