Neural stem cells derived from people with Batten disease can be used as a “disease model” to evaluate new treatment options for patients, according to researchers.
Infantile neuronal ceroid lipofucinosis (INCL or CLN1) and late infantile NCL (LINCL or CLN2), all types of neuronal ceroid lipofuscinoses (NCLs, or Batten disease), are caused by mutations in the PPT1 and TPP1 genes, respectively.
These genes code for enzymes that are involved in the normal functioning of lysosomes — small vesicles that function as the digestive system of cells.
Enzyme replacement therapy (such as FDA-approved Bineura) is one of the treatment options for Batten disease. But this therapeutic approach is limited by the inability of enzymes to penetrate the blood-brain barrier and reach the brain, and so is delivered in a very invasive manner through a surgically implanted catheter in the head.
As a result, other options like small molecules could become more relevant. To date, there are no approved small-molecule drug treatments for CLN1 (infantile) or CLN2 (late infantile), although small molecules such as δ-tocopherol andhydroxypropyl-β-cyclodextrin (HPBCD) were shown to have potential for the treatment of other lysosomal storage diseases.
To establish a disease model that could be used to develop and assess treatment options for NCLs, researchers from the National Institutes of Health (NIH) generated induced pluripotent stem cells (iPSCs; cells that can be made into almost any cell type) from the cells of patients with either CLN1 or CLN2.
The iPSCs were treated in the laboratory to eventually become neural stem cells containing the NCL-causing mutations. These cells were then used to assess treatment options for both CLN1 and CLN2.
Both patient cells and these laboratory-generated neural stem cells showed lipid accumulation and enlarged lysosomes, features observed in Batten patients.
Importantly, both enzyme replacement and small-molecule therapy approaches (δ-tocopherol and HPBCD) were able to reduce lysosome size in CLN1 and CLN2-derived cells.
“Patient iPSC derived [neural stem cells] are valid cell-based disease models with characteristic disease phenotypes that can be used for study of disease pathophysiology and drug development,” researchers wrote.