Krabbe disease (KD) is a devastating disease that affects neural development and causes early death. The most common form of KD occurs within the first six months of life and infants usually die by the age of two. Symptoms include being easily irritable, having difficulty in swallowing, muscle stiffness, seizures, cognitive and sensory deterioration. There is no cure and the treatments available only relieve the symptoms temporarily. Recently, deficits in several types of nervous system cells have been reported for KD, including the accumulation of a toxic compound and early cell death. This is due to a defect in a special cell compartment called the lysosome, which degrades unwanted biomolecules by serving as the waste disposal system of the cells. We have generated special cells, called induced pluripotent stem cells (iPSCs), from the skin cells of KD patients, and coaxed them to differentiate into nervous system cells. We propose to study these cells to find out what causes the degeneration and death of KD nervous system cells. Furthermore, these cells will provide a novel, unprecedented platform to screen for new drugs and to test novel treatments developed for KD. We expect our results will not only benefit KD patients, but also be beneficial to patients suffering from other neurological diseases that involve lysosomal defects and neuronal degeneration, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.
Statement of Benefit to California:
Stem cells provide great hope for the treatment of a variety of human diseases, including neurological disorders, which are usually devastating. KD is one such disorder, whose most common form is infantile and KD children usually die by the age of two. This disease is found in all ethnic groups. It is estimated that California has approximately 12% of all US cases of KD, and at present, there is no cure; treatment is primarily supportive and symptomatic. Therefore, there is a real need to understand the underlying mechanisms of this disease in order to develop an effective treatment strategy. At present, the primary defect of this disease is thought to be the deficiency of an enzyme that functions in the lysosomes of cells. Our proposal to establish stem cell-based cellular models for KD could lead to a better understanding of the underlying pathological mechanisms for KD, and to the development of new KD therapies that will have great benefits for Californian health care patients, and also for the Californian pharmaceutical and biotechnology industries. In addition to benefiting KD patients, we expect that our approach and results will also be relevant and translatable to other neurological diseases that have been reported to involve lysosomal defects, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Therefore, our research could meet the need of a broad range of Californians.