RESEARCH

The BRAINS FOR BRAIN Foundation is an International Task Force formed by outstanding scientists and clinicians leaders in the neurological field, grouped together with Biotech companies to create coordinated and organized research projects aimed at the comprehension and cure of rare genetic diseases that affect and seriously damage the brain, in particular the children’s one.

The Foundation is particularly promoting and coordinating research projects focused on the search of biomarkers for the understanding of pathophysiological process of neurometabolic disorders.

Among the more than 500 types of hereditary metabolic diseases known today, the Foundation mainly focuses its attention on a group of about 40 genetically and biochemically very well characterised diseases, called Lysosomal Storage Disorders (LSDs).

LSDs and The Importance of our Research
LSDs are distinct rare genetic diseases, each one resulting from a deficiency of a particular lysosomal protein or, in a few cases, from non-lysosomal proteins, normally required during the processes of macromolecules breaking down.
Although each LSD results from mutations in a different gene, all LSDs share a common biochemical characteristic consisting in the accumulation of undegraded substrates within lysosomes. Accumulation of undegraded molecules alters the proper cell functioning. This accumulation starts immediately after birth and progressively worsens, often affecting several tissue and organs, including the CNS. CNS pathology typically causes mental retardation and progressive neurodegeneration. Neurodegeneration in particular is in fact the prominent irreversible pathological hallmark of LSDs and it ultimately leads to premature and early death.

LSDs are ideal model in which to study CNS disease since they arise from genetic mutations of a single gene causing a single protein (enzyme) defect responsible for the storage of well characterized cellular toxic compounds. LSDS are therefore especially suitable for investigations that will lead to the development and monitoring of restorative/disease modifying therapies. They are the only group of paediatric neurodegenerative diseases for which therapy that can reverse the natural history of the disease in peripheral organs is available (Enzyme Replacement Therapy, ERT). Unfortunately, ERT is currently unable to effectively reach the CNS to stop the lethal progression of the neurodegeneration. Furthermore, the advanced knowledge of the genetic and biochemical features responsible for the development of neurodegeneration along with excellent animal models in these diseases makes it possible to begin to decipher the cascade of pathological events leading to loss of brain plasticity and mental retardation.

The advanced knowledge of the mechanism of action of LSDs will allow for the elucidation of features of neurodegenerative diseases that will most likely also prove to be useful in the study of the more prevalent neurodegenerative diseases, mostly affecting the elderly (e.g. Alzheimer’s and Parkinson’s disease). For instance, suppressing the primary cause of neurodegeneration (e.g. by supplementing the missing enzyme) in a young brain has the potential to maximise benefit as the brain at this stage of development retains considerable plasticity. Furthermore, secondary events that lead to neurodegeneration (e.g. brain inflammation, alteration of intracellular trafficking, impairment of autophagy, or oxidative stress) are common to both paediatric and adult neurodegenerative diseases. Therefore at least part of the observations relative to loss and recovery of brain plasticity in paediatric neurodegeneration can be extrapolated to adult disorders and will provide unique insights into the pathophysiology and restorative capacities of neurodegenerative diseases in general.