What We fight, informative material diseases

 

Among the various research projects, the BRAINS4RARE one is particularly important as it’s focused to increase knowledge in terms of pathophysiological mechanisms and new therapies for lysosomal storage diseases (LSD) and in particular:

Mucopolysaccharides (MPSs) MPSI , MPSI and MPS III, and Niemann Pick type C (NPC).

The project social relevance is supported by the following rationale:

LSDs are the most frequent causes of neurodegeneration in childhood .

The molecular genetics and biochemistry of these diseases are in most cases understood.

newborn screening for LSDs will be available before the end of the next decade, allowing early therapeutic intervention.

Treatments aimed at preventing mental retardation have the best chance of success if performed in very young children, ideally soon after birth.

Mechanisms of neuropathology in LSDs share some pathological features with adult neurodegenerative diseases, progress in LSDs may therefore have relevance to Alzheimer’s or Parkinson’s diseases.

 
Amongst the paediatric neurodegenerative diseases LSDs provided excellent models for developing a further understanding and new approaches for CNS restorative/disease modifying therapies. That’s because the administration of synthetic recombinant enzymes to patients affected by Lysosomal Storage Diseases (LSDs) has shown promising perspectives to change the natural history of diseases and improve the quality of the patient’s life.

Preclinical studies and preliminary results showed that early diagnosis coupled to early treatment (at birth)  might be a potential  way to prevent onset of chronic, irreversible  and therefore permanent symptoms. 

The overall objective of the BRAINS4RARE project is to explore every possibility of developing strategies for the newborn screening of treatable LSDs.

Moreover the project is focused to increase knowledge on the pathophysiological mechanisms leading to the development of neuropathology in LSDs, to stimulate and validate new therapeutic approaches that target the brain, and to facilitate the assessment of treatment efficacy in clinical settings in particular concerning mucopolysaccharidosis (MPS) and Niemann-Pick type C.

The BRAINS4RARE project concerns the following three key areas:

Pathophysiology

Little is known about LSDs pathophysiology. The “storage cytotoxicity theory” which was presented at mid 70’s is now considered the final step of a more complex process involving different cellular compartments.

Only by understanding these processes progress towards a cure/improved therapy of these diseases will be possible, by developing synergistic therapies taking into account and controlling the secondary cascade of events resulting from the primary defect.

Therefore, one of the major aim of this proposal is to deciphering biological and pathophysiological mechanisms responsible of the natural progression and clinical variability of LSDs and consequently and provide new insights into therapy. 

Moreover, considering that the regenerative capacity of the young brain is much greater than that of the older brains affected by most other neurodegenerative diseases, this presumed plasticity can be exploited to a greater extent to restore neurological function when disease progression is halted at an early stage. Therefore, this project will include the development and validation of cellular and molecular therapies aimed at restoring the (effect of the) genetically induced enzymatic defect within the Central Nervous System.

Biomarker discovery

There is currently a lack of appropriate reliable biological markers able to forecast the disease progression and the relevant clinical variability present within a given genotype. This lack impedes the therapeutic decision making process.

Therefore, one of the major aim of this proposal is to identify potential new biomarkers in cerebrospinal fluid and blood using proteomic approaches.

 

Therapy

Most of the LSDs, and in particular the MPSs, especially the MPS III, mainly involve the Central Nervous System with devastating neurological consequences.

At present, therapies are effective only in the periphery but not at the Central Nervous System level. In fact, due to the presence of the Blood-Brain Barrier (BBB) which prevents efficient delivery of corrective therapies to brain parenchyma, none of the (large) therapeutic enzymes currently used in the Enzyme Replacement Therapy are able to reach the brain and modify the course of neurodegeneration in the Central Nervous System.

Therefore, one of the major aim is to design, develop and validate efficient strategies to deliver effective therapy that reverses LSD neurodegeneration to the CNS by molecular and cellular tools as the direct injection of adeno-associated viruses (AAV) vectors carrying the missing enzyme gene in the brain.

Moreover the aim is to understand the target factors that drive disease progression and  clinically study the LSD-induced neurodegeneration and its possible therapeutic reversal

 

Informative material diseases