Neurodegenerative mechanisms and therapy of lysosomal diseases
Alessandro Fraldi is currently Associate Professor of Histology, at Department of Clinical Medicine, University of Naples "Federico II'. He is also Faculty Member of the European School of Molecular Medicine (SEMM).
From 2004 to 2011, he trained as postdoc at Telethon Institute of Genetics and Medicine (TIGEM) in Naples and Lysosomal Disease Research Unit” Woman’s and Children’s Hospital, Adelaide, Australia. From 2012 to 2020 he has been Faculty and Investigator (Molecular Therapy Program) at TIGEM. In 2021 he moved to CEINGE, where he is currently Principal Investigator.
Dr. Fraldi has a long-standing interest in lysosomal storage diseases. His research is focused both on the study of mechanisms underlying neurodegeneration and on the development of therapeutic strategies.
He is author or more than 40 original peer-reviewed articles published in top international journals including EMBO Molecular Medicine, Molecular Therapy, Developmental Cell and EMBO Journal. His research is currently funded by Sanfilippo Children’s Foundation, Cure Sanfilippo Foundation, Orphan Disease Center (Penn University) and Telethon Foundation for rare diseases.
Dr. Fraldi is co-founder and Board of Directors member of SupraThera I.n.c. a startup aimed at developing new therapies for neurodegenerative diseases based on the use of novel anti-amyloid drugs.
Over the years Dr. Fraldi have accumulated experience in the study of lysosomal storage diseases (LSDs), a group of inherited metabolic conditions characterized by lysosomal dysfunction and severe neurological involvement. Dr. Fraldi’s research is mainly focused on dissecting molecular determinants of neurodegenerative processes in LSD and in the development of innovative strategies to treat the neurological aspects in these severe disorders.
Lysosomal dysfunction and protein aggregation in neurodegeneration
Dysfunction of autophagy-lysosomal pathway represents a crucial player in neurodegenerative processes, particularly in those occurring in LSDs. Recently, by studying mouse models of mucopolysaccharidoses (MPS), a family of LSD caused by inherited deficiency of lysosomal enzymes required for degradation of GAGs, we discovered that progressive deposition of multiple amyloid proteins in neuronal cells is a major factor triggering autophagy impairment. Our data opens new avenues both in the study of mechanisms linking protein aggregation and autophagy and in development of new therapies for MPS based on inhibiting protein aggregation.
Developing innovative therapeutic strategies for the treatment of brain pathology in mucopolysaccharidoses.
A research line in Dr. Fraldi’s lab is focused on developing new therapeutic approaches to treat the CNS in LSD (particularly in the MPS) based on the use of either adeno-associated viral (AAV) vectors or lipid nanoparticles to transfer the therapeutic gene or the mRNA to the CNS and on the delivery of small molecules capable to target key neurodegenerative processes
Identification of new biomarkers for monitoring neurodegeneration in mucopolysaccharidoses
A further line of research in Dr. Fraldi's laboratory is focused on the identification of new non-invasive biomarkers useful for monitoring neurodegenerative processes in mucopolysaccharidoses. The discovery, characterization and validation of these biomarkers may greatly facilitate clinical trials and clinical practice for neuronopathic MPS.
- Giaccio M, Monaco A, Galiano L, Parente A, Borzacchiello L, Rubino R, Klärner F-G, Killa D, Perna C, Piccolo P, Marotta M. Pan X, Khijniak M, Siddique I, Schrader T, Pshezhetsky AV, Sorrentino NC, Bitan G and Fraldi A*. Anti-amyloid treatment is broadly effective in neuronopathic mucopolysaccharidoses and synergizes with gene therapy in MPS-IIIA. Molecular Therapy 2024. Nov 6;32(11):4108-4121. doi: 10.1016/j.ymthe.2024.09.030 *
- Monaco A, Maffia V, Sorrentino NC, Sambri I, Ezhova Y, Giuliano T, Cacace V, Nusco E, De Risi M, De Leonibus E, Schrader, T, Klärner FG, Bitan G, Fraldi A*. The amyloid inhibitor CLR01 relieves autophagy and ameliorates neuropathology in a severe lysosomal storage disease. Molecular Therapy, 2020. Apr 8;28(4):1167-1176. doi:10.1016/j.ymthe.2020.02.005
- Sambri I, D’Alessio R, Ezhova Y, Giuliano T, Sorrentino NC, Cacace V, De Risi M, Cataldi M, Annunziato L, De Leonibus E and Fraldi, A*. Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases. EMBO Molecular Medicine, 2017. 9, 112-132 -cover highlight-
- Fraldi A*, Klein AD, Medina DL, Settembre C. Brain Disorders Due to Lysosomal Dysfunction. Annu Rev Neurosci. 2016 Jul 8;39:277-95. *corresponding author
- Sorrentino NC, D’Orsi L, Monaco C, Nusco E, Sambri I, Spampanato C, Polishhuck EV, Saccone P, De Leonibus E, Ballabio A, Fraldi A*. A highly secreted sulfamidase engineered to cross the blood-brain barrier corrects the CNS pathology of mice with mucopolysaccharidoses type IIIA. EMBO Molecular Medicine, 2013 May; 5(5):675-90