The Telethon Institute of Genetics and Medicine (TIGEM) was founded in 1994 by the Telethon Foundation, one of Italy's leading non-profit organizations, to promote research aimed at diagnosing, preventing and curing human genetic diseases. TIGEM invited world-renowned geneticist Andrea Ballabio, then on faculty at Baylor College of Medicine, to lead the new endeavor. The longstanding relationships between faculty at BCM and TIGEM underpin the new, formal collaboration centered at the NRI: the complementary expertise enjoyed by NRI and TIGEM in lysosomal biology, molecular genetics, cell biology, biochemistry, physiology, bioinformatics, systems biology and viral-mediated gene delivery will allow the collaborators to utilize a variety of animal models (mouse and fruit flies) of human diseases to test discoveries in living organisms before proceeding to clinical trials. Close interactions, the free exchange of data and ideas as well as researchers, and collaborative funding will accelerate progress in developing innovative therapies. The preliminary results in animal models of lysosomal storage disorders are already proving very promising.
Below are the faculty at TIGEM and NRI who are cooperating in this lysosomal storage research project:
Alberto Auricchio (Investigator, TIGEM)
Dr. Auricchio's expertise is in gene therapy, specifically the development and use of Adeno-Associated Virus (AAV)-mediated gene transfer as therapeutic strategy for eye diseases and for inborn errors of metabolism. The Auricchio group has been involved in proof-of-principle gene delivery studies for Mucopolysaccharidosis type VI (MPS VI), a lysososomal storage disease caused by deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B, ARSB) the clinical manifestations of which include complex bone and cartilage abnormalities, corneal opacities, hepatosplenomegaly, and heart valve defects. Dr. Auricchio also runs an AAV core facility for production of viral vectors that are ideal tools both for in vivo functional studies and for gene therapy in human patients. AAV production and use will be a primary resource for the TIGEM-NRI program.
Andrea Ballabio (Director, TIGEM and Investigator, NRI)
Dr. Ballabio is widely acknowledged to be a world leader in the elucidation of the mechanisms of human genetic diseases. Dr. Ballabio's group identified the "master gene," TFEB, which regulates the expression of the CLEAR network in lysosomes. His group has shown that overexpression of TFEB in cultured cells and in murine models enhances lysosomal biogenesis, activates autophagy, and induces lysosomal exocytosis, all of which results in the efficient clearance of glycosaminoglycans, known to accumulate in lysosomal storage diseases, as well as toxic substrates such as the protein responsible for Huntington's disease. The next steps are to develop tools to modulate cellular clearance by acting on the CLEAR network and to use them to treat human diseases. The TIGEM-NRI program will be instrumental in meeting these challenges.
Hugo Bellen (Investigator, Howard Hughes Medical Institute and NRI)
Dr. Bellen's lab employs the fruit fly Drosophila to dissect the molecular mechanisms by which neurons maintain their integrity. Currently the Bellen lab is studying the role of the lysosomal degradation pathway in neuronal health by generating fly models for lysosomal storage diseases and testing rationally designed therapeutic strategies. They are also applying forward genetic screens to isolate mutants that display neurodegenerative phenotypes and defective lysosomal degradation. Their goal is to identify new players in the lysosomal degradation pathway and understand their roles. These studies should not only yield insight into the link between lysosomes and various neurodegenerative phenotypes but also provide excellent animal models in which to test therapeutic strategies.
Juan Botas (Investigator, NRI)
The goal of Dr. Botas' research is to discover either shared or disease-specific therapeutic targets for Alzheimer's, Huntington's and other less common neurodegenerative disorders such as the spinocerebellar ataxias. Dr. Botas' group is systematically testing all genes in the genome to reveal pathogenic mechanisms and identify therapeutic targets for all these disorders. Genes involved in autophagy are of particular interest in this context. The ‘whole genome' approach is possible only because of the development of Drosophila models of these disorders that recapitulate key features of these diseases (late onset, progressive behavioral deficits and disease-specific pathology). In addition to the whole genome modifier screens, the Botas lab is developing transcriptomic (RNA-seq) and metabolomic (NMR and MS) signatures for comparative analysis of disease mechanisms and for data integration with modifier gene datasets.
Nicola Brunetti-Pierri (Investigator, TIGEM)
The therapies currently available for the lysosomal storage disorders are quite limited, particularly in addressing the neurological aspects of these diseases. Dr. Brunetti-Pierri's group is exploring gene therapy strategies based on helper-dependent adenoviral (HDAd) vectors to correct such manifestations. HDAd vectors are devoid of all viral coding sequences and are safer than first-generation adenoviral vectors. They are attractive for brain-directed gene therapy because they efficiently transduce quiescent cells such as neurons. Recent data from Dr. Brunetti-Pierri's laboratory have shown that HDAd delivered by intrathecal injection results in extensive transduction and long-term transgene expression in neuroependymal cells and neurons. This approach could provide an effective strategy for treating the diffuse cerebral involvement in lysosomal storage diseases: the extensively transduced neuroependymal cells secrete lysosomal enzymes, which diffuse throughout the brain through the cerebrospinal fluid circulation and then penetrate affected brain cells through the mannose 6-phosphate receptor. Dr. Brunetti-Pierri's group is also involved in preclinical studies for liver-directed AAV-mediated gene therapy of mucopolysaccharidosis type II caused by deficiency of the iduronate sulfatase (IDS) enzyme. Their studies in non-human primates have shown long-term, high levels of serum enzyme following intravenous injection of a serotype 8 AAV, driving the expression of the IDS gene under the control of a liver-specific promoter. These studies will pave the way for gene therapy clinical trials for lysosomal storage diseases.
Giancarlo Parenti (Investigator, TIGEM)
Dr. Parenti's research is focused on the development of novel therapies (alternative or complementary to enzyme replacement) to treat patients affected by Pompe disease, an autosomal recessive metabolic myopathy due to a deficiency in the lysosomal hydrolase alpha-glucosidase. His group has demonstrated that two small-molecule therapeutic agents, the imino sugars deoxynojirimycin and N-butyldeoxynojirimycin, have a chaperone effect in fibroblasts from patients with Pompe disease and improve enzyme activity, maturation, stability and lysosomal trafficking of mutant alpha-glucosidase. A similar effect has also been demonstrated both in vitro and in vivo on the wild-type recombinant alpha-glucosidase approved for enzyme replacement therapy of Pompe disease. These results support the viability of pharmacological chaperone therapy for the treatment of Pompe disease. Another therapeutic approach, also based on small molecules, currently being tested by Dr. Parenti's group is substrate reduction for the treatment of mucopolysaccharidoses. Dr. Parenti's expertise in molecular chaperones and substrate reduction will be important for the TIGEM-NRI program, considering its potential applications to other lysosomal storage diseases as well as neurodegenerative conditions that afflict adults.
Marco Sardiello (Investigator, NRI)
Dr. Sardiello, one of the NRI's first new hires, is focused on neuronal ceroid lipofuscinoses (NCLs), among the most common neurodegenerative disorders affecting children. In NCLs, the deficiency of proteins participating in lysosomal metabolism leads to the intralysosomal storage of lipofuscin, which ultimately impairs the cell's function and viability. This project sprang from Dr. Sardiello's discovery of TFEB while he was a post-doctoral fellow in Andrea Ballabio's group. A major goal of Dr. Sardiello's project is to modulate TFEB activity in mouse models of NCLs as a therapeutic tool to enhance the clearance of stored toxic molecules. Dr. Sardiello's group is also dissecting the cellular pathways in which NCL proteins are involved. This project relies on the analysis of NCL gene and protein networks and aims to identify partners of NCL proteins that could present new therapeutic targets.