ABOUT
LSDs are a heterogeneous group of 50 or more inherited disorders, each of which result from the defects in lysosomal enzyme levels or function, caused by mutations in the genes encoding lysosomal enzymes or cofactors in the substrate degradation pathways. While individual LSDs are categorized as rare or orphan disorders, LSDs, as a group, are fairly common and affect a considerable number of individuals in the general population with a combined incidence of 1:5000 to 1:8000. Tay–Sachs disease was the first of these disorders to be described, in 1881, followed by Gaucher disease in 1882 and Fabry disease in 1889. However, it was until 1963 that a disease (Pompe disease) was be identified as an LSD. In 1991, an enzyme replacement therapy (ERT) was approved to treat indivuals with Gaucher disease. This was the first time that a treatment for an LSD addressed the underlying mechanistic defect of the disease rather than simply providing symptomatic management. Mannose targeted human recombinant ERTs are now the standard of care for multiple LSDs. In addition, there are new generation ERTs that are being developed, such as new ERTs for Pompe disease and the brain penetrant ERT for Hunter disease.
In addition to the advent of next-generation ERTs, several other therapeutic progresses have been advanced in the past decade, including substrate reduction therapy (SRT) and chaperone therapy for Gaucher and Fabry diseases, respectively.
Although the above therapies made available, there is a need for better treatment options and that has led to an increased interest to better understand the underlying pathophysiology of LSDs and that research is redefining how we perceive these rare conditons and how we may better diagnose and treat them. For example, research that is investigating beyond the traditional catabolic functions of the lysosomes has led to a better understanding of the role cell signaling and metabolite sensing, protein degradation, and pathways that involve cell death and survival play as major contributors to the LSD pathology and progression. Similarly, with the emergence of novel cellular and molecular techniques, advanced Omics technologies (i.e., genomics, metabolomics, epigenomics) are now being pursued across the globe that are leading to the development of disease-specific biomarkers for clinical use.
Additionally, significant advances have also taken place over the years in diagnostic and prognostic testing for LSDs. The enzymatic testing, performed by fluorometric method or tandem mass spectrometry, is still the first phase in the diagnosis of LSDs now is adapted to multiplex techniques with rapid and accurate results utilizing the dried blood spots. Enzymatic testing is almost always confirmed by molecular examination. Molecular testing has evolved from initial RFLP-PCR, ARMS-PCR, and mutation scanning to DNA sequencing. In 2013, Next-generation sequencing (NGS) was applied to Tay-Sachs disease and is now extended to multiple LSDs leading to enhanced recognition and early identification especially of the treatable forms of LSDs. The genomics techniques are time- and cost-effective and have several advantages, including the adaptability to large-scale studies, such as newborn screening and GWAS studies. NGS and the genomics advances, in turn, brought an explosion of available data sets, that led to the development and incorporation of various analytical platforms utilizing artificial intelligence and machine learning.
Finally, more advanced therapies for LSDs are in the pipeline that include stem cell, gene therapy, small molecule/nanomedicine approaches, RNA silencing, and genome editing. These therapies are often tied to our improved understanding of the pathophysiology of LSDs as well as finding newer methods to better target the therapies.
In summary, the advent of all the new and novel developments in recent years, as well as emerging technologies, makes it imperative to address the role of downstream pathways in LSDs to pursue precision or individualized medicine that results in patient-centric care for patients and families affected by LSDs. GRIDS 2022 will focus on the latest advances, technological breakthroughs and novel therapies that are changing the landscape in LSDs. The intent of GRIDS 2022 is to further the discussion about the role of cell signaling, metabolite regulation, inflammatory and other pathways not only to understand the disease process in LSDs, but also to develop new diagnostics and treatment strategies.
GRIDS 2022 presentations will cover the topics related but not limited to the following disorders:
· Fabry disease
· Gaucher disease
· Pompe disease
· Tay-Sachs and Krabbe diseases
· Mucopolysaccharidosis (MPS) I
· MPS II
· MPS IV
· MPS VI
· MPS VII
· GM1 & GM2 Gangliosidosis
· Metachromatic Leukodystrophy
· Mucolipidosis
· Niemann-Pick A/B diseases
· Niemann-Pick C disease
· Sialidosis
Global Learning Objectives
Get introduced to molecular and cellular mechanisms as related to different lysosomal functions and disease pathology and progression in LSDs,
Gain knowledge about burden/role of inflammatory pathways leading to cell death and the manifestation of LSDs,
Get introduced to the role of genomics and metabolomics approaches in precision or individualized medicine,
Gain insights into current treatment strategies and findings from preclinical studies in different model systems and clinical trials towards novel therapies,
Discuss the efficacy, safety of clinical studies involving next-generation enzyme replacement therapies that utilize hyper-mannosylation and other techniques such as antibody peptides and targeting sequences for improved tissue penetration,
Review pharmacochaperones and small molecular approaches as disease-specific or symptomatic treatment of various LSDs,
Learn about novel tools and technologies that incorporate big data and machine learning,
Discuss the clinical utility of sphingolipid and other biomarkers in the diagnosis, and therapeutic management of LSDs.