Lysosomal storage diseases in North America: a comprehensive review of enzyme therapies and unmet needs

This review explores enzyme replacement therapies (ERTs) for lysosomal storage diseases (LSDs), focusing on disease characteristics, mechanisms of action, clinical benefits, limitations, and implications for patient care and access. LSDs are a group of over 50 rare, inherited metabolic disorders caused by mutations affecting lysosomal enzymes, membrane proteins, or transporters. This leads to the accumulation of undegraded macromolecules in tissues such as the CNS (central nervous system), heart, and muscles, resulting in progressive dysfunction and possible death. ERTs, approved by FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency), have been the cornerstone of treatment since 1995, significantly improving the patient's quality of life reducing organ damage and stabilizing cardiac and renal function. However, ERTs require lifelong intravenous infusions and have limited efficacy to treat CNS symptoms due to their inability to cross the BBB (blood-brain barrier). Some patients develop immune responses known as ADA (anti-drug antibody), which can compromise treatment effectiveness. Emerging research into nanotechnology and combination therapies may help overcome these limitations. Newer formulations such as pegunigalsidase (Elfabrio®) use for FD (Fabry disease), exhibit lower affinity for developing ADA compared to other ERTs, offer reduced immunogenicity and safety profiles enhancement. Cost remains a major barrier, with annual treatment expenses often exceeding hundreds of thousands of dollars. Access to ERT is uneven, particularly in underfunded healthcare systems. In North America, reimbursement varies by region and payer, potentially delaying treatment and impacting outcomes. This review draws from MEDLINE, Cochrane Reviews, and PubMed (1984-2025) using search terms such as LSDs, ERTs, rare diseases, Gaucher disease, Fabry disease, and others. Ongoing research and health policy reforms are essential to improve access, equity, and therapeutic outcomes for patients with LSDs.