Critical Path for Lysosomal Diseases Pre-Consortium

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The Problem

Lysosomal diseases (LDs) are rare, inherited, metabolic disorders caused by deficiencies in enzymes vital for molecular breakdown within lysosomes. When these enzymes are compromised, molecules accumulate, leading to cellular dysfunction and tissue damage. The accumulated substrates and subsequent clinical manifestations differ among the 70+ lysosomal diseases. The complex pathophysiology of LDs progressively affects various organs, with clinical manifestations of over 75% of the LDs affecting the central nervous system (CNS). Although treatments for LDs exist, there is wide variation in available options across conditions. Currently available approaches include enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and gene therapy (GT), yet these therapies are disease specific, and effectiveness is often influenced by disease progression and/or severity.

The heterogeneity across the LDs with the wide range of clinical presentations has challenged the identification of a “universal” biomarker that could be leveraged to impact development of drugs effectively and efficiently and/or tools to improve LD patient outcomes. However, given the significant overlap in LDs displaying CNS symptoms initially focusing on a hypothesis-driven physiological approach toward illuminating the potential of neurological biomarkers to track disease progression and therapeutic efficacy warrants investigations. There is substantial data indicating that variations in brain volume, structural integrity, and signal patterns often align with LD severity, suggesting visualization of these variations mat provide insight into the utility of imaging as a central biomarker. Additionally, fluidic biomarkers, like neurofilament light chain (NfL), represent a more manageable strategy for longitudinal data collection with several timepoints these conditions with complex phenotypes that challenge image acquisition. With evolving therapies, the identification of relevant biomarkers that may be integrated into drug and tool development platforms to address the vast unmet needs in LD is critical.

For actionable solutions, understanding the upstream and downstream physiology of biomarkers in LDs is paramount.  Potential neurological biomarkers, bolstered by clinical data, especially regarding CNS, can pave the way for advanced therapies, preventing chronic conditions in adulthood. This necessitates direct pediatric clinical trials with age-specific endpoints and tools. A deeper grasp of neuropathology through combined neuroimaging/fluidic biomarkers will address drug development challenges, including long-term follow-up and standardized clinical outcomes.

The Solution

CPLD fosters collaboration among a broad spectrum of LD stakeholders – spanning industry, academia, patient advocacy, and regulatory entities. By solidifying existing alliances and forging new ones, CPLD seeks to pinpoint obstacles in LD therapeutic development, fulfill unaddressed needs, and devise strategies for improved patient outcomes.

The Impact

The consortium seeks to deepen our understanding of LDs by expanding collaborations with stakeholders from academia, industry, advocacy, and regulatory bodies. We aim to contribute to the LD literature and explore the potential of neuroimaging and NfL as biomarkers, hoping to reveal commonalities across various LDs. This foundational phase is essential in charting a sustainable course for CPLD’s future.

CPLD strives to:

  • Enhance the foundational pathophysiological knowledge related to multiple LDs.
  • Expand collaboration with various stakeholders, including academia, industry, and regulatory bodies.
  • Enrich the LD literature.
  • Investigate existing biomarker data, especially related to neuroimaging and NfL to determine potential overlaps among LDs. Evaluate existing biomarker data to determine diagnostic capabilities, track disease progression, and assess therapeutic response.
  • Identify knowledge gaps to refine LD drug development processes.
  • Establish a comprehensive database to maximize consortium-wide utility.

Connect With Us:

For further insights on unmet needs in lysosomal diseases, connect with Critical Path for Lysosomal Diseases at:



Amanda Klein, PharmD, CDCES
Executive Director, CPLD

Klaus Romero, MD, MS, FCP
Chief Executive Officer, Chief Science Officer

Krista Casazza, PhD, RD, CSSD
Scientific Director, Pediatrics, CPLD

Sarah David, MPH
Associate Director of Pediatric Programs

Nicole Spear
Project Manager, CPLD

Olivia Giola
Project Coordinator, Pediatrics, CPLD

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