We recently attended the GBA1 conference in Montreal, which brought together researchers, clinicians, biotech leaders, and patient advocates to discuss cutting-edge developments across GBA1-associated diseases, including Parkinson’s disease (PD), Gaucher disease, and dementia. The meeting revealed major scientific progress and critical gaps in the systems surrounding patient care, trial design, and genetic access. In this blog, we’ll share some of our key learnings.
A precision medicine paradox
GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), which plays a critical role in breaking down glycolipids within cells. Mutations in GBA1 can impair GCase function, leading to lysosomal storage issues that cause Gaucher disease and significantly increase the risk of developing Parkinson’s disease and other neurodegenerative disorders.
A major takeaway from the conference was that precision medicine is both essential and underutilized. In PD, for instance, GBA1 variants are among the most common genetic contributors, but routine genotyping remains rare, creating bottlenecks for identifying eligible patients for trials and limiting the clinical adoption of targeted therapies.
Some mutations, like GBA1 E326K, highlight the need for more nuanced approaches. Although this variant does not reduce GCase enzymatic activity, it disrupts lysosomal trafficking. A therapeutic intervention to enhance GCase activity would therefore be ineffective in patients with this variant. Additionally, stratifying patients in clinical trials based solely on single genetic mutations is inefficient and does not accurately reflect the heterogeneity of these conditions.
As an alternative, symptom-based clustering to account for variables like age, sex, and non-motor symptoms has more accurately captured clinical variability. Still, the field may benefit from broader genomic approaches, such as polygenic risk scores or variant class-based groupings, especially when integrated with phenotypic and biomarker data. A future framework will likely combine genetic and clinical profiles with molecular signatures to drive smarter patient selection and better-targeted interventions.
Uncovering new modifiers and interactions
Rare variant burden testing is shedding light on novel genetic modifiers like SNAPIN, MFSD12, and PCSK4, which could influence disease progression or therapeutic response. Talks also highlighted the importance of gene-environment interactions. For example, GBA1 and LRKK2 variants affect immune response profiles, but outcomes may shift depending on sex, pathogen exposure, and environmental triggers.
Therapeutic progress and persistent bottlenecks
Therapies targeting GCase function were a major focus, including small molecules and gene or cell therapies delivered via intrathecal, viral vector, or intracranial routes. However, there's growing recognition that targeting GBA1 alone may not be enough and combination therapies with different targets are likely to be necessary.
This could be a significant challenge as widespread under-genotyping of neurological patients makes it difficult to identify who might benefit. Without more accessible and routine genetic testing, even the most promising therapies risk missing their intended populations.
Patient engagement and trial inclusion: A call for reform
GBA1 variant carriers face additional barriers when it comes to clinical trial access. Many are excluded from general PD trials despite being a key subgroup due to efforts to limit cohort variability. Others are ruled out by diagnosis windows, such as restrictions to within 2–5 years post-diagnosis, leaving more advanced patients without options.
This selective inclusion discourages participation and limits the scope of data collected. The field urgently needs inclusive, patient-centered trial designs and centralized platforms where individuals can access clear updates about trial opportunities, eligibility criteria, and evolving treatment landscapes.
Navigating complexity: Decisions in the face of uncertainty
Patients and families must often weigh complex options (deep brain stimulation, gene therapy, cell therapy) with limited guidance and little room for second chances. These decisions are made even harder by unclear eligibility rules and long approval timelines. Patients are left balancing potential acceleration of decline against unknown benefits, with emotional and practical consequences.
Still, many people with GBA1-associated conditions are proactively engaging in research and lifestyle strategies, including exercise, diet changes, and supplement use. Minimal-risk interventions offer both psychological support and physical benefit.
A path forward: Inclusion, innovation, and partnership
Patients want advisory roles, clear communication channels, and a seat at the table when studies are designed. Researchers were praised not just for their scientific contributions but for their compassion and willingness to listen.
Going forward, the success of GBA1-targeted therapies won’t depend solely on molecular precision but also on system-wide alignment. That means breaking down silos between genetic testing, clinical care, trial design, and community engagement. By listening to patients, integrating genomic and phenotypic data, and designing smarter, more inclusive studies, we can move closer to a future where personalized care is the standard.
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