Research

Leinonen Retina Laboratory (LRL)

Research Statement

This research statement outlines the development of my research program, from doctoral training to the current activities in LRL.

Table of Contents:

1. Historical perspective: why the retina, why electrophysiology?
2. Current research focus: two converging programs in a single lab philosophy
3. Program I: Drug repurposing and systems pharmacology for disease-modifying retinal therapy
4. Program II: Homeostatic plasticity of the retina
5. Near-future vision: unifying therapy and plasticity into a coherent translational roadmap
6. Summary

1) Historical perspective: why the retina, why electrophysiology?

My research trajectory has been shaped by a deceptively simple observation: the retina is a central nervous system (CNS) tissue that can be interrogated with exceptional precision, repeatedly, and often non-invasively. During my doctoral work, I became interested in whether functional tests of the visual pathway could act as sensitive readouts of neurodegeneration, especially in disease contexts historically considered “brain disorders.” In my PhD dissertation, I established and optimized rodent electroretinography (ERG) and visually evoked potential (VEP) approaches tailored for genetically modified mouse models, and used these tools to test whether retinal and cortical visual function can reveal early pathology across multiple neurodegenerative conditions. 

Indeed, a central technical contribution of that period was building an experimental and analytical framework in which retinal output (ERG) and central visual pathway activation (VEP) could be measured systematically and interpreted in relation to retinal structure and molecular hallmarks. These early studies did more than teach me how to run ERGs and VEPs; they formed my scientific identity around a guiding principle that still drives my lab today: quantitative physiology is often the fastest route from mechanism to translation, as it provides interpretable outcome measures that can be aligned with clinical endpoints.

Following my PhD, my postdoctoral training in the Department of Pharmacology at Case Western Reserve University and later at the Center for Translational Vision Research at the University of California, Irvine further refined my focus toward therapy development – specifically, how pharmacological modulation of stress pathways and network function can alter the course of retinal degeneration. 

2) Current research focus: two converging programs in a single lab philosophy

My laboratory´s research can be described as retinal systems pharmacology: we study the retina as a CNS circuit in which disease progression is driven by interacting molecular stress responses and circuit-level adaptations. We pursue this through two tightly connected research directions:

1. Drug repurposing and systems pharmacology to reduce retinal cell stress and slow degeneration
2. Homeostatic plasticity in retinal circuits, and how it can be harnessed (or corrected) therapeutically

While these programs have distinct hypotheses and work packages, they converge on a shared question:
How do cellular stress pathways and circuit adaptation interact during progressive retinal degeneration, and how can pharmacological interventions shift that interaction toward resilience?

3) Program I: Drug repurposing and systems pharmacology for disease-modifying retinal therapy

Retinal degenerations, including inherited retinal degenerations (IRDs) and dry age-related macular degeneration (AMD), remain major unmet medical needs, in part because of heterogeneity (hundreds of genetic causes in IRDs and multifactorial mechanisms in AMD). This motivates an approach that is not narrowly etiology-specific but rather targets convergent stress and signaling pathways shared across retinal diseases. 

My lab aims to develop disease-modifying therapy concepts based on repurposing clinically used G protein-coupled receptor (GPCR)-active drugs in rational combinations. The underlying rationale is that multiple retinal GPCRs converge on interconnected second-messenger pathways (notably cAMP/Ca²⁺-linked modules), and that coordinated, multi-receptor modulation can reprogram pathological signaling more robustly than single-agent approaches. 

A foundational example is a three-drug combination (α1-antagonism, β1-antagonism, and D2-like agonism; currently implemented using tamsulosin, metoprolol, and bromocriptine) that has shown mutation-agnostic protection in multiple preclinical retinopathy paradigms (Leinonen et al. 2024, Nat Commun). This strategy is designed to be translationally realistic: repurposed drugs can substantially reduce early-stage safety barriers, and the retina enables unusually direct functional tracking of therapeutic response through electrophysiology and minimally invasive ophthalmic imaging.

Where are we now in mechanism-aided translation?
A key scientific question that now defines this program is why certain drug combinations can provide protection where monotherapies fail. Rather than treating combination therapy as empirical polypharmacy, our aim is to understand the underlying mechanistic basis of these effects, so that therapeutic responses can be predicted more reliably, clinical trial design can be improved, and potential failures in translation can be interpreted in a mechanistically informed manner. This research is funded by the Research Council of Finland (2021-2026), the Federation of European Biochemical Societies (FEBS Excellence Award 2024-2026), and Jane & Aatos Erkko Foundation (2026-2029).

Methods and platform capabilities (drug research).
Our core research techniques include:

• In vivo retinal physiology: scotopic and photopic electroretinography (ERG), including waveform decomposition and kinetic analyses to localize effects to photoreceptor activation versus post-receptoral gain control.
• In vivo ophthalmic imaging: optical coherence tomography (OCT) to assess retinal layer integrity and disease progression longitudinally.
• Ex vivo retinal approaches: isolated retina preparations suitable for controlled pharmacological manipulation and mechanistic studies.
• Histology and immunohistochemistry: routine retinal histology and immunohistochemical analyses to evaluate cell-type–specific markers, synaptic organization, and disease- or treatment-associated structural changes.
• Proteomics and targeted molecular validation: proteomic profiling to identify stress-pathway modulation and synaptic or metabolic remodeling, paired with immunoblotting and ELISA-based validation of selected molecular targets (e.g., stress regulators and redox-associated markers).
• Metabolite quantification: LC-MS–based measurements of cyclic nucleotides, neurotransmitters and their metabolites, as well as energy-related metabolites.

By integrating physiology, signaling, and omics, we aim to build a mechanistic evidence stack that connects local retinal dynamics to whole-retina output, enabling rational decisions on compound selection, dosing, and drug delivery.

Connection to published work.
This direction is anchored by recent peer-reviewed outputs demonstrating mutation-agnostic efficacy in preclinical models and by broader work (Montaser et al. 2024, MCP) positioning cyclic nucleotide and GPCR signaling (Vainionpää et al. 2025, FEBS Letters) as actionable nodes in retinal neuroprotection. 

4) Program II: Homeostatic plasticity of the retina

Retinal degeneration is not only a story of cell loss, but also a story of adaptation. Even early in disease, retinal circuits remodel. While some of these changes are known to distort signaling and create negative downstream consequences for central processing, others may in fact help to preserve function (Leinonen et al. 2023, Neural Regen Res). A major aim of my lab is to identify which adaptations are compensatory, what mechanisms drive them, and whether pharmacology can modulate plasticity to improve functional outcomes.

A particularly powerful model for mechanistic work is the rod → rod bipolar cell (rod-RBC) synapse, the first synapse of the night-vision pathway. This synapse is experimentally tractable and sits at a strategic point where homeostatic gain control can preserve vision even when many photoreceptors are lost (Leinonen et al. 2020, eLife). In a proposal basis for this program, we build on evidence that early retinal degeneration can coincide with potentiation of rod-RBC signaling and preserved night vision, and we pursue the hypothesis that synaptic scaling is a major mechanistic driver (Roihuvuo et al. 2025, IOVS). 

Cortex and behavior: does retinal adaptation help or hurt downstream processing?
One key component is understanding consequences beyond the retina: how altered retinal output affects primary visual cortex (V1) physiology and vision-relevant behavior. Through external collaborations, we work together to link retinal remodeling to central processing, receptive field changes, and visual performance using a combination of VEPs, single-unit recordings, and behavioral visual tasks in rodent degeneration models. 

This research is funded by the Sigrid Jusélius Foundation and the Emil Aaltonen Foundation.

5) Near-future vision

In the near term, our goal is to position the lab at a point where mechanistic neuropharmacology and translational therapy development reinforce each other rather than competing for bandwidth. Concretely, this translates into three forward directions:

(a) From “it works” to “we can predict when it will work”: mechanistic signatures of combination efficacy.
A major deliverable for the drug-repurposing program is a predictive, quantitative framework linking: drug combinations → corrective signaling shifts → suppression of cellular stress responses → improved retinal function and delayed degeneration. 

This includes optimization of dosing and candidate compounds for ocular delivery strategies.

(b) Plasticity as a therapeutic variable, not just an observation.
As vision restoration technologies advance (gene therapy, optogenetics, prosthetics, synthetic retinoids), the limiting factor may increasingly be whether adult circuits can interpret and integrate restored inputs. Our plasticity program therefore treats homeostatic mechanisms as druggable targets: not to create “more plasticity” indiscriminately, but to shape plasticity toward a useful and behaviorally meaningful function. 

(c) A translational loop built around electrophysiological endpoints.
A recurring theme across my career is that electrophysiology provides interpretable, scalable endpoints that bridge mechanistic inference to treatment outcomes. The near-future strategy is to strengthen this translational loop by aligning rodent assays with more clinically meaningful functional constructs (including studies in higher-order species and human tissue when feasible), while building the molecular layers needed for mechanism-informed therapeutic strategies.

Finally, I view computationally enabled drug repurposing as an increasingly important complement. It cannot substitute physiology, but it can help us to prioritize hypotheses and maximize the value of experimental throughput. In the coming years, I expect the most productive path will be iterative: computational prioritization → biological experiments → refined parameters for in silico work → return to biological models with improved prediction.

6) Summary

Our research programs sit at the intersection of visual electrophysiology, plasticity, and mechanism-driven pharmacology. The historical foundation of my work is the development and use of ERG and VEP methods to reveal functional signatures of disease in retina and visual cortex. 

Today, my lab pursues two converging directions: (1) systems pharmacology and drug repurposing to reduce retinal cell stress and slow degeneration, and (2) homeostatic plasticity mechanisms that preserve or reshape visual function during disease and may be pharmacologically modulated to improve outcomes. Across both directions, the guiding idea is consistent: by combining rigorous quantitative physiology with molecular mechanism and translational pragmatism, we can move from descriptive models of retinal degeneration to interventions that are both scientifically explanatory and clinically feasible.