Leinonen Retina Laboratory

Leaders

• 

  Henri Leinonen

  Academy Research Fellow

  School of Pharmacy, Faculty of Health Sciences

Cooperation

• Peter Wipf, Ph.D.

  Distinguished University Professor, Department of Chemistry, University of Pittsburgh, USA

• Krzysztof Palczewski, Ph.D.

  Distinguished Professor, Chair of Ophthalmology, University of California Irvine, USA

• Zhongjie Fu, Ph.D.

  Assistant Professor of Ophthalmology, Harvard University, Boston Children´s Hospital, USA

• Simon Petersen-Jones, D.V.M., Ph.D.

  Professor, College of Veterinary Medicine, Michigan State University, USA

• Frans Vinberg, Ph.D.

  Assistant Professor, Ophthalmology & Visual Sciences, University of Utah, USA

• Andrzej Foik, Ph.D.

  Principal Investigator, Polish Academy of Science, International Centre for Experimental Eye Research, Poland

• Shinya Sato, Ph.D.

  Laboratory Chief, National Cerebral and Cardiovascular Center, Osaka, Japan

• Peppi Koivunen, M.D., Ph.D.

  Professor, Dean, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland

• Philip Kiser, Ph.D., Pharm.D.

  Assistant Professor, Physiology and Biophysics, University of California Irvine, USA

• Dorota Skowronska-Krawczyk, Ph.D.

  Assistant Professor, Ophthalmology, University of California Irvine, USA

• Vladimir Kefalov, Ph.D.

  Professor, Ophthalmology, University of California Irvine, USA

• 
  Neuropharmacology and Drug Targets Consortium (NDTC) 01.01.2022 -
• 
  Ocular Drug Delivery group (ODD) 01.01.2010 -
• 
  Kaarniranta AMD Lab 01.01.2004 -
• 
  Neuroinflammation research group 01.01.2017 -
• 
  Neurobiology of Memory 12.11.2022 -
• 
  Biomedical Image Analysis 01.11.2016 -
• 
  Transporter-Targeted Drug Delivery 01.09.2012 -

RESEARCH DESCRIPTION

The laboratory leader´s interest towards the eye´s retina was initially based on the realization that the retina  manifests pathological changes in diseases that are primary known as brain diseases (such as Alzheimer´s and Parkinson´s Diseases). The goal of this research branch is to develop retina-based biomarkers for brain diseases. Hopefully, with the help of retina-based biomarkers, these diseases could be diagnosed in an early disease phase, or even before clinical disease manifestation.

The laboratory´s research project (1) follows up my PhD project’s idea that the retina of the eye provides a window to study central nervous system, here in particular from neuroplasticity point of view. Our recently published data (Leinonen et al. 2020, eLife) show that according to mass retinal electrophysiology responses, signal transmission from photoreceptors (PR) to rod bipolar cells (BC) is potentiated upon PR decline. This is seen in mice with PR degenerative disease and by pharmacological suppression of PR function in healthy normal mice. The potentiation in PR-BC transmission is associated with reorganization of synaptic proteins as shown by expression analyses. Furthermore, despite dying PRs, behavioral visual function is well-maintained in a mouse model of retinitis pigmentosa. We believe that the inner retina responds to sensory deprivation by means of homeostatic plasticity, which helps to maintain function at brain level. Our current focus is to decipher the molecular mechanisms of retinal homeostatic plasticity.

The objective of the research project (2) is to test pharmacological treatments based on a systems pharmacology approach in rescuing retinal photoreceptors in various mouse models of retinal degenerative diseases (including Leber congenital amaurosis, Retinitis Pigmentosa and dry AMD). Inherited and idiopathic retinal degenerative diseases, including the dry form of age-related macular degeneration (AMD) and Retinitis Pigmentosa (RP), generally lack treatments that would halt the progression of vision loss after diagnosis. In most retinal degenerative diseases, the retinal pigment epithelium and rod photoreceptors degenerate first followed by damage to cone photoreceptors and remodeling of the inner retina. As for human vision, the preservation of cone photoreceptors and inner retina would suffice to retain visual acuity even if the rods were partially lost.

Our systems pharmacology approach utilizes a combined therapy comprised of existing clinical drugs that act on G protein-coupled receptors (GPCRs). We have shown that prophylactic treatment with a targeted combination therapy with several simultaneously administered GPCR-acting drugs at low doses (sub-therapeutic if given as monotherapy) can prevent acutely induced retinal degeneration in distinct mouse models of retinal degenerative diseases. We are pursuing this promising drug development pipeline by expanding the trials into more translationally relevant progressive retinal degenerative disease models that differ in etiology, but which have the same blinding endpoint, and finally to initial clinical trials. A subsequent crucial task is to uncover the exact molecular mechanisms that can explain the retinal protective effects of our combination therapy. This will facilitate in further development of the treatment concept, and can launch innovative novel drug development pipelines.

Drug repurposing approach re-evaluates the usefulness of drugs that have already survived the costly drug development pipeline, and have proven to be safe for the use in humans. Drug repurposing has the potential to provide an economical and an effective alternative to treat patients suffering from disparate retinal degenerative diseases, and may be useful in the treatment of other complex neuronal diseases as well. Most importantly, the use of approved drugs surpasses several formally required drug development phases, and can therefore provide novel clinical remedies fast.

Homeostatic plasticity in the retina - mechanistic hypothesis

Keywords