About Rodin

Therapeutic Strategy

 

Rodin’s initial clinical focus is on Alzheimer’s disease (AD), one of the largest areas of global unmet medical need.

There are many other neurological and neuropsychiatric disorders that could benefit from improved synaptic function through targeted epigenetic regulation.  Rodin’s discovery efforts have been driven by a disease-agnostic approach; with the goal of demonstrating preclinical safety and efficacy, as measured by the molecular, structural and functional drivers of synaptic resilience.  We believe this approach offers the best chance of success in these challenging disease areas.

Our early clinical and translational efforts are focused on confirming that our proprietary compounds are safe and brain penetrant, with appropriate pharmacokinetic properties. Critically, we also plan to leverage target engagement and pharmacodynamic biomarkers to confirm the sustained, significant increase in synaptic resilience shown preclinically with our compounds.

Proof of mechanistic principle – confirming that our compounds improve synaptic resilience in human brain, as they do in preclinical models – will enable multiple potential development pathways.

Alzheimer’s Disease

 

Rodin is working to discover and develop epigenetic modulators of synaptic resilience for the treatment of cognitive and functional impairment due to AD, one of the most significant public health problems of the 21st century. The number of AD patients in the US is estimated at 5.2 million and projected to double by 2050, and the overall cost of care for these patients is projected to reach $1.2 trillion by 2050. There is thus a pressing need to develop better therapies to relieve the cognitive and functional impairments of AD, reducing caregiver burden, cost of care, and delaying the institutionalization of AD patients.

Multiple post-mortem studies have demonstrated that synaptic loss is a key event in AD, starting in the earliest stages of the disease. Evidence supports that loss of synapses is a more critical feature of AD pathology than plaque accumulation or tau tangle load; even more critical than total neuronal loss. Of all measures of pathology, lower brain synapse count correlates most closely with memory test performance.

Our lead program is thus focused on enhancing synaptic health and function, which, given the key role of synaptic dysfunction in AD, should ultimately provide a therapeutic benefit to AD sufferers.

Parkinson’s Disease

 

Rodin is also investigating our synaptic resilience boosting compounds for the cognitive dysfunction and functional impairments associated with Parkinson’s disease (PD). Cognitive impairment is a common and life-altering symptom of PD that is not addressed by standard motor-targeted therapies. In fact, cognitive decline is one of the most debilitating manifestations of disease progression in PD and is a key determinant of a patient’s quality of life and independence. Parkinson’s disease with dementia is termed Parkinson’s disease dementia (PDD) and is in urgent need of effective therapies.

α-Synuclein is an abundant neuronal protein which localizes predominantly to presynaptic terminals and is linked strongly to PD, both genetically and pathologically. Evidence supports that α-synuclein plays an important role in synaptic vesicle and presynaptic function. Other genes and their protein products that are linked genetically to PD, such as DJ-1, PINK-1 and LRRK2 have also been linked to synaptic function. Clinically, decreases in presynaptically released dopamine are a defining early characteristic of PD; there is evidence of early presynaptic micro-aggregates of α-synuclein associated with synaptic vesicles in the postmortem brains of PD patients. As well, decreases in synapse numbers, spine density, dendritic tree size and complexity have been observed in the postmortem brains of PD patients. Preclinical studies suggest that early synaptic impairment is a critical underlying driver for PD pathogenesis contributing to motor and cognitive dysfunction.

By enhancing the function of remaining synapses critical for learning and memory, Rodin compounds have the potential to improve cognition and function in PD and PDD. Moreover, through HDAC complex selective inhibition, Rodin compounds may have an impact on the course of the disease, by protecting still functioning neurons from neurodegeneration.

 

Others

 

Because Rodin’s discovery, development and translational strategy is based on research demonstrating that synaptic loss and impairment is a primary driver of disease state, our approach may also be relevant to other neurological and neuropsychiatric diseases characterized by synaptic dysfunction, beyond AD and PD.  These diseases include: 

  • Frontotemporal Dementia (FTD) is a disease caused by progressive loss of neurons starting in the frontal and/or temporal lobes of the brain. FTD is a neurodegenerative disease that is linked to the aggregation of the protein Tau, also important in AD. As in AD, synaptic deficits are important in the pathology of FTD, and HDAC inhibitors have demonstrated preclinical efficacy in various FTD models.
  • Huntington’s disease (HD) is a devastating neurodegenerative disorder associated with motor, cognitive and behavioral deficits. HD is caused by a trinucleotide repeat mutation in the gene that encodes the protein huntingtin, leading to an abnormal protein and resulting in neuronal dysfunction and death. Profound synaptic dysfunction and dendritic spine abnormalities exist in HD, and are believed to play a crucial underlying role in behavioral and motor dysfunctions observed in these patients. HDAC inhibitors have been shown in preclinical models to have potential for the treatment of HD.
  • Memories of a traumatic event can cause feelings of grief, guilt, or loss, as well as negative emotional responses such as anger, rage or aggression. However, a memory can be modified to reduce negative associations and stressful reactions.  HDAC inhibitors have been shown preclinically to lessen fearful memories, suggesting the potential to reduce not only the immediate effects of trauma but also prevent or reduce the development of later disease, including Post Traumatic Stress Disorder (PTSD).
  • Traumatic brain injury (TBI) is associated with cognitive, social, emotional, and behavioral symptoms. There is evidence for increased histone acetylation and synaptic degeneration in animal models of traumatic brain injury, and HDAC inhibitors have been shown to decrease inflammation and injury in rat and mouse models of TBI.
  • The pathophysiology of Rett syndrome is thought to be mediated by epigenetic changes. In addition, Rett patients show alterations in dendritic spine structure and deficits in synaptic proteins involved in synaptic signaling, such as BDNF. Because of the biological role played in Rett pathology by epigenetics, it has been proposed that HDAC inhibitors could be an effective approach to therapeutic intervention for this disease.

 

LITERATURE

Dash, PK, et al. Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats. PLoS One. 2010 Jun 30;5(6). PubMed PMID: 20614021.

Davies, C. A., et al. A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci 78, 151–164 (1987). PubMed PMID: 3572454.

DeKosky, ST and Scheff, SW Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol. 1990 May;27(5):457-64. PubMed PMID: 2360787.

DeKosky, ST, Scheff, SW, and Styren, SD. Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration. 1996 Dec;5(4):417-21. Review. PubMed PMID: 9117556.

de Wilde, M. C., et al. Meta-analysis of synaptic pathology in Alzheimer’s disease reveals selective molecular vesicular machinery vulnerability. Alzheimer’s & Dementia 12, 633–644 (2016). PubMed PMID: 26776762.

Ferrante RJ, Kowall NW and Richardson EP Jr. Proliferative and degenerative changes in striatal spiny neurons in Huntington’s disease: a combined study using the section-Golgi method and calbindin D28k immunocytochemistry.  J Neurosci. 1991 Dec;11(12): 3877-3887: PubMed PMID: 1836019

Ferrer, I Neurons and their dendrites in frontotemporal dementia. Dement

Geriatr Cogn Disord. 1999;10 Suppl 1:55-60. Review. PubMed PMID: 10436342

Gräff, J, et al. Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell. 2014 Jan 16;156(1-2):261-76. PubMed PMID: 24439381.

Gao, X, et al. Moderate traumatic brain injury causes acute dendritic and synaptic degeneration in the hippocampal dentate gyrus. PLoS One. 2011;6(9). PubMed PMID: 21931758

Katz DM. Brain-derived neurotrophic factor and Rett syndrome. Handb Exp Pharmacol. 2014;220:481-95. Review. PubMed PMID: 24668484.

Lipton AM, et al. Contribution of asymmetric synapse loss to lateralizing clinical deficits in frontotemporal dementias. Arch Neurol. 2001 Aug;58(8):1233-9. PubMed PMID: 11493163.

Lui, H, et al. Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell 165, 921–935 (2016). PubMed PMID: 27114033

Masliah, E et al. Synaptic and neuritic alterations during the progression of Alzheimer’s disease. Neurosci Lett. 1994 Jun 6;174(1):67-72. PubMed PMID: 7970158.

Masliah, E. et al. Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology. 2001 Jan 9;56(1):127-9. PubMed PMID: 11148253

Petkau, TL et al. Synaptic dysfunction in progranulin-deficient mice. Neurobiol Dis 2012; 45, 711–722. PubMed PMID: 22062772

Shein NA, et al. Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury. FASEB J. 2009 Dec;23(12):4266-75. PubMed PMID: 19723705.

Terry RD, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991 Oct;30(4):572-80. PubMed PMID: 1789684.

Smith R, Brundin P and Li JY. Synaptic dysfunction in Huntington’s disease: a new perspective. Cell Mol Life Sci. 2005 Sep;62(17): 1901-1912: PubMed PMID: 15968465

Wang G, et al.  Scriptaid, a novel histone deacetylase inhibitor, protects against traumatic brain injury via modulation of PTEN and AKT pathway: scriptaid protects against TBI via AKT. Neurotherapeutics. 2013 Jan;10(1):124-42. PubMed PMID: 23132328

Wong VS and Langley B. Epigenetic changes following traumatic brain injury and their implications for outcome, recovery and therapy. Neurosci Lett. 2016 Jun 20;625:26-33. Review. PubMed PMID: 27155457

Xu X, Miller EC, and Pozzo-Miller L. Dendritic spine dysgenesis in Rett syndrome. Front Neuroanat. 2014 Sep 10;8:97. Review. PubMed PMID: 25309341.