Synapse loss in Alzheimer’s disease and how SPG302 can help

June is Alzheimer’s and Brain Awareness Month. We take this timely opportunity to hear our Chief Science Officer, Dr. Peter Vanderklish, describe how SPG302 – our novel, regenerative medicine approach to neurodegenerative diseases – can be of benefit in Alzheimer’s disease.

The burden of Alzheimer’s disease
Over 44 million people worldwide suffer from Alzheimer’s disease, the most common and well-known form of dementia1 . From every perspective (patients, family and friends, caregivers), the impact of Alzheimer’s is devastating, robbing those afflicted of their memories and other faculties of mind that form the essence of who they have become over a lifetime.  

Peter Vanderklish, PhD
Chief Science Officer

Unfortunately, an effective treatment for Alzheimer’s has remained elusive despite its near 120-year recognition as a clinical entity. While the search for new treatments has been vigorous, involving billions of dollars in government and private investment and the participation of tens of thousands of patients in clinical trials, there are still no therapies that prevent, stop, or reverse the progression of Alzheimer’s. The small handful of therapies that have been approved offer only a modest and temporary reduction in symptoms or the rate of disease progression. This situation is by any measure a crisis, not only for patients and their families, but also economically. In the US alone, it is estimated that Alzheimer’s and other dementias could impose an annual economic burden of $1.1 trillion by 2050 unless successful therapies are developed2 .

Recently, antibody therapies (“biologics”) for Alzheimer’s have emerged that clear the brain of amyloid beta deposits that are a hallmark of Alzheimer’s disease. The approval of Lecanemab (Leqembi®) in 2023, with Donanemab likely to follow this year, mark what may be the dawn of a new era in dementia drug development in which the transition from concept to clinic is more rapid and guided by biomarkers of the disease process. However, the very modest clinical benefits of such therapies, along with their cost and significant risks, leave much to be done to create meaningful change in the lives of patients. Spinogenix aims to provide an entirely new approach to treating Alzheimer’s focused on regeneration. By reversing a central feature of the disease process, synapse loss, Spinogenix has the potential to help reverse cognitive decline and improve memory with a once-a- day pill.

Synapse loss is the heart of the problem in Alzheimer’s disease
The beginnings of a new path forward in Alzheimer’s treatment emerged in the 1980s as several investigators discovered that Alzheimer’s was associated with large reductions in the numbers of synapses, the connections between neurons in the brain, in brain areas affected by the disease3 . In particular, it was found that synapses using the amino acid glutamate – i.e. glutamatergic synapses, the most common type of excitatory synapse in the brain – were lost in an early and progressive manner in Alzheimer’s. These findings were subsequently replicated and extended by many scientists using a multitude of techniques in animal models and human brain tissue, including the recent use of PET imaging in living Alzheimer’s patients 4 . The crucial role of synapses found more support in studies showing that people who are cognitively normal, despite having large amounts of the hallmark amyloid deposits in their brains, have more synapses5 . It is now recognized that, at its core, Alzheimer’s Disease is a synaptic failure and that synapse loss both correlates with and drives cognitive decline. Loss of synapses essentially disconnects neural circuits involved in learning, memory and cognition. This fundamental observation prompted the hypothesis decades ago that for any therapy to be successful in Alzheimer’s it must stop synapse loss or, ideally, regenerate synapses6. This path forward, one that is in principle capable of reversing symptoms of Alzheimer’s if synaptic regeneration can be achieved, has been essentially blocked by a lack of pharmacological or other approaches that can regenerate glutamatergic synapses.

SPG302 has the potential to regenerate synapses in Alzheimer’s disease
Spinogenix has advanced the novel compound SPG302 into human Phase 1 clinical trials (NCT05882695). SPG302 belongs to a new class of synaptic regenerative small molecules developed by Spinogenix (the SPGs) that have the potential to reverse synapse loss in Alzheimer’s disease and a broad set of other diseases that, like Alzheimer’s, are characterized by synapse loss – the “synaptopathies” – such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease, as well as neuropsychiatric disorders such as schizophrenia. SPG302 induces the regeneration of synapses that use the amino acid glutamate as a neurotransmitter, the most common type of excitatory synapse in the brain, the majority of which are comprised of a specialized structure called a dendritic spine that is on the receiving end of synaptic communication. Such synapses are greatly reduced by Alzheimer’s disease, provide cognitive reserve when present at normal levels, and are the type regenerated by SPG302. Preclinical studies with SPG302 have demonstrated that it can induce regeneration of synapses and improvements in cognition in an animal model of Alzheimer’s7. In addition, studies in animal models of ALS and spinal cord injury8 have revealed benefits on motor function, respiration and survival. Notably, the beneficial effects of SPG302 in animal models of Alzheimer’s, ALS and SCI manifest within weeks of daily treatment.

Launching human clinical trials in Alzheimer’s disease
Having established safety and tolerability in healthy human subjects, and a dose that achieves an exposure level associated with efficacy in animals models, Spinogenix is now planning to initiate a Phase 2 clinical trial in Alzheimer’s disease in 2024 (NCT06427668). The trial will enroll people with mild to moderate Alzheimer’s and involve multiple readouts of potential efficacy including cognitive, neurophysiological and other measures. As discussed in a prior blog by Dr. Craig Erickson, Spinogenix is including neurophysiological measures in each of its trials of SPG302 due to the potential for rapid increases in synaptic density to produce changes in brain activity that can be detected by electrophysiological recording techniques such as EEG. In addition, because SPG302 is a rapid-acting synaptic regenerative therapy, we project that the duration of our Alzheimer’s trial may be less than that of prior studies of treatments that were designed to slow the rate of progression. Such strategies (used in testing the most recently approved drug, Leqembi®) required long treatments to see even modest differences between groups. Our hope is that in Alzheimer’s, ALS, and other synaptopathies, our unique synapticregenerative technology will, for the first time, result in actual improvements in symptoms and function – in essence, becoming the first therapy that patients themselves can tell is working.

  1. GBD 2016 Dementia Collaborators, Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet NeurolJan;18(1):88-106 (2019). Epub 2018 Nov 26.

  2. Velandia, P. P. et al. Global and regional spending on dementia care from 2000-2019 and expected future health spending scenarios from 2020-2050: An economic modelling exercise. EClinicalMedicine. Mar. 13:45:101337 (2022). Mar eCollection 2022. 

  3. Scheff, S. W. & Price, D. A. Alzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus. Journal of Alzheimer’s disease : JAD 9, 101-115 (2006).

  4. Mecca, A. P. et al. Synaptic density and cognitive performance in Alzheimer’s disease: A PET imaging study with [(11) C]UCB-J. Alzheimer’s & dementia : the journal of the Alzheimer’s Association (2022). 

  5. Boros, B. D. et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann. Neurol. 82, 602-614 (2017). 

  6. DeKosky, S. T. & Scheff, S. W. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann. Neurol. 27, 457-464 (1990). 

  7. Trujillo-Estrada, L. et al. SPG302 Reverses Synaptic and Cognitive Deficits Without Altering Amyloid or Tau Pathology in a Transgenic Model of Alzheimer’s Disease. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (2021). 

  8. Fogarty, M. J. et al. Novel regenerative drug, SPG302 promotes functional recovery of diaphragm muscle activity after cervical spinal cord injury. The Journal of physiology 601, 2513-2532 (2023). 

Synapse loss in Alzheimer’s disease and how SPG302 can help

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