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Neurodegenerative disorders and Parkinson’s disease.

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Nirupama Deshpande on December 6, 2021

The idiom “to lose one’s nerves” is literally true when it comes to neurodegenerative disorders. These disorders are characterized by the progressive loss of disease-specific neural populations in the brain that manifests either as problems with movement (ataxias) or mental function (dementias). These disorders include Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).

Amongst these, Parkinson’s Disease pathology is the most common movement disorder affecting many areas of the nervous system and different types of neurons. However, substantial emphasis has been on the degeneration of dopaminergic neurons in the substantia nigra pars compacta region of the brain. This region is critical for facilitating movements and dopamine deficiency here is thought to cause the classical PD motor symptoms: tremor, bradykinesia, and rigidity, and later postural instability. Also, there are often many non-motor symptoms that may precede the motor problems such as sleep disorders, hyposmia, cognitive impairment, and pain1.

PD is a multifactorial disease. There are many theories about what causes PD. Although different, all theories involve aggregation of α-synuclein – a presynaptic protein important for synaptic vesicle trafficking. In PD, α-synuclein misfolds, forming oligomers that aggregate into intraneuronal inclusions named Lewy bodies2. Added to this, recent research on the mechanism of PD has identified lysosomes and mitochondria as organelles prone to malfunction. One of the theories suggests that PD-associated mutations impair lysosomal protein degradation, which causes the accumulation of α-synuclein. Mitochondrial abnormalities such as electron transport chain impairment, alteration in morphology, and mutations in the mitochondrial DNA are linked with the pathogenesis of PD3. Another idea is that misfolded α-synuclein is released from neurons and transmitted to the neighboring microglia and astrocytes. These cells then trigger the release of proinflammatory mediators that promote dopaminergic neuronal degeneration. 

Current treatments for Parkinson’s Disease Pathology

The multifactorial nature of Parkinson’s Disease pathology has eluded the development of curative therapy. The only therapies available for PD today provide symptomatic relief and they do little to halt the progression of the disease. Currently, the most used treatment for PD is a dopamine precursor: Levodopa, which is a dopamine replacement therapy that compensates for the lack of dopamine, for the treatment of motor symptoms. However, one of the major limitations of Levodopa has been the debilitating side effects caused by long-term use.

These include disturbing dyskinesias, or uncontrolled movements, and equally disturbing on-off effects in which the effect of the drug suddenly stops, freezing patients almost mid-sentence. Mechanisms underlying these complications are still unclear. Erratic drug delivery due to the short half-life of Levodopa, variability in its absorption, and blood-brain barrier transportation is thought to play an important role in the development of motor complications4.  

Many studies have focused on improving the bioavailability of Levodopa. Also, many derivatives, improved reformulations, and innovative routes of administration have been developed. Current Levodopa preparations contain Carbidopa or Benserazide, inhibitors of the enzyme catechol-O-methyltransferase, that increase the bioavailability and the half-life of Levodopa by blocking the breakdown of dopamine1.

Recently, an inhaled version of Levodopa, Inbrija was approved by the FDA. This is taken as an adjunct to Levodopa/Carbidopa when experiencing the return of symptoms. Another class of drugs that inhibit the enzyme monoamine oxidase-B, such as Selegiline, Rasagiline, and Safinamide, lead to an increase in the synaptic dopamine concentration. These drugs are used as an adjunct to Levodopa, as they reduce the Levodopa requirements and are reasonably well tolerated in patients.

Finally, dopamine agonists such Apomorphine and Rotigotine are known to induce less dopamine receptor stimulation than Levodopa and can markedly reduce the risk of motor complications when they are being used as initial monotherapy. Furthermore, Apomorphine and Rotigotine formulations can be administered transcutaneously, thereby permitting a continuous drug delivery.

Parkinson’s Disease Pathology: New Treatment and Ongoing Clinical Trials of Disease-Modifying Therapies

One of the main research objectives of Parkinson’s Disease pathology today is to develop disease-modifying therapies that can slow or stop the neurodegenerative process. Several treatments are being developed and tested, which include investigational molecules aiming to disrupt α-synuclein aggregates, compounds that alter the activity of the immune system, and gene therapy to improve intracerebral drug delivery.

Currently, there are 145 ongoing clinical trials, of which 57 trials are focused on long-term disease-modifying therapies, while the remaining 88 trials are focused on therapies for symptomatic relief (Figure 1)5. A large portion of trials in phase 1 (51 trials) and phase 2 (66 trials) are disease-modifying therapies such as immune and stem cell therapy for Parkinson’s Disease.

Some of the promising therapeutics in these trials are studies targeting α-synuclein reduction, involving both immunotherapy (BIIB054 & Prasinezumab) and small molecule inhibitors of α-synuclein aggregation (Mannitol & ENT-01). Some of the trials on symptom relief agents, include APL-130277, a sublingual film of apomorphine, and the Accordion Pill of carbidopa/levodopa in a gastric-retentive dosage form that uses biodegradable polymeric films to load the drug which is then folded into an undulated shape and then placed inside a capsule. Gene therapies aiming to deliver genes for biosynthetic enzymes to enable substantia nigra pars compacta to synthesis dopamine such as VY-AADC01 and OXB-102 are also ongoing.

Finally, some of the promising phase 3 disease-modifying therapy trials include evaluations of Exenatide, a glucagon-like peptide 1 receptor (GLP-1R) agonist, and Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, which is being evaluated for its ability to inhibit α-synuclein cell-cell transmission.  

Spatial transcriptomics and Parkinson’s Disease

The rapidly evolving field of spatial transcriptomics is enabling researchers to link differentially expressed genes to tissue structure and cell location which is critical for understanding cell-cell interactions and functions in the context of tissue. NanoString’s GeoMx® Digital Spatial Profiler (DSP) can spatially resolve gene and protein expression patterns and at the same time quantify location in a specific population of cells or tissue regions across many samples. Expression levels can be read out using the nCounter® Analysis System or via NGS using an Illumina sequencer. The nCounter Analysis System can quantify differential gene expression changes for up to 800 targets for a given sample without any conversion of mRNA to cDNA.

Further, a panel of genes analyzed can be preselected based on the application or disease area of interest. For example, the nCounter Neuropathology Panel contains genes involved in the six fundamental themes of neurodegeneration: neurotransmission, neuron-glia interaction, neuroplasticity, cell structure integrity, neuroinflammation, and metabolism, and could be used in research Parkinson’s Disease pathology and treatment.

On the spatial biology front, the GeoMx Human Whole Transcriptome Atlas (GeoMx Hu WTA) could provide an opportunity for measuring 18,000+ protein-encoding genes in tissue sections, across different brain regions or ages, and map where disease-related changes in expression occur, uncovering new pathways that could be explored as therapeutic targets for PD.

Spatial transcriptomics can address some of the problems faced in unraveling the molecular mechanism of PD as well as therapeutic targets. This approach is far more informative than studying the whole tissue, particularly in the brain, where different pathologies affect a specific subset of cells.

One of the major challenges has been the early detection of PD due to the lack of a robust clinical biomarker. An accurate biomarker is urgently required so that prevention is possible before the occurrence of irreversible brain damage. Under these circumstances, GeoMx DSP can help identify potential biomarkers and therapeutics for PD.

As an example, a study by Liu et al. screened for altered gene expression associated with PD in erythrocytes of patients using  GeoMx. A significant reduction in mRNA expression of the gene CHCHD2 was observed in the erythrocytes. Since erythrocytes are also easily accessible through liquid biopsy, it makes CHCHD2 a promising early diagnostic marker of PD6.

Another challenge to PD studies has been exploring stem cells as a therapeutic agent. These studies often show a lack of correlation between the in vitro and in vivo behavior of the stem cells most likely due to a difference in the microenvironment. Application of the GeoMx DSP system in this manner may help develop stem cell therapies by shedding light on understanding the surrounding environment of the stem cell and the cell-cell interactions.

References

  1. Radhakrishnan DM, Goyal V. Parkinson’s disease: A review. Neurol India. 2018 Mar-Apr;66(Supplement):S26-S35.
  2. Mahul-Mellier AL, Burtscher J, Maharjan N et al. The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proc Natl Acad Sci U S A. 2020 Mar 3;117(9):4971-4982.
  3. Puspita, L.; Chung, S.Y.; Shim, J.W. Oxidative stress and cellular pathologies in Parkinson’s disease. Mol. Brain2017, 10, 53.
  4. Poewe W., Antonini A. Novel formulations and modes of delivery of levodopa. Mov Disord 2015;30:114-20. 
  5. McFarthing K, Buff S, Rafaloff G, et al. Parkinson’s Disease Drug Therapies in the Clinical Trial Pipeline: 2020. J Parkinsons Dis. 2020;10(3):757-774.
  6. Liu, Xiaodan et al. “Reduced erythrocytic CHCHD2 mRNA is associated with brain pathology of Parkinson’s disease.” Acta neuropathologica communications vol. 9,1 37. 8 Mar. 2021
Post by Nirupama Deshpande