How an enhanced whole genome sequencing test helped identify genetic markers predicting piromelatine treatment response in patients with mild Alzheimer's disease

In a study published in The Journal of Prevention of Alzheimer's Disease (JPAD) - and co-authored by the Department of Psychiatry and the Behavioral Sciences, and Department of Neurology, Keck School of Medicine, and Leonard Davis School of Gerontology of the University of Southern California, Neurim Pharmaceuticals in Tel Aviv, the Department of Neurobiology, Faculty of Life Sciences, Tel-Aviv University, and our R&D team at Dante Labs - results demonstrated the benefits of whole genome sequencing in identifying genetic markers predicting treatment response in Alzheimer’s disease patients. 


An extract is below. Please follow this link for the full article


Current treatments for Alzheimer disease are only modestly effective over a limited time, and the unmet need for preventive and personalized treatments for Alzheimer patients is great.


Authors of the study stated, “Pharmacogenomics and biomarkers have been used for improving the benefit/risk ratios of drugs and treatment across medicine. In Alzheimer’s drug development most phase 2 and 3 clinical trials failed to show clinical benefit. To overcome this circumstance, the importance of using biomarkers for enhancing recruitment and potential treatment efficacy is well-recognized (e.g. APOE-4 carriers may respond differently than APOE-3 carriers to treatments).”


Piromelatine is both a melatonin and serotonin receptor agonist developed for mild Alzheimer;s disease. Dante Labs partnered with Neurim Pharmaceuticals and academic institutions, including Keck School of Medicine and Leonard Davis at the University of Southern California, Los Angeles on a study aimed at identifying genetic markers predicting piromelatine treatment response using a whole genome and whole exome sequencing approach, the cluster may predict efficacy of piromelatine in mild Alzheimer’s disease patients.


The authors identified several SNPs associated with a differential response to piromelatine treatment in patients with mild Alzheimer’s disease. The SNPs identified had not been previously reported to be associated with Alzheimer’s disease or with response to therapeutic agents. 


In particular, the results suggest that the 5-6 2q12 (2:107,510,000-107,540,000) 5-6 SNPs polymorphism cluster may serve as a predictor of cognitive enhancement with piromelatine treatment measured by cNTB, but of worsening measured by the ADAS-Cog14 in patients with mild Alzheimer’s disease.


Thus far, the intergenic 2:107,510,000-107,540,000 range has not been described in relation to any disease. However, copy number variants in chromosome 2q12 region encompassing the 2:107,510,000-107,540,000 range are associated with schizophrenia. Rare copy number variants (deletions or duplications; CNVs) in Chromosome 2 region 2q12.2 (2: 106992995-108507424 in GRCh37) in vicinity of or encompassing the 2:107,510,000-107,540,000 locus) were reported in three of 1656 (0.18%) people with schizophrenia and in one of 4036 (0.02%) healthy controls and suggested as a schizophrenia susceptibility risk factor, but not formally associated with the disease nor with symptomatic Alzheimer disease.


This study suggests that piromelatine, especially in higher doses, may be particularly effective for mild Alzheimer’s disease patients who do not carry this 2q12 polymorphism cluster. 


A further investigation in a larger, prospective early stage clinical trial of Alzheimer’s disease patients who are non-carriers of the polymorphism cluster may be beneficial in understanding how genomic sequencing can affect Alzheimer’s disease.

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Source: https://www.jpreventionalzheimer.com/keyword/clinical-trials

Prevention of Alzheimer's Disease Carriers of the 2q12 polymorphism cluster