Early testing, markers and risk factors for Alzheimer disease Diagnosis of Alzheimer disease is currently made with clinical assessments of memory and cognitive impairment along with diag- nostic tests, such as MRI and PET scans, which are expensive and unavailable for some patients. The limitations of current diagnos- tic tests combined with the growing rate of Alzheimer disease and dementia worldwide highlight a need for more accurate, affordable diagnostic tests. Blood test for Alzheimer disease diagnosis An international team of researchers have developed a blood-based test for the diagnosis of Alzheimer disease that is more accurate than MRI brain scans, and as accurate as PET scans and spinal taps. The test measures a form of tau protein in blood, which is a protein re- sponsible for the devastating tangles that promote damage within the brain. The test can not only differentiate between Alzheimer demen- tia and other forms of dementia, but can also predict how quickly a person’s cognitive ability will decline by measuring the amount of the protein in their blood. The test needs to undergo further clinical trials but could be available within the next two to three years. Disruption of blood-brain barrier early marker In a recent study published in Nature , researchers suggest that the APOE4 gene, long known to increase a person’s risk for Alzheimer disease, causes damage to the blood-brain barrier (BBB) which nor- mally helps to keep toxins out of the brain. The research team found that people who were cognitively healthy and carried at least one copy of APOE4 had a leaky BBB in two brain regions important for memory and cognition. Surprisingly, these effects preceded any signs of tissue loss, suggesting that BBB disruption is an early event in the onset of neurodegeneration.
NEW FINDINGS — HUMAN HEALTH
Building a genetic map of psychiatric disorders
Gene editing: promises and pitfalls
one gene in human embryos but showed large-scale, unintended DNA deletions and rearrangements, some as large as a whole chromosome. While it is well known that gene editing can cause "off target" mutations, these studies suggest a much larger land- scape of CRISPR-influenced errors. Because of the unknown nature of CRISPR-based gene editing, many countries limit its use to human somatic cells, banning editing in germline, or reproductive, cells. The CRISPR-baby scandal rocked the scientific community and sparked controversy across the globe when a Chinese scientist, He Jiankui, secretly created the world’s first genetically edited babies. He was recently sentenced to prison for illegally practicing medicine, supporting the notion that the practice of human gene editing should be approached in a methodical and cautious manner, backed by supportive research in accepted experimental models.
The burden of psychiatric disorders continues to grow world- wide with more than a fourth of the population being affected with one or more disorder in any given year. Psychiatric disor- ders refer to a wide range of mental health conditions that affect a person’s mood, thinking and behavior. Results from research in twins and large-scale genomics studies suggest that genetic variation has a major influence on psychiatric disorders. The Cross-Disorder Group of the Psychiatric Genomics Consortium is an international group of researchers who seek to map out the genetic landscape of psychiatric disorders in an effort to improve and customize the diagnosis, prognosis and therapy of the disorders. In a recent publication in Cell , the team reported results from the largest study on the genetics of psychiatric disorders to date. Researchers performed genetic analysis on over 230,000 patients with anorexia nervosa, autism, ADHD, schizophrenia, bipolar disorder, depression, obsessive-compulsive disorder or Tourette Syndrome and nearly 500,000 control individuals without the disorders. The researchers discovered 109 genetic variants that were associated with at least two of the eight disorders and 26 that were associated with four or more. Using this knowledge, clinicians could estimate a person’s genetic risk to develop other disorders based upon the disorder with which they are clinically diagnosed. Another important discovery from the study shows that the genes in which the variants are found are usually active during the second trimester of pregnancy. Because this is a crucial stage in the development of the nervous system, the gene variants may play a role in brain development and confer a broad risk of psychiatric disease. The Consortium plans to continue mapping the genetic landscape of genetic disorders through the analysis of other genetic variations and also epigenetic changes that could give insights to interactions between genes and the environment. REFERENCE: Cross-Disorder Group of the Psychiatric Genomics Consortium. Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell (2019) 179:1469-1482 doi:10.1016/j. cell.2019.11.020.
CRISPR is a gene editing technology that creates targeted and specific changes to DNA. It is widely used in a labo- ratory setting to cheaply and efficiently study the function of specific genes. However, CRISPR-based gene therapy to treat genetic disease in humans is gaining popularity. Recent studies suggest that while gene therapy shows promise, direct gene editing of human embryos should be approached with caution. CRISPR Promising Results Treating Rare Inherited Diseases Beta thalassemia and sickle cell disease are inherited blood disorders caused by mutations that affect the production or structure of hemoglobin, the protein that carries oxygen in red blood cells. Promising preliminary results presented at a scien- tific meeting this year report that due to CRISPR-based therapy three people with these disorders no longer require the blood transfusions they previously relied on to treat their symptoms. For the gene therapy, bone marrow stem cells were removed from the affected individuals and the gene that turns off fetal hemoglobin production was disabled with CRISPR. The edited cells were transfused back to the patient and the now active fetal hemoglobin, which is normally turned off after birth, can carry oxygen throughout the body. In Vivo Gene Editing In another promising advance for gene editing, scientists used CRISPR to try to edit a gene while the DNA was still inside the person’s body. Scientists engineered a harmless virus to deliver the instructions to manufacture the CRISPR gene-editing machinery within the body. The virus was injected into the eye of patients with blindness due to a rare genetic disorder. Once inside the eye, the CRISPR machinery repaired the genetic defect that caused the blindness in hopes that the person’s vision is ultimately restored. CRISPR Cautionary Tales Not all of the buzz surrounding the advancement of CRISPR gene editing to treat human disease is positive. Three recent studies that were published on the preprint server bioRxiv reveal how gene editing can go awry. Each of the studies set out to edit
REFERENCES: CRISPR Therapeutics. CRISPR Therapeutics and Vertex Announce New Clinical Data for Investigational Gene-Editing Therapy CTX001™ in Severe Hemoglobinopathies at the 25th Annual European Hematology Association (EHA) Congress. 12 June 2020. Web. 31 August 2020. https://crisprtx.gcs-web. com/news-releases/news-release-details/crispr-therapeutics-and-vertex-an- nounce-new-clinical-data. NPR. In A 1st, Scientists Use Revolutionary Gene-Editing Tool To Edit Inside A Patient. 4 March 2020. Web. 31 August 2020. https://www.npr.org/sections/ health-shots/2020/03/04/811461486/in-a-1st-scientists-use-revolutionary- gene-editing-tool-to-edit-inside-a-patient. Alanis-Lobato, G. et al. Frequent loss-of-heterozygosity in CRISPR-Cas9- edited early human embryos. Preprint posted to Biorxiv 5 June 2020. doi: 10.1101/2020.06.05.135913. Zuccaro, M.V. et al. Reading frame restoration at the EYS locus, and allele-specific chromosome removal after Cas9 cleavage in human embryos. Preprint posted to Biorxiv 18 June 2020. doi: 10.1101/2020.06.17.149237. Liang, D. et al. Frequent gene conversion in human embryos induced by double strand breaks. Preprint posted to Biorxiv 20 June 2020. doi: 10.1101/2020.06.19.162214. AP News. China convicts 3 researchers involved in gene-edited babies. 30 December 2019. Web. 31 August 2020. https://apnews.com/7bf5ad- 48696d24628e49254df504e3ee. However, the big breakthrough came when they looked at the week immediately preceding the flare up. The scientists found an RNA signature (a combination of RNA molecules) that matched a type of inflammatory fibroblast previously identified as an aggressor in the joints of patients. They named these cells pre-inflammatory mesenchymal cells, or PRIME cells. Although the patient set was small, the results of the study are extremely promising. A home test of this kind would greatly improve quality of life for individuals with rheumatoid arthritis by alerting them of a pending flare up, giving them time to consult with their doctor to take necessary steps to avert or minimize the flare up. REFERENCE: Orange, D.E. et al. RNA identification of PRIME cells predicting rheumatoid arthritis flares. The New England Journal of Medicine . (2020) 383:218-228 doi: 10.1056/NEJMoa2004114.
Genetic risk factor for multiple neurodegenerative diseases
A group of researchers recently uncovered gene variants that double a person’s risk of multiple neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis and frontotem- poral dementia. The gene, TET2, codes for a protein involved in DNA demethylation, or removing chemical groups from DNA that changes how it is read. Other studies suggest that DNA becomes more meth- ylated as we age meaning the TET2 genetic variants with impaired de- methylation processes discovered in this study might mimic the aging process, putting people at higher risk of neurodegenerative disorders. While these tests and biomarkers still require further testing, they provide promise for affordable, early detection of Alzheimer disease and other neurodegenerative diseases.
Predicting arthritis flare-ups with a blood test
The ability to self-administer a blood test and have an early warning of symptom flare-ups would be life-changing for people with chronic diseases. The medical community is one step closer to offering this type of test to patients with rheumatoid arthritis, an autoimmune disease characterized by off and on joint stiffness, swelling and pain. Four rheumatoid arthritis patients provided blood samples and disease symptom diaries to scientists every week for several years. The scien- tists sequenced messenger RNA from samples from the weeks prior to, during and after a flare up to detect changes from baseline. Two weeks prior to symptom relapse, they detected a change in the RNA profile that was consistent with an increased abundance of immune cells.
The laboratories of HudsonAlpha faculty researchers Richard M. Myers, PhD, and Greg Cooper, PhD, contributed to the TET2 research.
REFERENCES: Palmqvist, S. et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer Disease versus other neurodegenerative disorders. JAMA (2020) 324:772-781. doi: 10.1001/jama.2020.12134. Montagne, A. et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. (2020) 581:71-76. doi: 10.1038/s41586-020-2247-3. Cochran, N. et al. Non-coding and loss-of-function coding variants in TET2 are associated with multiple neurodegenerative diseases. The American Journal of Human Genetics (2020) 106:632-645. doi: 10.1016/j.ajhg.2020.03.010.
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