Immune cell fingerprint Historically, health care has been approached from a one size fits all mentality. Treatments are developed based on the anticipated response
Successful treatment for sickle cell anemia Gene therapy holds promise for treating a wide range of diseases, but historically it has seen more failures than successes. However, within the last decade the field has begun stacking up some impressive wins. Recently, sever- al patients with a blood disorder called sickle cell disease have found relief from their excruciating symptoms thanks to a clinical trial using CRISPR-based gene therapy. Sickle cell disease is an inherited blood disorder caused by mutations that affect the production or struc- ture of hemoglobin, the protein that carries oxygen in red blood cells. The defective hemoglobin turns red blood cells into deformed, sickle shaped cells that get stuck inside blood vessels and clog up blood flow. This causes excruciating attacks of pain, organ damage, and often premature death. Early clinical trials for CRISPR-based gene therapy are showing promise for individuals with sickle cell disease. CRISPR is used to edit stem cells and allow them to pro- duce a slightly different type of hemoglobin called fetal hemoglobin which is normally inactivated after birth. Bone marrow stem cells are removed from the affected individuals and the gene that turns off fetal hemoglobin production is disabled using CRISPR. The edited cells are transfused back to the patient and the now active fetal hemoglobin can carry oxygen throughout the body. One year after her treatment, the first U.S. patient to receive the gene therapy has not had any severe pain attacks and has not required any emergency room treat- ments, hospitalizations, or blood transfusions. Nearly every red blood cell in her body produces some level of fetal hemoglobin and about 46% of her total hemoglobin is fetal. The company that produces the gene therapy also reported favorable results on seven additional sickle cell patients and fifteen patients with a related condition called beta thalassemia. Although these treatments are still in early trials, the results look promising and could one day bring relief to other individuals suffering from these types of blood-based genetic diseases. n REFERENCES: www.npr.org/sections/health- shots/2020/06/23/877543610/a-year-in-1st-patient-to-get-gene- editing-for-sickle-cell-disease-is-thriving. And “Vertex and CRISPR Therapeutics Present New Data in 22 Patients With Greater Than 3 Months Follow-Up Post-Treatment With Investigational CRISPR/Cas9 Gene-Editing Therapy, CTX001™ at European Hematology Associa- tion Annual Meeting” 11 June, 2021. www.businesswire.com/news/ home/20210611005069/en/Vertex-and-CRISPR-Therapeutics-Present- New-Data-in-22-Patients-With-Greater-Than-3-Months-Follow-Up- Post-Treatment-With-Investigational-CRISPRCas9-Gene-Editing-Ther- apy-CTX001%E2%84%A2-at-European-Hematology-Association-Annu- al-Meeting. Accessed 31 August 2021. Press Release.
of an ‘average’ patient, yet expected to benefit an entire diverse population. Unfortunately for many patients, this strategy doesn’t work, with drugs either not working for them or causing disrupting side effects. A new resource could help researchers understand why some treatments work well in some patients but not others. A multi-national team of researchers used single-cell RNA sequenc- ing to create a library of more than 1 million immune cells collected from hundreds of healthy individuals from Australia. Looking at single cells allows researchers to detect subtle changes in individual cells. The study identified genes and immune cell types linked to specific autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, type 1 diabetes, and Crohn’s disease. An individual’s unique genetic immune profile could be used to design and deliver treatments tailored to their immune system. In fact, the findings have led to clinical trials in Sydney to predict which treatments will work for individual Crohn’s disease patients. The researchers made the full dataset publicly available so that other researchers could use it for new drug development and repurposing current drug treatments for autoim- mune diseases. n
REFERENCE: Yazar, S., et al. Single-cell eQTL mapping identifies cell type–specific genetic control of autoimmune disease. Science (2022) 376 (6589) DOI: 10.1126/science.abf3041
Kidney disease disparities Many types of severe kidney disease occur more frequently among individu- als of African ancestry. In 2010, scientists discovered that the major contrib- utor to this disparity is genetic change in one particular gene, APOL1 , which arose thousands of years ago in populations living in sub-Saharan Africa. APOL1 variants protect against parasitic African sleeping sickness but also increase a person’s risk of developing severe kidney diseases. A recent paper summarized the current understanding of APOL1 risk variants and how kidney disease presents in the clinic. A person can have either zero, one, or two APOL1 gene changes. Having two changes, one on each copy of the gene, significantly increases risk. Having two changes one on each copy of the gene significantly increases risk. However, not all indi- viduals with two APOL1 changes develop kidney disease. This suggests that other genetic and environmental factors affect risk, and a person’s APOL1 status is not a perfect predictor of risk. Identifying an APOL1 gene change can help identify the cause of a patient’s kidney disease. However, currently, there are no targeted therapies or modifications to treatment options based on a patient’s APOL1 gene status. In the context of kidney transplants, multiple studies show that donor kidneys with high-risk APOL1 gene changes fail at a higher rate than those without high-risk changes. Many transplant centers have begun testing possible kidney donors for APOL1 gene changes. More research must be done utilizing large and diverse datasets to fully understand how APOL1 gene changes lead to kidney disease and leverage this information to develop APOL1 targeted therapeutics. n
REFERENCE: Friedman, D. J. and M. R. Pollack. APOL1 Nephropathy: From genetics to clinical applications. CJASN (2021) 16: 294–303. DOI: 10.2215/CJN.15161219
9
SCIENCE FOR LIFE
Made with FlippingBook - Online magazine maker