From MedicalResearch.com
Gene-edited Kidney Organoids Re-Create Human Disease
Benjamin Freedman, Ph.D.
Assistant Professor | University of Washington
Department of Medicine | Division of Nephrology
Member, Kidney Research Institute
Member, Institute for Stem Cell and Regenerative Medicine
Seattle WA 98109
Medical Research: What is the background for this study? What are the main findings?
Dr. Freedman: We are born with a limited number of kidney tubular subunits called nephrons. There are many different types of kidney disease that affect different parts of the nephron. The common denominator between all of these diseases is the irreversible loss of nephrons, which causes chronic kidney disease in 730 million patients worldwide, and end stage renal disease in 2.5 million. Few treatments have been discovered that specifically treat kidney disease, and the therapeutic gold standards, dialysis and transplant, are of limited availability and efficacy.
Pluripotent stem cells are a renewable source of patient-specific human tissues for regeneration and disease analysis. In our study, we investigated the potential of pluripotent cells to re-create functional kidney tissue and disease in the lab. Pluripotent cells treated with a simple chemical cocktail matured into mini-kidney ‘organoids’ that closely resembled nephrons. Using an advanced gene editing technique called CRISPR, we created stem cells with genetic mutations linked to two common kidney diseases, polycystic kidney disease (PKD) and glomerulonephritis. Mini-kidneys derived from these genetically engineered cells showed specific ‘symptoms’ of these two different diseases in the petri dish.
Medical Research: What should clinicians and patients take away from your report?
Dr. Freedman: Pluripotent stem cells are a new area for kidney study and care. We have shown that the cells can turn into primitive mini-kidneys that can perform certain basic functions of the kidney in a petri dish. What is perhaps more impressive is that these very simple tissues can actually re-create ‘symptoms’ of kidney disease, such as PKD cysts from tubules and junctional defects in glomerulonephritis. This is especially important because these types of cells are typically hard to grow and study in the lab.
Gene editing techniques like CRISPR allow us to modify the human genome, which is breathing new life into the field of gene therapy. In our study, the only difference between mini-kidneys that showed disease symptoms and those that did not was a small mutation in a single stretch of DNA. By inference, correcting disease in patients may be as simple as correcting a single gene. Technologies like CRISPR and pluripotent cells are in their infancy, and are not yet ready for the clinic, but might someday revolutionize the way we practice medicine.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Freedman: In the short term, our lab and others like it will use these genetically engineered mini-kidneys to investigate how diseases like PKD, glomerulonephritis, and nephrotoxicity actually work. The organoids can be produced in multi-well format, which raises the possibility of performing ‘clinical trials in a dish’ for thousands of candidate drugs to rescue disease symptoms. This high-throughput discovery approach will lead to better-informed and more successful clinical trials. The approach can be extended to many different types of kidney disease.
In the long term, pluripotent cells are a way to produce tissue on-demand that would be 100 % immunocompatible with the original patient. There is still a long way to go. The mini-kidney cells are trying to form a kidney nephron, but key structural components are missing or need to be integrated. We show in this study that mini-kidney tubules can survive after transplantation into mice. The holy grail is to further develop these grafts to be safe, efficacious, and disease-free for clinical use in human patients.
PKD Treatment
From Coventry Observer, United Kingdom
A LIFECHANGING drug which was trialled and tested in University Hospital Walsgrave, Coventry, is now available to members of the public as of today (October 28).
People living with Autosomal dominant polycystic kidney disease (ADPKD) will now be able to access Jinarc (tolvaptan) – the first treatment shown to slow progression of the life-threatening condition which affects the kidneys.
ADPKD is an inherited condition that causes small, fluid-filled sacs called cysts to develop in the kidneys.
The condition can cause a wide range of problems including abdominal pain, high blood pressure and kidney stones.
Though children are born with the condition, it is not often noticeable until someone reaches 30 years old.
For many people, kidney failure at a young age can be daunting prospect.
However the introduction of tolvaptan will ensure those living with ADPKD can slow their progression towards kidney failure and reduce the number of symptoms they experience.
Tess Harris, CEO of the PKD charity who raise awareness and funds to help combat the condition, explained how the new drug will – in the long run – save thousands of pounds and provide a better quality of life for those diagnosed.
Ms Harris told The Observer: “This is the first ever drug in the world to treat this condition.
“As chief executive of the charity, our aim has been to fundraise to help support patient education, raise awareness of the condition and give verbal evidence to the public about the problems ADPKD cause.”
Tess continued and stated that to fund someone on a dialysis machine each year costs the NHS £40,000.
Not only will the new drug save money, but it will also make more transplants available to those who suffer from poor kidney function – who will not be eligible to take the drug.
Tess said: “The majority of my family is affected by the condition – my father passed away when he was 57 whilst myself, my brother, sister, niece and nephew are all affected also.
“A new quality of life will be discovered for those eligible to take the drug.”
Kieran McGovern – currently in his 30s – is just one of the 64,000 people affected by the condition in the UK.
After trialling the drug for the past eight years, Kieran revealed that taking tolvaptan has provided him with huge psychological boosts and that he feels as though he can lead a normal life.
Kieran added: “I knew that my Dad had the ADPKD so when I was 21 I decided to go and get checked up to see if I also had the condition.
“The result displayed that I did and it massively affected me – there were various complications that I had to adapt to such as my diet where I was restricted on various protein and dairy items.
“At the time I was living over in Ireland, where my blood pressure was continuously high.
“However since being on the drug I have discovered that it gives you a perk.”
Judith Dignum, chair of trustees at the PKD charity, said: “Up until now if you have been diagnosed with ADPKD you would’ve had no treatment – you’d just have to wait and worry about yourself and your children.
“This drug will help make a massive difference by delaying the progression of the disease, it will allow for extra healthy years.
“There are five stages of a kidney disease – the fifth stage would be when someone requires dialysis, this drug is required when someone would be at the second of third stage of treatment.”
PKD Foundation
On October 1, Congress gave final approval to HR 719, the FY16 Continuing Appropriations Act (or “CR”). In general, the law funds federal programs at their FY15 level until December 11, 2015. Most people hope that Congress will fund the government through the rest of FY16 by the end of this calendar year.
The next eight weeks will be very busy in Congress, starting with the election of a new Speaker of the House and Republican leadership team. In addition to annual appropriations, Congress needs to work on a host of other important legislative proposals: a budget deal to prevent automatic cuts in both domestic and defense spending (sequestration); an increase in the national debt ceiling; a transit and highway bill; a bill extending various tax breaks; the Export-Import Bank; and maybe other matters. Given the nature of the legislative process (especially at the end of a calendar year), it is too early to even speculate on when Congress may complete action on any of these proposals. Quite possibly, several of these key bills may be combined into an “omnibus” bill. How changes in the Republican House leadership may affect any of these issues and their timetables remains to be seen.
New FDA Commissioner
President Obama has nominated Dr. Robert Califf to be the new FDA Commissioner. As you know, the FDA is responsible for approving new drugs and medical devices. One of those drugs would benefit PKD patients.
The Senate Health, Education, Labor and Pensions (HELP) Committee will have to confirm Dr. Califf for his new position. A confirmation hearing provides an opportunity for Senators to question the nominee on FDA policies and procedures.
21st Century Cures Act
A significant portion of the funding increase for NIH in the 21st Century Cures bill (HR 6) would come from selling oil from the national Strategic Petroleum Reserve (SPR). Several Senators, including Sen. Lisa Murkowski (R-AK), object to the use of SPR for non-energy purposes. On October 6, the Senate Energy and Natural Resources Committee, which Sen. Murkowski chairs, held a hearing on the SPR and Energy Security.
In July, the Committee approved S. 2012, a bipartisan bill introduced by both Murkowski and ranking Democrat Maria Cantwell (D-WA). The key provision is Section 2103(b), which restricts the uses of funds raised from any drawdown to purposes directly related to either the operation of the Reserve or projects that enhance U.S. energy security. The Senate has not yet debated S. 2012.
Murkowski: In her opening statement on October 6, Sen. Murkowski stated that the SPR is “not an ATM for new spending” that could cause the country to lose the substantial benefits of the SPR. She added that some in Congress are treating our own SPR as a “cash machine.” Sen. Debbie Stabenow (D-MI) agreed that using SPR for other purposes makes “no sense”.
Sen. Elizabeth Warren (D-MA) focused on the transportation and 21st Century Cures bills. The proposed sales in these bills would fund the government with no flexibility. If oil drops to $1 a barrel, that oil would have to be sold to fund those programs. Mandating an inflexible sell-off is another bad idea for funding the federal government. She’d prefer, by inference, closing tax loopholes and getting serious about tax reform. Note that Warren also serves on the HELP Committee, which will draft its own 21st Century Cures bill.
As anticipated, most of the Senators on the Committee support the Murkowski position. Finding adequate and guaranteed funding for 21st Century Cures is imperative, but it will not be easy. [Read more]
No comments:
Post a Comment