Dec 27 2016

An injection of optimism into biomedical research – Part 2: Improved management for two textbook diseases

by at 8:54 pm under General

This is Part 2 of my Injection of Optimism into Biomedical Research Series.  To read Part 1, click here.

Two diseases which have not (yet) been virtually eliminated – as phenylketonuria and congenital hypothyroidism have – but for which sufferers have seen huge benefits from early diagnosis and improved management are cystic fibrosis (CF) and sickle cell disease (SCD). Both of these diseases are caused by mutations in a single gene and inherited in an autosomal recessive manner. Though rare overall, they are among the most common genetic disorders in the world. As such, they are often “textbook examples” in introductory genetics classes. They are both now included in newborn screening programs in all 50 US states.

CF is present in 1 in between 2.500 and 3,500 births in Caucasians in the US, being the most common life-limiting genetic disorder amongst Caucasians. It leads to damage to multiple organ systems through the buildup of sticky mucus due to an abnormality in a chloride channel. In particular, it can result in severe nutritional and respiratory problems. While no curative treatment exists for this still-devastating disease, improved management has played a huge role in both quality of life and lifespan. This includes dietary recommendations to prevent malnutrition, therapeutic approaches to clear out the airways from thick secretions, and proactive use of antibiotics for treating airway infections. It is difficult to precisely understand the effect of this improved management on life expectancy, as when CF was first recognized as a stand-alone disorder in 1938 it was through autopsies of malnourished infants who had a life expectancy of 6 months. Less severe cases started being identified in the 1950s with the introduction of standardized “sweat tests” which led to comprehensive programs and improved survival. The responsible gene was finally identified in 1989. In the early 1970s the life expectancy for these “milder” cases was only in the teens, increasing to 25 years in 1985 and 37 years in 2008. There is increased hope that targeted gene therapy will provide a curative treatment, and the progress obtained in the last few decades must still not be overlooked.

SCD is a group of disorders which are characterized by hemoglobin – the protein in red blood cells that carries oxygen from the lungs throughout the body and returns carbon dioxide back to the lungs – having an abnormal and stiff shape. This leads to red blood cells (RBCs) which are sickle shaped instead of the usual flexible disc shape. The abnormal RBCs can stick to the vessel walls, leading to a lack of oxygen in surrounding tissues. This can result in severe “pain crises,” as well as anemia, increased susceptibility and impaired response to infections, and progressive organ damage.  SCD is the most common inherited blood disorder in the US and occurs in 1 in 365500 African Americans. The use of screening and other management strategies in early childhood, including penicillin prophylaxis and pneumococcal vaccines have led to an increase in life expectancy from < 20 years in the 1970s to the 30s or 40s since the early 1990s. Adult patients may also be prescribed hydroxyurea, which may reduce the frequency of the pain crises and the need of blood transfusions – this medication was initially approved in 1967 by the FDA to treat cancer and received a new indication for SCD in 1998 and is thus a great example of drug repurposing.

As the sickle cell trait is associated with protection against malaria when the disease-causing allele is present in a single copy, SCD is also very common in sub-Saharan Africa, estimated to affect 3% of all births in some regions. Indeed, it appears to be a major but often ignored cause of early childhood mortality, with some estimates ranging from 50-90% of individuals with SCD dying in early childhood and SCD accounting for 5-16% of under-5 mortality in certain regions. Similarly to CF, there is hope in using modern targeted approaches, including CRISPR, however the impact of improved management has been tremendous and indeed, its adoption in sub-Saharan Africa could substantially lower childhood mortality. Even in the US, there are limitations in terms of access to care for many SCD patients, meaning that improving overall management could improve outcomes even further.

Acknowledgment: Dr. Jacob Corn from UC Berkeley, the senior author of this paper on using CRISPR for SCD, was a keynote speaker at the 2016 ICBI Symposium. I learned a lot about SCD from talking to him, which made it very easy for me to look up the references for the second part of this post.


One response so far | Categories: General

One Response to “An injection of optimism into biomedical research – Part 2: Improved management for two textbook diseases”

  1. Simina Boca on 18 Jan 2017 at 11:40 pm

    I should have mentioned that there are a number of targeted therapies approved or under consideration for subsets of people with CF. In particular, ivacaftor (Kalydeco) and the combination therapy lumacaftor/ivacaftor (Orkambi) were approved by FDA in 2012, respectively 2015. Kalydeco is approved for a mutation present in ~4% of patients, and Orkambi for a mutation present in ~70% of patients These approvals are very recent so their health impact has yet to be quantified, but will hopefully further improve outcomes for individuals with CF.

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