Here’s a New York Times article from today that explains the strange world of drugs for rare, or orphan, diseases. A new drug for Short Bowel Syndrome, which affects about 5000 people in the US, will cost $300,000 a year. But the company that makes the drug provides it for free to people without insurance and pays for “coordinators” that help get insurance companies to pay for it for those who do. No person, apparently, pays more than $10 a month out-of-pocket.
Those Marvelous Zebrafish
Zebrafish have been vital part of BBS research. The fish grow rapidly and are transparent when they are young. This allows researchers to manipulate certain genes and watch as the fish develop to see how they are affected. This process has been central in understanding the role of cilia in development. Dr. Nico Katsanis’s lab at Duke University, the Center for Human Disease Modeling, has thousands of zebrafish that they are using to model what happens with various BBS genes.
But they are not the only ones using zebrafish. Here’s a video about another lab that is using zebrafish to better understand how brains work.
BBSFA Newsletter
The new BBSFA newsletter, the first under our new name is now available. Click here to read about news from our latest conference, about the possibility of a BBS Center of Excellence in the US, and other updates.
Click here to download a copy of the newsletter in PDF form.
Big Changes at the LMBBS Association
At the link below you’ll find a letter from the President and Board of the LMBBS Association that explains big changes we are making in the association. The most important two changes are:
1) We are changing the name of the association to the Bardet Biedl Syndrome Association. The reason for this change is that LMBBS is no longer used in the medical community. Anyone who is diagnosed with the syndrome today only hears of Bardet Biedl Syndrome. We want anyone who is affected by BBS to be able to find us easily–and that means having a name that everyone will immediately recognize.
2) We are changing the association into a 501©3 non-profit. The reason for this change is to make it easier to raise funds to support research and other services for families affected by BBS.
You can read more about the changes, including our new Vision and Mission statements in the letter from the President and Board.
Click here to download the letter in PDF format.
A new approach to treating retinal degeneration
Scientists at the University of Oxford have tested a new approach to restoring retinal cells on mice with great success. Current work on gene therapies have focused on introducing a replacement gene for a defective one in people with a degenerative retinal condition. This approach injects not a replacement gene, but full replacement cells.
The gene therapy approach is in clinical trials for people with Leber’s Congenital Amaurosis (LCA) and in animal trials for one BBS-variant. This new almost-stem-cell approach has only been tested in mice. Typically it takes almost ten years between animal testing and the beginning of a clinical trial in people.
Conference Highlights: Dr. Nico Katsanis
Dr. Nico, of course, needs no introduction. He concluded our day with a discussion about the present and future of diagnosis and treatment for BBS and other ciliopathies. Here I want to summarize the most important message of his talk:
We have to be patient with treatment and get it right.
Dr. Nico called the promising therapies that are emerging “ameliorating mitigations”–meaning that these therapies promise to either slow deterioration or restore some, but not all, function of some, but not all, cillia in a BBS patient. We are not talking about cures, but about lessening the effects of BBS.
The two most promising therapies for the short term are TUDCA, discussed earlier, and an extract from broccoli. Both have shown some success in animal models of BBS. Both are being used or are in Stage III clinical trials in human beings for other diseases, so an important safety milestone has been passed.
However, this doesn’t mean that these therapies are not potentially dangerous. And it doesn’t mean that anyone should go out and start using one of these compounds.
There are several reasons for this:
1) Because BBS is so variable, we have to test therapies very carefully. Some therapies may work for some genes but not others, and some may work for some mutations but not other mutations of the same gene. If we are not careful with testing we may come to the false conclusion that something doesn’t work when it does work for some small part of the population.
2) If anyone goes out and starts using these compounds on their own and is hurt by taking too much or even some unknown and unique interaction in their body it will put a halt to all trials of that compound for everyone. It will delay anyone’s ability to use the therapy. Trying to self-medicate isn’t just dangerous for you, it could hurt everyone with BBS.
3) Often the promising compounds for therapy like TUDCA and Vitamin A are toxic in the wrong doses. Even worse, getting these compounds from unregulated sources (like a natural food store or over the internet) is especially dangerous. Testing of compounds from unregulated sources have shown that less than 50% are what the label claims they are. Many of them are just sugar pills. Others are much less or much more concentrated than the label claims. Others are contaminated with dangerous pollutants. The only safe way of taking these compounds is working with doctors in clinical trials.
4) A huge benefit of the lab research that has been done over the last few years–and the use of all the genetic material donated by BBS patients and their families–is that we can accelerate the testing of various therapies because we can easily make zebrafish models of many different variants of BBS. That means we can test each compound quickly to see if they have an effect. Therapies can be developed much more quickly now that all this preliminary work has been done–and that is why donating genetic material is so important to the future treatment of BBS.
5) We have made great progress in just the last few years. For the first time we have promising therapies–gene therapy, TUDCA and other compounds. But the worst thing we can do now is get ahead of ourselves. It is hard to be patient when you see your child, loved one or yourself battling the effects of BBS. But moving too fast with these therapies could hurt all of us and set back the progress we’ve made. We have to be patient.
I’ve got more notes to share from Nico’s presentation in the next few days, but I thought this message of Nico’s was so important that it needed to get out quickly.
Conference Highlights: Dr. Erica Davis, genetic researcher at CHDM, Duke University
Dr. Phil Beales from the UK was going to join us for the conference this year, but unfortunately his father is very ill. We wish Phil and his family all the best.
Dr. Erica Davis who is part of the Center for Human Disease Modeling at Duke and who works with Nico and Phil on much of their research presented in Phil Beales’ place on the history and current progress of genetic research.
Here are some highlights:
1) BBS6 was the first gene identified in 2000. Since that time 16 additional genes have been discovered (BBS1 through BBS17) and verified covering 75% of BBS families. Using the genetic material donated through the BBS associations in the US and the UK, CHDM believes they have identified two more genes. After further testing and validation identification of those two genes should be published over the next few years.
2) The key to unlocking BBS was the identification of BBS8 in 2003 and its association with situs inversus (having organs on opposite sides of the body than normal). It was already known that situs inversus is related to cilia defects. So finding a BBS gene with a clear symptom that was cilia-related opened the doors to all the research that followed–it was the clue that BBS was all about cilia.
3) In many ways, we are lucky that BBS is a ciliopathy (or disease caused by mutations to cilia). The cilia are a very discreet and relatively easy to study part of cells. It is relatively easy to see what is happening (or not happening) with cilia as opposed to other types of cell damage.
4) One important way that the genetic research has improved lives is that in 1999 the median age of diagnosis was 9 years (in other words, half of people diagnosed were older than 9 when they discovered the cause of their symptoms). Today, that is being reduced substantially and children are being diagnosed prenatally with a molecular confirmation within a few months of birth.
5) One of the things we’ve been learning from the genetic research is that most mutations of BBS genes are unique to the family carrying them. There are two common mutations–1 of BBS1 and 1 of BBS10–that many people carry, but for the most part every family is slightly unique in their specific mutations. More than 100 different DNA changes have already been described in BBS.
6) While there are at least 20 genes that code for proteins that affect cilia in such a way to cause BBS symptoms, there are more than 1000 proteins in total that affect cilia. There are many other diseases that are caused by defects in cilia or cilia-associated proteins–these are known as ciliopathies.
7) A big leap forward in research has been the creation of central database known as the cilia proteome. This is a place where researchers from around the world can find information about all of the genes and the proteins associated with cilia formation or function. This enables much more collaboration between researchers studying any form of ciliopathy–and will help accelerate the progress of research.
Dr. Elise Heon, Ophthalmologist from Toronto's Hospital for Sick Children
Dr. Heon is a practicing ophthalmologist in Toronto and presented about her work with BBS patients. Highlights:
1) The first principle we have to remember is that most therapies aren’t yet fully tested and can do harm. Even Vitamin A only helps a small percentage of RP patients and actually reduces vision of others. The Vitamin A available in stores is not reliable–could be much stronger or weaker than it says and could be contaminated. Do not just start taking Vitamin A or anything else.
2) Why aren’t we all taking TUDCA already? Because the dosage used in the mouse study would be quite dangerous to human beings.
3) What we need now is fundraising and pressure for funding of clinical tests to establish safety and efficacy of the therapies.
4) Another thing that would be hugely useful for doctors is an international database of clinical findings of patients associated with identified mutations so we can figure out interactions.
5) It is unfortunate that people still say that Mental Retardation is a feature of BBS. It is not. There are developmental delays and some cognitive impairment in some BBS people, but it is by no means mental retardation as classically understood and most impairments can be overcome with standard therapies and accommodations. You wouldn’t say someone with dyslexia has mental retardation and you shouldn’t say that someone with BBS has MR.
6) Important to keep in mind that there are no validated IQ tests that are modified for visual impairment. So you have to be skeptical about any IQ measurement of a person with a visual impairment.
7) One easy and safe thing to do to protect retinas is a diet high in anti-oxidants (green vegetables, dark fruits for instance)
Dr. Eric Pierce Presents on Retinal Degeneration Therapies
Highlights from Dr. Pierce’s Presentation:
1) There are three different therapeutic approaches: Neurotrophic Function Therapies (NFTs), Gene Therapy and Stem Cell Therapy
2) NFTs include things like Vitamin A and TUDCA. They introduce elements necessary for the healthy functioning of neurons at the back of the retina. The challenge is that they are also potentially toxic in the wrong doses. TUDCA has been positive results in mice models of BBS4. But need to determine proper dosage that is both effective and safe. The good thing is that TUDCA is already approved for treatment of a liver disease, so the possibility to move to use for BBS is quite good.
3) Gene Therapies introduce a good copy of a defective gene into the retina. They can help restore photoreceptors that have stopped working but aren’t dead. Thus there is some possibility of improving vision but not for restoring vision that is lost due to complete degradation. Gene therapies are in human trials for a variety of retinal diseases and there have been very good results. There is a current trial of a gene therapy for several BBS genes in animal models.
4) Stem Cell Therapies grow new photoreceptor cells and entirely replace completely damaged or dead photoreceptors.
5) NFTs are in human testing today and there is a strong chance we will have approved NFTs in the next 5 years.
6) Gene therapies are probably 5 - 10 years away.
7) Stem Cell therapies are at least 20 years away but some promising advances are being made.
Dr. Haws Presents on Kidneys in BBS
Dr. Haws provided a terrific overview of how BBS affects the kidneys and what to look out for.
Here are some specific important notes:
1) BBS patients do not show classic symptoms of chronic kidney disease. You must monitor kidney function through metabolic tests at least yearly
2) BBS patients are never “in the clear”. Kidney disease can appear at any time.
3) Many doctors react to the extra amount of urine BBS kids produce by suggesting that parents restrict fluids. THIS IS ABSOLUTELY THE WRONG THING TO DO. IT IS DANGEROUS.
4) Other doctors prescribe DDAVP to help concentrate urine. Again, THIS IS DANGEROUS for BBS kids
5) Every BBS patient should have a full imaging of their urinary system. It is very likely that there are other abnormalities in the urinary tract or bladder in addition to the kidneys.
6) However, kidney imaging is not conclusive. The only way to really tell what is happening is metabolic testing.
7) A large study of children with kidney disease showed there are very positive effects from targeting 50th percentile for blood pressure (rather than just “normal range”)
8) Preferred medications for high blood pressure are ACE inhibitors or ARBs. Avoid Beta blockers, thiazides or calcium channel blockers.
9) Other common sense ways to preserve kidney function: Avoid NSAIDS (like ibuprofen, naproxen), avoid dehydration, treat UTI aggressively.
LMBBSA Conference 2012
Today I’ll be posting updates from the 2012 LMBBSA Family conference being held at Duke University. Dr. Nico Katsanis and the Center for Human Disease Modeling are our gracious hosts.
Presentations from Dr. Haws (Nephrologist), Dr. Peirce (Pediatric Ophthalmologist) and Dr. Katsanis are coming up today.
You can follow closer to “live” updates on Twitter via @bardetbiedl