Need for better Blood Tests

Sat, 23 Feb 2008 15:04:51 GMT

I think an unrecognized problem that needs to be addressed is to find a better set of measures, than currently exist, that provide a more rapid and sensitive feedback on the benefits of a treatment.

At the moment there are 3 main ways to determine the state of a DMD patient.

1) CK tests

2) Physiological Assessment

3) Muscle Biopsy

I'll point out why these are not inadequate for the tasks that face us ahead.

1) CK Tests are insensitive. (a) In DMD their range is 20K +/- 10K, which is a 50% range variability range, when a clinical measure of 5% is what is needed. (b) They vary greatly depending on the child’s physical activity and age.

2) Physiological Assessments take too long (a) They may take many years to get a good measure of a treatment and (b) in the short term they measure strength, when fibrosis is the real pathological mechanism.

3) Muscle Biopsies have ethical issues (a) they are painful and invasive and (b) they are really a one-shot wonder because there is not enough evidence to support longitudinal contamination.

So is there a better solution?

I think that measures such as p63, TGF-Beta, TNF-A, ROS, cytokines, AT-2, TSP-1 etc, etc could provide a better feedback mechanism for clinicians. But it is necessary that these measures are presented as part of a pathological model. In DMD there is no accepted pathological model, the model is complex, with several arms relating to ca+2, inflammation and fibrosis. As a parent I would want to know how a drug affects the DMD pathology and for this I would like to see a pathological model which is loosely coupled to a set of pathological markers.

We have struggled to prove steroids work, and it has taken years, when the boys are on and off a cocktail of various versions of drugs I don’t think the current measures are sufficient to provide a good clinical assessment.

Duchenne Muscular Dystrophy vs Cystic Fibrosis

Thu, 01 Nov 2007 14:13:29 GMT

If we are to beat this disease we have to understand where we are and how we got there.

There are about 6500 Cystic Fibrosis (CF) and 3500 Duchenne Muscular Dystrophy (DMD) sufferers in the UK. The pathology in both diseases are caused by a genetic variation that effects children and both diseases start with an obvious weakness and result in fibrosis. DMD could have been called Muscular Fibrosis.

With the internet it's relative easy to find statisics on improvements in the two diseases. The comparison I'm going to look at has been done by simply searching www.pubmed.org for the number of papers that have been published on both diseases by searching for "clinical trial Duchenne" or "clinical trial Cystic Fibrosis" for each of the following years.

Year DMD CF
1964 1 0
1966 1 2
1967 0 1
1968 0 1
1969 0 1
1970 0 1
1971 3 0
1972 0 0
1973 0 2
1974 2 3
1975 1 6
1976 1 6
1977 0 3
1978 1 6
1979 1 5

As you can see in the 1960s and 1970s there was a gradual increase in the number of clinical trials in CF over DMD. When we move on to the late 1990s we can see the trend has continued.

Year DMD CF
1998 5 85
1999 4 92
2000 6 95
2001 7 103
2002 8 115
2003 10 116
2004 11 89
2005 13 127
2006 11 92
2007 9 75

There are now on average over 10 times more papers published on clinical trials in CF than DMD - even though there are less then twice as many patients.So what has caused this? I can see there are several possible reasons:-

* A lack of funding
* A lack of research
* A difficult problem
* A lack of motivation

Certainly the clinical trials require research and research requires money. Perhaps finding the dystrophin gene distracted all the researchers for a long time - who have only now got the tools to deliver treatments using stem cells and exon skipping. Perhaps not.

There is another comparison that that is worth looking at on pubmed, between the ratio of research that makes it past the test tube into animals and past animals into clinical trials. The following searches on pubmed show the number papers published with the wordsCF or DMD + vitro (in a test tube) or vivo (in an animal).

Cystic Fibrosis + vitro = 1665
Cystic Fibrosis + vivo = 908
Differential = 0.545

Duchenne + vitro = 316
Duchenne + vivo = 242
Differential = 0.765

The numbers show that (whilst there was substantially more funding in CF) the ratio of in vitro studies is 5.2 and the ratio of in vivo studies is 3.7. This implies that despite less cash, as a ratio, MORE studies made it through to animal studies in DMD than CF. Yet the ratio of clinical trials is above 10*. So whilst more studies made it through to animal studies in DMD much more studies made it through to clinical trials in CF than DMD.

SO the question is why? Finding a drug in DMD (and I suspect in many other diseases) has been down to judgement and luck. Try a drug in the right area and get lucky. See Steroids, Losartan and Protandim as examples.

It appears from the statistics the reason more trials got run in CF has been largely due to clinicans trying their luck. Certainly DMD has shown promising areas where drugs could be tried, and once trials get successful then this pulls in more money. One day we might start to publish more clinical trial papers into DMD.

This purpose of this post isn't intended to be a detailed comparison of the improvements in treatments of the two diseases, but I hope it will stimulate people to compare the development of treatments for the two diseases in more detail.

Blog: Robins Blog

Need for better Blood Tests

Duchenne Muscular Dystrophy vs Cystic Fibrosis