Therapeutics
routinely used in clinical practice, but none of these biomarkers are considered validated from a regula- tory perspective. There can also be significant vari- ability in the rates of disease progression and dif- ferences in clinical outcome between patients with the same disease. For example, Gaucher Disease is an inherited lysosomal storage disorder caused by a deficiency in the enzyme glucocerebrosidase. However, there are three different forms of Gaucher Disease and within these forms clinical effects can be manifested in different ways and at different rates13. Such complexities can lead to sig- nificant challenges in defining the appropriate cri- teria for patient enrolment into clinical studies for rare diseases.
Even when rare diseases are linked to mutations in a single gene, there may be hundreds of muta- tions in these genes, and the link between genotype and clinical phenotype is complex and only par- tially understood. In Metachromatic Leukodystrophy (MLD) there is an infantile form of disease caused by mutations resulting in the lack of expression of the enzyme arylsulfatase A with
this form of the disease being severe and rapidly progressing. In other MLD patients, there may be different mutations which result in reduced levels of expression of the enzyme or lower enzymatic activity; this can even manifest as adult forms of the disease which are less severe, more slowly pro- gressing, and which can present with very different (eg psychiatric) phenotypes14. These findings also highlight a challenge of pediatric studies in rare diseases; the highest medical need for MLD patients is associated with the infantile form of the disease, and it would be very difficult to conduct clinical studies in a small population of adult MLD patients where the disease is slowly progressing and clinical endpoints may not be relevant to the infantile population.
In addition to complexity associated with dif- ferent mutations in disease genes, it is likely that additional genetic variation in secondary genes associated with disease pathways will also modify clinical phenotypes. For example, there are founder effects with monogenic diseases, but even in isolated communities with the same genotype
Make connections. Share intel. Get ahead.
Join the nearly 10,000 members of the Life Science Network and you’ll find yourself making new contacts, finding collaborators, following trends and attending great networking events.
The group was created specifically to bring scientists, entrepreneurs, investors, executives and media together for mutual benefit. There’s no agenda. No sell. No membership fee.
Just like-minded people who would like to connect with you.
To join, go to
www.lifesciencenetwork.com/join.
Drug Discovery World Spring 2013
13
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80