New Approach to Genetically Informed
Treatment
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1
Harvard Medical School, Massachusetts General Hospital, United States
Recent advances in understanding the molecular of genetic disorders offer unheralded opportunities to develop genetically informed therapy. Such therapy can be viewed as consisting of either gene therapy, through replacement of absent or nonfunctioning genes, or pathway therapy, through regulation of the pathway perturbed by the genetic mutation.
To date, gene therapy successes have been few in number. However recent work replacing the RPE65 gene in patients with a genetic form of severe retinal dystrophy is encouraging. This work will be discussed to highlight the possibilities as well as the challenges of gene replacement therapy. The most robust examples of pathway therapy consist of treatment of inborn errors of metabolism by implementation of special diets and/or cofactor supplementation. Exciting new approaches, such as treating Progeria with farnesyl transferase inhibitors, and treating Marfan syndrome with Losartin, will also be discussed.
Can insights be gained from the above precedents that will lead to novel therapies for patients with Williams syndrome? This question was the central focus of a recent meeting entitled “Cardiovascular Disease in Williams-Beuren Syndrome: Understanding Pathophysiology to Pioneer Treatment” held May 7-9, 2008, which brought clinical experts with a broad swath of laboratory scientists working in the field of vascular biology. The current state of knowledge is that deletion of one elastin allele is the major cause of cardiovascular disease in individuals with Williams syndrome. Experimental data indicate that increasing elastin protein levels, either in cells cultured from individuals with Williams syndrome or in elastin knock out mice, ameliorates the cardiovascular phenotype. Ways to supply additional elastin protein during vascular development such as through gene therapy or micro-RNAs to “turn on” the intact elastin allele were discussed as potential therapeutic targets. Although theoretically possible, the feasibility of introducing these therapies at the correct developmental stage and to the correct tissue remains daunting. Far less is known about pathway abnormalities triggered by elastin protein deficiency so that opportunities for targeted pharmacotherapy are currently elusive.
The cardiovascular disease that typifies Williams syndrome appears to be the easiest and most compelling target for development of novel therapies. If successful, then lessons learned from these pioneering efforts may set the foundation for developing treatments for other aspects of Williams syndrome.
Conference:
12th International Professional Conference on Williams Syndrome, Garden Grove,CA, United States, 13 Jul - 14 Jul, 2008.
Presentation Type:
Oral Presentation
Topic:
Keynote Address
Citation:
Pober
B
(2009). New Approach to Genetically Informed
Treatment.
Conference Abstract:
12th International Professional Conference on Williams Syndrome.
doi: 10.3389/conf.neuro.09.2009.07.007
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Received:
29 Apr 2009;
Published Online:
29 Apr 2009.
*
Correspondence:
B. Pober, Harvard Medical School, Massachusetts General Hospital, Boston, United States, Barbara.Pober@childrens.harvard.edu