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Volume 2

Novel therapeutic tools and strategies to fight polycystic kidney disease (GTPKD)



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EU Contribution

1,751,209 Euro


36 months



Starting date

01 January 2002

chromosomal mapping
gene therapy
knockout mice
modifier genes

Our goal is to establish a successful gene therapy protocol for autosomal dominant polycystic kidney disease (ADPKD), which is the most frequent renal genetic disease (prelevance 1:1,000). 50% of ADPKD patients require renal replacement therapy by the age of 60, resulting in health care costs of 500 million Euro/year. No causal therapy for ADPKD is known. We will pursue a gene therapy strategy by establishing adequate modifiers affecting the severity of ADPKD. Our work will not only advance the basic knowledge on ADPKD, but it will also yield a number of candidates for gene therapy. Meanwhile, efforts will be devoted to optimising existing kidney gene transfer methods by novel delivery strategies and vectors. Finally, gene therapy experiments in animal models will set the basis for further studies in humans.


The key objective of this proposal is to establish gene therapy for autosomal dominant polycystic kidney disease (ADPKD), the most common renal genetic disorder.

To achieve such an ambitious goal, our multidisciplinary team will not only try to answer basic questions which will lay the foundation for feasible genetic interventions, but it will also address technological challenges such as efficient and safe gene delivery to the kidney in vivo. The two activities will merge in defining gene therapy protocols for ADPKD in new animal models of the disease, which should eventually lead to preclinical and clinical studies in patients.


Three strategies can be adopted for ADPKD gene therapy:

  1. correction of the original genetic defect by delivery of the wild-type PKD1 or PKD2 gene.
  2. interference with the pathogenetic cascade triggered by mutations in the PKD genes.
  3. delivery of modifier genes to reduce disease severity.

We will address each of these strategies.

  1. To correct PKD2 mutations, a suitable animal model is needed. PKD2 knockout mice are available, but homozygous animals die prenatally, while heterozygous animals display a normal phenotype until late adulthood. We will therefore generate conditional PKD2 knockout mice, in which renal cyst formation begins perinatally, for gene therapy experiments with the PKD2 cDNA. Alternative gene therapy strategies will be investigated as follows.
  2. Metalloproteinases and their inhibitors regulate the turnover of the extracellular matrix. To elucidate their role in the process of cyst formation, knockout mice for the metalloproteinase MMP9 and transgenic mice for the inhibitor TIMP-2 will be generated and crossed to PKD mice.
  3. ADPKD shows remarkable variation in severity among patients sharing the same PKD mutation, pointing to the existence of modifier genes.

To identify such genes, we will perform chromosomal mapping in PKD/Mhm (cy/+) rats, a spontaneous ADPKD model. The activities outlined above will yield important insight into gene therapy of ADPKD. Since low efficiency and transient expression limit the current methods for gene delivery to the kidney, we will implement novel gene transfer approaches in both rats and mice. The safety of the optimised method will then be evaluated in PKD animals. Finally, therapeutic genes will be applied, and the efficacy in preventing cyst formation in the polycystic kidney will be evaluated.


By addressing key questions relevant to the development of ADPKD gene therapy, we will:

  1. generate animal models to study the pathogenetic mechanisms leading to end-stage renal disease.
  2. generate conditional PKD2 knockout mice for gene therapy experiments.
  3. identify modifier genes affecting the severity of the disease.
  4. improve the existing gene transfer technology for the kidney.
  5. ultimately provide gene therapy protocols for polycystic kidney disease.
Prof. Dr Norbert Gretz
Fakultät für Klinische Medizin Mannheim der
Universität Heidelberg
Zentrum für Medizinische Forschung
68135 Mannheim, Germany
Tel: +49-621-383 5602 /5588
Fax: +49-621-383 2108
Dr Marie-Therese Bihoreau
The Wellcome Trust Centre
for Human Genetics
University of Oxford
Roosevelt Drive Headington
OX 37 BN Oxford, United Kingdom
Tel: +44-1865-287 622
Fax: +44-1865-287 533

Dr Brigitte Lelongt
Hôpital Tenon
4, rue de la Chine
75020 Paris, France
Tel: +33-15-601 65 14
Fax: +33-15-601 62 17

PD Dr Ralph Witzgall
Universität Heidelberg
Institut für Anatomie und Zellbiologie I
Im Neuenheimer Feld 307
69120 Heidelberg, Germany
Tel: +49-6221-548 686
Fax: +49-6221-544 951

PD Dr Bernd Dworniczak
Institut für Humangenetik
Universität Münster
48129 Münster, Germany
Tel: +49-251-835 54 30
Fax: +49-251-835 69 95

Dr Lucia Monaco
Biotechnology Division
Keryos S.p.A.,
via Maritano 26
I-20097 San Donato Milanese (MI), Italy
Tel: +39-02-52778449
Fax: +39-02-55600077