Markey Genetic Medicine Center
The Markey Genetic Medicine Center builds on existing strengths in medical genetics and molecular biology at the University of Washington
and at FHCRC to develop a program which applies basic biological approaches to problems of human genetic disease.
This program is a natural evolution of existing research interests and interactions carried out by medical and molecular
geneticists at the University of Washington and molecular biologists of the Division of Basic Sciences at the Fred
Hutchinson Cancer Research Center
Pharmacologically Regulated Cell Therapy
A major obstacle to the future development of cell therapy rests in
our inability to control what happens to a cell after it has been transplanted.
Selective expansion of genetically modified cells for both hemopoietic
and nonhemopoietic disorders
Mixed Chimerism Stem Cell Plasticity
- Potential applications in liver diseases,
neurological diseases, muscle diseases, blood diseases, diabetes,
Adenovirus-based technologies for treatment of cancer and inherited blood disorders
Technology 1: Capsid-modified Adenoviruses (Adenochimera)
Tumor Gene Therapy
- Specific targeting of metastatic tumors after intravenous adenovirus application
- No toxic side effects associated with vector administration
Technology 2: Replication-activated gene expression (Ad.IR)
Tumor Gene Therapy
- New concept for tumor-specific gene expression from adenovirus vectors
- New concept for tumor-specific adenovirus replication allows for elimination
of liver metastases in mouse models after a single vector administration
- Tested for breast, lung, colon, prostate and cervix cancer
Technology 3: Stable transduction of human hematopoietic stem cells (DAd.AAV)
Stem cell gene therapy
- New method for production of adenovirus vectors devoid of all viral genes with large insert capacity
- Modified capsid allows for efficient transduction of human hematopoietic cells
- Integration into the host genome through AAV ITRs
- Stable transgene expression (for example g-globin)
Technology 4: Efficient transduction and activation of dendritic cells or progenitors (Ad.IT)
Immunotherapy & Vaccination
- Ad11 based vectors devoid of all viral genes
- High level antigen expression in immature dendritic cells
- Activation of prophylactic or therapeutic T- and B-cell responses
- Applicable for immunotherapy of cancer or infectious diseases
Adeno-Associated Virus (AAV) Vector Technologies
Technology 1: Vectors Based on Adeno-Associated Virus Serotype 6 Advantages of AAV6 Vectors
Superior Performance in the Lung
Could be used to treat cystic fibrosis as well as acquired lung diseases.
Superior Performance in the Muscle
Could be used to make blood proteins such as clotting factors to treat
hemophilia, or to treat muscle diseases such as muscular dystrophy
or heart disease.
Superior Performance in the Liver
Could be used to treat metabolic diseases or hepatitis.
Technology 2: Gene Targeting with Adeno-Associated Virus Vectors
- AAV Vectors Accurately Target the Single Copy HPRT Locus in up
to 1% of Normal Human Fibroblasts
- AAV Vectors Disrupt the Mutant Collagen Gene in Mesenchymal Stem
Cells from Patients with Brittle Bone Disease (Osteogenesis Imperfecta).
Reinfusion of these Cells Could Cure the Disease
- AAV Vectors Disrupt the PrP Gene in Cows, Which Can be Used to
Clone a Cow Resistant to Mad Cow Disease
Advantages of Gene Targeting
- Accurate control of gene regulation
- Can target normal human cells at high frequencies (5-6 logs better
than conventional methods)
- Can introduce multiple types of mutations - insertions, deletions,
- Can eliminate dominant mutations
- Can avoid unwanted random integrations
- Can be use to modify stem cells, target genes after in vivo delivery,
and create genetically engineered livestock by cloning or embryonic
stem cell manipulations
Development of Therapies for Sickle Cell Disease
- My group develops technologies related to gene regulation, stem cell
gene therapy and functional genomics.
- In parallel, we have a long-term goal to develop new pharmacological
treatments for sickle cell disease and beta thalassemia
- Sickle cell disease affects about 1 per 500 Americans of African
descent. The sickle cell gene is also very frequent in several other
populations. WHO estimates that worldwide about 100,000 individuals
with a sickle cell syndrome are born each year.
- Beta thalassemia is a severe anemia which leads to death in early
childhood if left untreated. The disease is common in populations
living around the so-called malaria belt – from Southern Italy
to SE Asia. Treatment consists of frequent transfusions (usually
every 15 days). Even well treated patients usually die in early
- Both diseases are due to mutations of the adult globin genes.
The patients are born normal because they have fetal hemoglobin
in their red cells. However, when fetal hemoglobin switches to adult
hemoglobin, the disease appears. Both diseases could be cured if
one could induce abundant production of fetal hemoglobin in the
patient's red cells.
- My lab tries to develop therapies of sickle cell disease and
thalassemia based on induction of fetal hemoglobin in the patient’s
- Our previous studies have shown that fetal hemoglobin can be induced
by cell cycle cytotoxic drugs.
- Our pre-clinical and clinical studies led to the introduction
of the drug hydroxyurea in the treatment of sickle cell disease.
- Today hydroxyurea is the standard treatment for sickle cell disease
- However, this treatment is not effective in beta thalassemia and
in several patients with sickle cell disease.
- Therefore, we tried alternative treatments.
- With studies in primates we showed that butyrate and other short
chain fatty acids induce fetal hemoglobin in adult animals.
- These studies led to several clinical trials which demonstrated
that butyrate can induce fetal hemoglobin in patients with sickle
- However, the need for IV infusion of this drug inhibits its application
in the practice of medicine, especially in the third world countries.
- More recently we found that fetal hemoglobin can be induced by
inhibitors of histone deacetylase (HDAC).
- We have synthesized a large number of HDAC inhibitors.
- Several compounds which are potent inducers of fetal hemoglobin
in low micromolar or nanomolar concentrations have been identified.
Examples of their effects are shown in the figures in the left.
- Selected histone deacetylase inhibitors are currently tested
in pre-clinical studies.
- Our ultimate goal is to develop a drug that is not toxic, it is
a strong inducer of fetal hemoglobin and can be taken orally. Such
a compound will be useful for the treatment of thalassemia and sickle
cell anemia especially in the third world countries where these
diseases are very common.