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Overall Research Objectives

Our research focuses on the use of hematopoietic stem cells and gene therapy for the treatment of degenerative multi-systemic disorders and hereditary nephropathies. As a model, we are using cystinosis. We are developing a multi-systemic strategy consisting of transplantation of autologous hematopoietic stem cells genetically modified ex vivo using lentivirus vectors. For hereditary nephropathies, we are developing a kidney-specific strategy using adeno-associated virus (AAV) vectors. The main objectives of the laboratory are the clinical translation of these strategies. We are also investigating the mechanisms of tissue repair by bone marrow-derived stem cells after hematopoietic stem cell transplantation in the context of a non-hematopoietic disease.

Summary of each Research Project

Hematopoietic Stem Cell Gene Therapy for Cystinosis

HSC gene therapy cystinosis

Cystinosis is an autosomal metabolic disease belonging to the family of lysosomal storage disorders. Mutations in the CTNS gene, encoding a lysosomal cystine transporter, lead to cystine accumulation and multi-organ failure such as end stage renal failure, blindness, myopathy, diabetes and central nervous system defects. Treatment is available with the drug cysteamine to reduce intracellular cystine content, but it only delays the progression of the disease. We showed that wild-type Hematopoietic Stem and Progenitor Cell (HSPC) transplant in the mouse model of cystinosis, the Ctns -/- mice, led to the abundant tissue integration of bone marrow-derived cells, significant decrease of tissue cystine accumulation, and long-term preservation of the kidney, eye and thyroid function and structure. Because allogeneic transplants are associated with high risks of mortality and morbidity, we developed an autologous transplantation strategy of HSPCs genetically modified ex vivo to express a functional CTNS gene using a SIN-lentivirus vector. This approach led to the reduction of cystine in all tissues and of improvement of the kidney function in the Ctns -/- mice. performed the toxicology/pharmacology studies, manufacturing development for this strategy, designed the clinical trial, and obtained FDA-clearance after an Investigational New Drug (IND) application submission in December 2018. We started a phase 1/I2 clinical trial in July 2019 at UC San Diego and the preliminary results in patients look promising.

Mechanism of Hematopoietic Stem Cell-mediated Therapy in Cystinosis

mechanism of hsc in cystinosisThe extent of efficacy of HSPCs to rescue cystinosis was surprising especially considering that cystinosin is a transmembrane lysosomal protein. The study of the mechanism by which Ctns-expressing HSPCs led to tissue repair in the Ctns -/- mice showed that a large subset of HSPCs differentiated into macrophages that can transfer cystinosin-bearing lysosomes to the deficient host cells via long tubular extensions known as tunneling nanotubes (TNTs). Conversely, diseased cells also exploited the same route to transfer cystine-loaded lysosomes to the macrophages, providing a bidirectional correction mechanism. Cellular stress from the Ctns-deficient cells stimulated the formation of the TNTs. While cross-correction, either upon secretion- recapture after bone marrow transplantation was shown in several lysosomal storage disorders caused by defective soluble hydrolases, our study is the first demonstration of cross-correction in the context of a lysosomal transmembrane protein and of TNTs as key cellular device in the transfer. We also showed for the first time that TNTs could cross the thick, dense and stiff renal tubular basement membrane in vivo and transfer cystinosin-bearing lysosomes to the proximal tubular cells, providing a mechanism underlying the long-term kidney preservation after HSPC transplantation in the Ctns -/- mice. We also showed that the mechanism of HSPC-mediated therapeutic action was similar for the ocular defects and for the thyroid rescue in the Ctns-/- mice. Our objectives are now to investigate the molecular protagonists and activating signal(s) involved in the TNT formation as well as the phenotype of the macrophages involved in tissue repair.

Hematopoietic Stem Cell Gene Therapy for Friedreich's Ataxia


Because mitochondria can also be transferred via tunneling nanotubes, we hypothesized that HSPC transplantation could also treat mitochondrial diseases. We thus tested this hypothesis in a mouse model of Friedreich's Ataxia (FRDA), the YG8R mice. FRDA is an autosomal recessive mitochondrial disease characterized by neurodegeneration, cardiomyopathy and muscle weakness and patients will be in wheelchair within 10-15 years of onset. FRDA is caused by homozygous GAA repeat expansion mutation within intron 1 of the frataxin gene (FXN) leading to the reduction of expression of the mitochondrial protein frataxin. There is no effective treatment for this debilitating and lethal disorder. We showed that HSPC transplantation in the YG8R mice completely prevented the development of the locomotor deficits and muscle weakness. Degeneration of the large sensory neurons in the dorsal root ganglia (DRG) was fully prevented in the HSPC-transplanted YG8R mice as well as mitochondrial dysfunction in brain, skeletal muscle and heart. Abundant GFP+ HSPC-derived cells were observed in tissues as differentiated phagocytic cells such as microglial cells in the brain and spinal cord, and macrophages in DRGs, heart and skeletal muscle. Finally, we observed in vivo transfer of frataxin-GFP and cox8-GFP mitochondrial proteins from HSPC-derived microglia/macrophages to diseased neurons and cardiac/muscular myocytes. Thus, this work showed for the first time that one-time HSPC transplantation holds the potential to become a life-long curative therapy for FRDA that may prevent the sequelae of this disorder. Our objective is to develop an autologous HSPC gene therapy for FRDA. Because the GAA repeat mutation is in an intron and is carried by 98% of the patients with FRDA, we developed a strategy to remove the hyper-expansion mutation using CRISPR/Cas9 technology and optimized the protocol for the human CD34 + cells isolated from FRDA patients. The gene-corrected cells exhibit increased frataxin expression and better mitochondrial function. Our objective is the translational development of this new cell and gene therapy approach for FRDA for which there is pressing unmet medical need. Moreover, this study should bring new perspectives in the treatment of other diseases involving mitochondrial genetic defects.

Hematopoietic Stem Cell Gene Therapy for Alzheimer's Disease

AD Mouse  Model

Microglia have been shown to be involved in the clearance of the Aβ plaque, which is impaired in Alzheimer's disease (AD). As such, the promotion of Aβ plaque clearance by healthy microglia provides a potential therapeutic opportunity. We have previously demonstrated that single systemic transplant of wild-type (WT) hematopoietic stem and progenitor cells (HSPCs) led to long-term rescue in both mouse models for cystinosis, a lysosomal storage disease, and Friedreich's ataxia (FA), a neurodegenerative disease. Using the 5xFAD double transgenic mouse model of AD, which expresses mutant human amyloid beta (A4) precursor protein 695 (APP) with the Swedish (K670N, M671L), Florida (I716V), and London (V717I) Familial Alzheimer's Disease (FAD) mutations and human presenilin 1 (PS1) harboring two FAD mutations (M146L and L286V), we demonstrated that single WT HSPC transplantation led to the preservation of memory and neurocognitive performance, and to the reduction of the Aβ plaque burden in hippocampus and cortex. WT HSPCs differentiated into microglia with active amyloid plaque clearance potential while also leading to the reduction of neuroinflammation. This work opens new therapeutic avenues using HSPC gene therapy for the treatment of AD.

Kidney-targeted Gene Delivery Using AAV

kidney targeted gene therapy

A wide range of monogenic kidney disorders has been identified and so far no gene therapy approach has been developed to target specifically the kidney whereas renal transplantation is associated with significant morbidity and mortality. Moreover, due to the severe shortage of donor organs, patients may wait three to six years for transplantation. The main goal of our project is to develop an efficient and minimally invasive kidney-targeted gene delivery system using recombinant Adeno-Associated Viruses (rAAV). We optimized a kidney-targeted gene delivery via retrograde renal vein injection by testing several rAAV serotypes that have the potential of transducing a wide range of renal cells and showed that the serotype 9 was the most efficient to transduce the different type of renal cells. This strategy could be used to prevent kidney transplantation in many monogenic hereditary nephropathies.