GTMB 7 - Gene Therapy & Molecular Biology

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David et al: Current status and future direction of fetal gene therapyTable 1: Examples of candidate diseases for fetal gene therapyDisease Therapeutic gene product Target cells/organCystic fibrosis (CF) CF transmembrane regulator airway and intestinal epithelial cellsMetabolic disorders:Ornithine transcarbamylase deficiency Ornithine transcarbamylase hepatocytesGlycogen storage disorders:Pompe disease α1,4-glucosidase hepatocytes, myocytes and neuronsSphingolipid storage disorders:Tay-Sachs disease β-N-acetylhexosaminidase fibroblasts, neuronsMucopolysaccharide storage disorders:Sly disease β-glucuronidase hepatocytes, neuronsMuscular dystrophies:Duchenne dystrophin myocytesNeurological disorders:Spinal muscular atrophy survival motor neuron protein motor neuronsHaemophilias:Haemophilia B human factor IX clotting factor hepatocytesHaemoglobinopathies:β o -thalassemia β-globin chains of haemoglobin haematopoietic precursor cellsImmunodeficiency disorders:X-linked severe combinedγc cytokine receptorhaematopoietic precursor cellsimmunodeficiencySkin disorders:Dystrophic epidermolysis bullosa type VII collagen keratinocytesNon-inherited perinatal diseases:Hypoxia-ischaemia neurotrophic factors cortical neuronsInfectious diseases:Herpes simplex herpes DNA oral mucosaPlacental disorderSevere pre-eclampsia nitric oxide synthase trophoblastsII. The candidate diseasesFetal gene therapy has been proposed to beappropriate for life-threatening disorders, in whichprenatal gene delivery maintains a clear advantage overcell transplantation or postnatal gene therapy and forwhich there are currently no satisfactory treatmentsavailable (Wilson and Wivel 1999). Some of the diseasesthat may be suitable for in utero treatment are listed inTable 1 and are discussed as examples for conditions withsimilar manifestations and/or target tissues.A. Cystic fibrosisCystic fibrosis (CF) appears to be an ideal candidatefor treatment with in utero gene therapy. Firstly it is themost common lethal autosomal recessive disorder inCaucasians with an incidence of 1 in 2000 livebirths inWestern Europe and North America. Several mutations ofthe Cystic Fibrosis Transmembrane Regulator (CFTR)gene encoding the CFTR protein have been identified andthe resulting disease is characterized by abnormalelectrolyte transport in the epithelia of the airways, theducts of the sweat glands and exocrine pancreas, and theintestine. The main sites of CFTR expression in the non-CF human bronchi are the submucosal glands (Engelhardtet al, 1992). In vitro studies where normal and CF airwaycells were mixed, suggest that as few as 6-10% of cellsexpressing normal CFTR are required to correct thechloride transport defect of an epithelial cell monolayer(Johnson et al, 1992); thus, successful gene therapy mayrequire only relatively low level epithelial airwaytransduction.Phase I gene therapy trials directed towardspulmonary disease in CF have shown equivocal resultsand highlight the problems of present gene therapyapproaches in adults (Bigger and Coutelle 2001). Thelungs may already be severely damaged or obstructed,even in young adult patients, limiting delivery of genetherapy to the airway epithelium. Fluorocarbon liquidssuch as perflubron have recently been shown to improvedistribution of adenoviral vectors and gene expression innormal and diseased adult lungs (Weiss et al, 1999a,2001). Pretreatment of airways with detergents (Parsons etal, 1998) or the fatty acid sodium caprate (Gregory et al,2002) or EGTA (Wang et al, 2000) also improvesadenovirus-mediated airways transduction. A comparisonof agents to modulate paracellular permeability showedthat pretreatment of adult murine airways with sodiumcaprate had a good safety profile, and enhancedadenovirus-mediated gene transfer to the trachea moreefficiently than sodium laurate, another fatty acid sodiumsalt or EGTA, a calcium chelator (Johnson et al, 2003).Immune responses to the vector, particularly in the case ofadenoviral vectors, limit the dose that may be safelyadministered, and reduce the duration of expression.The CFTR gene has been proposed to play animportant, albeit still unknown, physiological role innormal fetal development (Gaillard et al, 1994; Tizzano etal, 1994). Furthermore the cystic fibrosis disease processappears to begin during development of CF fetuses sinceby the mid-trimester a pro-inflammatory state exists infetal CF airways (Hubeau et al, 2001) and there areabnormalities of the pancreas and small bowel (Boué et al,182
Gene Therapy and Molecular Biology Vol 7, page 1831986). Prenatal diagnosis is usually performed bydetection of the CFTR mutation in placental tissue, fetalskin cells or blood after chorionic villus biopsy,amniocentesis or cordocentesis respectively.Submucosal gland development has been studied inthe rhesus monkey fetus (Plopper et al, 1986) and althoughnot characterized in the human fetal airways, submucosalgland progenitors have been identified in the human adultlung (Engelhardt et al, 1995). Gene transfer to a humanfetal lung xenograft model in SCID mice was efficientlyachieved using adenoviral vectors (Peault et al, 1994) andlong-term expression in the surface epithelial andsubmucosal gland cells was observed up to 4 weeks and 9months after administration of adeno-associated andlentiviral vectors respectively (Lim et al, 2002, 2003).The early disease manifestation and poor results fromgene therapy treatment of adults with CF has led toresearch on in utero gene therapy for this disease in animalmodels. Despite the multiorgan manifestation of CF, firstapproaches are directed towards gene delivery to the fetalairways, which has been achieved by intra-amnioticapplication and, in larger animals by intratracheal injection(see chapter IV). Other genetic diseases which couldbenefit from progress achieved in pulmonary genedelivery are α1-antitrypsin deficiency (Stecenko andBrigham 2003) and surfactant protein B deficiency (Coleet al, 2003).B. Metabolic disordersInherited inborn errors of metabolism can affect anumber of metabolic pathways. For example the ureacycle disorders are caused by defects in genes encodingenzymes or membrane transporters in ureagenesis. Theirprevalence is approximately 1:30,000 births and ornithinetranscarbamylase (OTC) deficiency is one of the mostsevere of these conditions (Summar and Tuchman, 2001).OTC deficiency is transmitted as a partially dominant X-linked trait. In patients with partial OTC deficiency, suchas hemizygous males and heterozygous females, the firstclinical episode is delayed for months or years with lesssevere hyperammonemia. However, patients withcomplete OTC deficiency present with life-threateninghyperammonemia within one week of birth and despitemedical therapy to reduce the ammonia levels, 50% of thechildren are dead by the age of 4, and of those surviving,the mean IQ is less than 50 (Maestri et al, 1999). Since theurea cycle is principally sited in the liver, gene therapydirected towards hepatocytes has the potential to correctthe metabolic abnormality. Indeed the success of orthopticliver transplantation in long-term treatment of thiscondition supports the concept (Lee and Goss, 2001).Adenoviral vectors have been shown to transientlycorrect OTC deficiency in the sparse fur murine modelafter neonatal and adult treatment (Stratford-Perricaudet etal, 1990; Ye et al, 1996). In a phase I human clinical trialin patients with partial OTC deficiency, adenoviral vectorsexpressing the human OTC–cDNA were administered.There was evidence of dose-related toxicity to theadenovirus and the last patient treated suffered a systemicinflammatory response syndrome that lead to his death(Raper et al, 2002).Because of its early onset, severity and presentdifficulties in postnatal gene therapy, OTC deficiency is aninteresting candidate for in utero gene application targetedto the fetal liver (see chapter IV). Prenatal diagnosis forOTC deficiency by detection of the genetic mutation infetal DNA is available in families with a known congenitalabnormality. In non-informative families, deficiency ofOTC enzyme can be detected in the fetal liver after liverbiopsy (Holzgreve and Golbus, 1986). Other seriousgenetic diseases that would primarily require hepatocytedirected gene transfer are amino acid disorders (e.g.phenylketonuria, tyrosinaemia), carbohydrate disorders(e.g. galactosaemia) and fatty acid oxidation disorders(e.g. long-chain acyl-CoA dehydrogenase deficiency)(Preece and Green 2002).C. Storage disordersThe lysosomal storage disorders (LSDs) are a groupof congenital deficiencies of one or more lysosomalenzymes. In mucopolysaccharidosis type VII (MPS typeVII) a deficiency of β-glucuronidase activity leads toaccumulation of undegraded glycosaminoglycans inlysosomes. Clinically, patients develop hepatosplenomegaly,mental and growth retardation, hearing and visiondefects, skeletal deformities and die of cardiac failure.Many of the LSDs present already during fetal life withhydrops fetalis and prenatal diagnosis can be performed bydetection of β-glucuronidase deficiency in chorionic villior fetal blood (Geipel et al, 2002). Although individuallyrare, as a group they occur in approximately 1 in 7500 livebirths and are one of the more prevalent groups ofinherited diseases in humans (Wraith, 2002). Bone marrowtransplantation and enzyme replacement therapy are beingdeveloped for many of the mucopolysaccharidoses.However, the short half-life of lysosomal enzymes in thecirculation means that patients need biweekly parenteraladministration which increases the risk of an immuneresponse to the infused enzyme. In addition, systemicallyadministered enzyme is unable to cross the blood-brainbarrier and can therefore not be used to treat centralnervous system disease manifestation.The LSDs are considered to be good candidates forgene therapy and the liver may be the ideal site for genetransfer. Newly synthesized lysosomal enzymes aresecreted into the systemic circulation and are recapturedby distant cells. Based on the observed enzyme levels inpatients with mild late-onset disease, the amount ofenzyme needed to correct the deficiency may only be 1-10% of normal levels (Cheng and Smith, 2003). Genetransfer to naturally occurring animal models of MPS typeVII has been investigated using adeno-associated virus(Daly et al, 1999), adenovirus (Kamata et al, 2003) andlentivirus (McCray Jr et al, 2001). Intravenousadministration of retroviral vectors containing canine β-glucuronidase to neonatal MPS type VII dogs preventedsome bone and joint abnormalities, corneal clouding andheart valve defects that commonly occur in this animal183
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