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Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects
Molecular Genetics and Metabolism 100 (2010) S77–S83
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Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects Jochen Meyburg *, Georg F. Hoffmann Department of General Pediatrics, University Children’s Hospital, Heidelberg, Germany
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Article history: Received 7 October 2009 Received in revised form 13 January 2010 Accepted 13 January 2010 Available online 29 January 2010 Keywords: Hepatocyte transplantation Ornithine transcarbamylase deficiency Carbamoylphosphate synthase deficiency Citrullinemia
s u m m a r y Despite advances in pharmacological therapy of urea cycle disorders (UCDs), the overall long-term prognosis is poor, especially for neonatal manifestations. Transplantation of liver tissue or isolated cells appears suitable for transfer of the missing enzyme. Liver transplantation (LT) for UCDs has an excellent 5-year survival rate of approximately 90% and is the only way to completely cure the disease. However, major neurological damage can only be prevented if the operation is performed during the first months of life. Unfortunately, such early LTs have a substantial risk for peri- and postoperative complications, mostly caused by a relatively large liver graft. Liver cell transplantation (LCT) is less invasive than LT, but has still to be regarded as an experimental therapy with about 100 patients treated since its first use in 1993. UCDs are a model disease for LCT, because of the poor prognosis, mainly hepatic enzyme defects, and excellent outcome after LT. So far, 10 children underwent LCT for UCDs with very few technical complications and encouraging clinical results. A first prospective study on its use in severe neonatal UCDs has recently started. However, availability of hepatocytes is limited by the scarcity of donor livers; therefore the use of stem cells is under investigation. Several different cell types may be regarded as liver stem cells, and in vivo transformation into hepatocyte-like cells has been shown in animal studies. However, a clear proof of principle in animal models of human metabolic disease is still missing, which is the prerequisite for clinical application in humans. Ó 2010 Elsevier Inc. All rights reserved.
Introduction The prognosis of urea cycle disorders (UCDs) has improved with the introduction of alternative pathway medication. Data from a large US therapeutic trial show that the frequency of metabolic crises could be substantially reduced by the addition of phenylbutyrate to the treatment of UCDs [1]. However, the long-term prognosis under pharmacological and dietary therapy is still poor, especially for neonatal UCDs [2–4]. Besides high mortality rates, neurological sequelae cause serious morbidity in the surviving children [5]. Whereas gene therapy is tempting, its potential use in UCDs is no longer under clinical investigation following the death of a study subject [6]. Transplantation of liver tissue or liver cells may be a suitable substitute. Transplantation medicine is rapidly evolving. Whereas liver transplantation (LT) was regarded experimental in the 1980s, it is now an important successful long-term therapeutic alternative to conventional therapy. Besides LT, cell-based therapies have been developed over the last years and are under investigation. The aim of this review is to give an overview about the
* Corresponding author. Address: Department of General Pediatrics, University Children’s Hospital, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany. Fax: +49 6221 565626. E-mail address: [email protected] (J. Meyburg). 1096-7192/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2010.01.011
impact of these techniques on the treatment of UCDs and an outlook about their future use in a multidisciplinary approach.
Liver transplantation An overview of published studies on liver transplantation for UCDs is given in Table 1. First case reports at the end of the 1980s demonstrate that liver transplantation could permanently normalize elevated ammonia levels in patients with UCDs [7,8]. Until 1996, about 20 successful transplantations were reported. However, these individual case reports are hardly comparable with respect to long-term clinical outcome, and there is always a tendency to publish primarily successful cases (ascertainment bias). An evaluation of 16 LT in 4 US transplant centers between 1986 and 1996 was published by Whitington et al. [9]. Of the 16 patients (8 children and 2 adult females with OTCD, 3 CPSD, 3 citrullinemia), 14 (87%) were alive at the end of the study after a maximum observation period of 6 years. One patient had died from immediate postoperative complications, another from aspiration pneumonia. No metabolic decompensations occurred during the observation period. Leonard and McKiernan collected more recent data published in 2004 [10]. Based on the literature and personal communications, they report on a total of 59 patients (32 OTCD, 18 citrullinemia, 6 CPSD, 2 ASLD, 1 argininemia). Also in this larger patient cohort,
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Table 1 Selected studies on LT for UCDs. Number of patients
Diagnosis
Age at LT
Type of LT
Authors
Outcome
About 20
Various UCDs
Various
OLT
Various 1987–1996
16
Various
OLT
Whitington et al. [9]
Various
OLT
Leonard et al. [10]
3
8 OTCD children 2 OTCD adults 3 CPSD 3 Citrullinemia 32 OTCD 18 Citrullinemia 6 CPSD 2 ASLD 1 Argininemia OTCD girls
Good Ascertainment bias? 2/16 died Hyperammonemic crises ceased Slight neurological improvement in 3 patients 4/59 died No protein restriction Hospital admissions reduced
APOLT
Kasahara et al. [18]
Good No protein restriction
2
Citrullinemia type II
APOLT
Yazaki et al. [20]
Good
13
7 Citrullinemia type II 6 OTCD girls Citrullinemia type I
2½ years 3 years 5½ years 32 years 43 years Various
8 OLT 5 APOLT LRLT
Morioka et al. [19]
Good
Ban et al. [22]
Good despite transplantation of only 8% calculated enzyme activity
59
1
6 years
a very high survival rate (55/59 patients, 93%) was found. Two patients died from immediate postoperative problems, another two from aspiration pneumonia later (the latter two children were severely handicapped). Quality of life substantially improved in all surviving children. Discontinuation/normalization of diet and reduction of hospital admissions were considered most important. Recent and comprehensive data can be obtained from the UNOS Organ Procurement and Transplant Network Database. Between 1988 and 2004 a total of 113 patients underwent LT for UCDs in the US Overall 5-year patient survival was excellent with 86% (OTCD: 86.2%, CPSD: 100%, citrullinemia: 100%, ASLD/argininemia 88.9%, unspecified UCD: 60%). Deaths after LT were attributed to infection, multiorgan failure, primary non-function of the graft, brain death, and recurrence of disease (no further information available) [11]. Due to the nearly exclusive hepatic expression especially of the proximal urea cycle, the success of LT for UCDs is not surprising. Only small amounts of defective enzymes that are localized in kidney and gut are not replenished by LT, and LT for UCDs may thus be regarded as a gene-respective enzyme replacement therapy. An open question is however the physiological importance of substantial cerebral expression of the distal urea cycle enzymes, especially argininosuccinate lyase and arginase. Therefore, reduced (OTCD and CPSD) or still elevated (citrullinemia) concentrations of citrulline may still be observed after LT in the systemic circulation [8,12]. However, there is convincing evidence that further neurological impairment can be prevented by LT [9], and that even neurological improvement could be observed in individual cases [13,14]. This concept does not refer to the rare cases of UCDs presenting as acute liver failure. Teufel et al. 2009 reported a previously healthy 3-year old girl presenting for the first time with fulminant liver failure. After the diagnosis of OTCD was made, emergency treatment including hemodialysis was started, but liver failure could not be controlled. Her condition dramatically improved after emergency LT three days after admission, and she is healthy two years thereafter [15]. UCDs with neonatal onset, i.e. OTCD, CPS1D, and citrullinemia, usually have a dramatic initial presentation, and very poor longterm prognosis [2–4]. Currently only early LT can prevent severe brain damage and opens the chance for a reasonable to good outcome. In the early series of LT for UCDs, patient’s ages at the time of transplantation have not been reported [9,16]. However, it can be assumed that the majority was older than 12 months of age,
since LT was only performed exceptionally in infancy due to the high rate of complications at that time. In the small series reported by Maestri et al., 2 of 3 patients were already profoundly retarded at the time of LT [16]. More patients were collected by Whitington et al. and classified by a custom neurological scale [9]. They documented severe neurological impairment (no social interaction, no ambulation, no communication) in 3 of 14 patients, moderate impairment (limited social interaction, bipedal ambulation, and limited communication) in 5 of 14 patients, and mild to moderate impairment (definite social interaction, fair ambulation, and some use of language) in 5 of 14 patients. Only one child in this series was mildly impaired, and two adult female patients were within the normal spectrum of neurologic and psychologic abilities. Following LT, neurological deterioration ceased in all surviving patients, and a slight improvement was noted in 3 of 12 children. Developmental outcome after early LT was prospectively investigated by McBride et al. [17]. They evaluated three children (age at LT 5, 11 and 3 months, respectively) and one female (partial OTC child transplanted in early childhood) with the Griffiths Mental Developmental Scales. After LT, only mild to moderate psychomotor delay (average overall score 66.7, normal range 100 ± 10.8) was found. Although this was only a small series of patients, these seem to favour the concept of early LT. Special considerations have to be made for female OTCD patients. Because the disease is X-chromosomal recessively inherited, all affected girls can pass on the defected gene as conductors, but some may themselves develop severe progressive symptoms often starting in early adulthood. For these patients, auxiliary partial orthotopic liver transplantation (APOLT) appears conceptually an attractive therapeutic option [18,19]. APOLT has also been successfully performed in adult patients with citrullinemia type II [19,20]. Although small patient cohorts indicate that OLT might be superior to APOLT [19], recent results in children with non-cirrhotic metabolic diseases indicate good long-term results similar to OLT [21]. Because the concept of brain death is not established in Japan, liver transplantations are only performed as living-related liver transplantations (LRLT). A total of 13 patients that underwent LRLT for a UCD at the Kyoto transplant center are described by Morioka et al. [19]. Long-term patient and graft survival in their series are excellent, approaching 90% after 10 years, compared to about 75– 80% in non-UCD patients. However, the patients in this series consisted of adults with citrullinemia type II and girls with OTCD, both with a better prognosis than neonatal onset UCDs. In inherited
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metabolic diseases and LRLT the question of heterozygote donors arises. Ban and Sugiyama report on a 6-year-old girl with citrullinemia type I in whom liver transplantation was indicated because of recurrent metabolic decompensations. The only suitable living donor was her mother who was heterozygous for the disease. Ammonia levels normalized after LRLT and a normal diet could be established stepwise. The transplanted left liver lobe of the mother had a volume of 42% of the whole liver, the activity of argininosuccinate synthase had been determined to be only 20% of controls. From this case it can be calculated that only about 10% of enzyme activity had been transplanted to the child, apparently enough to normalize metabolic function [22]. However, possible differences between in vitro and in vivo enzyme activity could also have played a role.
Liver cell transplantation At the present time, 27 patients have been published who received liver cells for the treatment of inborn errors of metabolism whereof 10 patients suffered from UCD (Table 2). The first infusion was done in 1997 by a group from Pittsburgh. A 5-year-old boy with OTCD initially showed marked improvement of his laboratory parameters. Pathological levels of ammonia and glutamine normalized within 48 h. However, he experienced a severe metabolic decompensation four weeks after the transplantation following a protocol liver biopsy. He subsequently died after 2 weeks from pneumonia [23]. Since then an additional 9 children with different UCDs have been treated with LCT. A modest response to hepatocyte transplantation was seen in a male neonate with prenatal diagnosis of OTCD. Laboratory parameters as well as protein intolerance improved only slightly. The authors speculate that insufficient immunosuppression might have caused a rejection of the transplanted cells [24]. Another boy with the prenatal diagnosis of OTCD received hepatocytes in London immediately after birth using an umbilical vein access. After transplantation, he tolerated a normal protein supply, and no metabolic crises were observed. Because of uncertainties about the long-term stability after LCT, he received an auxiliary liver graft after 7 months and is doing well since then [25,26]. Two UCD patients were treated by the Brussels group. A 14month-old boy with OTCD had already been listed for OLT, and liver cell therapy was offered to stabilize the child until an organ was available. The patient’s ammonia levels decreased significantly and urea production increased after cell transplantation, which was repeated after 5 months. Four weeks after the last transfusion, a suitable organ became available for liver transplantation [27]. The other child was a 3-year-old girl with ASLD. Eight months after transplantation, the amount of transplanted cells (male donor) was estimated to be about 5% in several liver biopsies using FISH to detect chimeric hepatocytes with Y chromosomes [28]. A further LCT in citrullinemia has been reported anecdotally [29]. After two
applications of liver cells citrulline and ammonia dropped, but no further details of this case are available. Finally, a small series of four children with different UCDs was recently treated in our cell transplantation program [30]. The first patient, a boy with CPS1D, suffered from a very unstable clinical course from birth over the first two months before LCT was started to stabilize the child until LT later on. His ammonia levels normalized and no further metabolic crises occurred. According to the parents’ wishes, he received a full-organ transplantation 15 months after LCT. A 3-year-old girl with citrullinemia was evaluated for liver transplantation because of frequent crises and psychomotor delay, but the parents were objective to surgery. She underwent LCT and has remained metabolically stable and free of crises now 30 months hence. Finally, two boys with OTCD were treated shortly after birth. In one of these boys, the defect was already known prenatally; therefore LCT took place on the first day of life. Although his ammonia and glutamine levels improved and his urinary excretion of orotic acid normalized after LCT, he died from a fatal metabolic decompensation during an infection at the age of 4 months. The second boy was treated after neonatal manifestation and stabilization of the OTCD. Paralleled by significant improvement of ammonia, glutamine and urinary orotic acid excretion, he remained free of crises for 10 months, until the parents opted for a whole liver graft. During cell application, two possible complications have been observed in animal studies on LCT: portal vein thrombosis and shunting of liver cells into the systemic circulation resulting in pulmonary embolism. Since it has been shown that these events are highly dose-dependent, fractionated application of liver cells in multiple sessions over several days is used nowadays in most centers involved in human LCT. Thorough monitoring of the cell applications is mandatory to detect early changes in the portal venous circulation and to discontinue the infusion if necessary. The flow in the portal vein can be easily quantified by measuring the maximum flow velocity by Doppler ultrasound. Congruent with observations in animal studies, some authors found a transient decrease of portal vein flow in therapeutic attempts in humans [31,32], while others only report the absence of gross changes in flow velocity [27,28]. In animal models it has been shown that the pressure in the portal vein is inversely related to portal vein flow [33,34]. Moreover, the increase of portal vein pressure was directly related to the amount of cells given [34]. Published data on portal vein pressure in human LCT is available for 18 patients so far. Portal vein pressure temporarily increased during cell application in 5 of 6 adults [32,35] and 11 of 12 children [23,24,26,31,36–40]. The extent of the pressure increase was between 50 and 500%. In all patients, portal vein pressure almost or completely returned to baseline values within hours after cell infusions. Shunting of liver cells through the sinusoids into the systemic circulation seems to be a rare phenomenon even in animal models of LCT [34,41,42]. In human LCT, pulmonary shunting of hepatocytes was suspected
Table 2 Published experience of LCT in children with UCDs. Authors
Center
Diagnosis
Age at LCT
Observation period
Outcome
Strom et al. [23] Horslen et al. [24] Mitry et al. [25,26] Stephenne et al. [27] Stephenne et al. [28] Lee et al. [29] Meyburg et al. [30] Meyburg et al. [30] Meyburg et al. [30] Meyburg et al. [30]
Pittsburgh Omaha London Brussels Brussels Seoul Heidelberg Heidelberg Hannover Padua
OTCD OTCD OTCD OTCD ASLD Citrullinemia CPS1D Citrullinemia OTCD OTCD
5 years 1 day 1 day 14 months 3 years N.A. 2 months 3 years 1 day 9 days
6 weeks 6 months 7 months 6 months 15 months N.A. 15 months 30 months 4 months 10 months
Died OLT OLT OLT OLT N.A. OLT No crises yet Died OLT
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in two adult patients with acute liver failure and proven in one of them at autopsy [43]. However, both subjects received huge doses of liver cells in those pioneer days of human LCT, about 50–100 times higher than foreseen in actual pediatric protocols. No further pulmonary complications have been reported since. Besides safety considerations, the key issue in human LCT is the question of long-term efficacy. However, in contrast to animal studies where the transplanted cells can be labelled and manipulated in many ways, and the animals can be sacrificed to study their livers and the cells, quantification of therapeutic access is still a major obstacle in human LCT, especially for urea cycle disorders. Objective parameters like survival rates or frequency and extent of metabolic crises are almost impossible to assess due to the very low patient numbers that could be expected even in international multicenter studies. Therefore, surrogate parameters such as biochemical markers (ammonia, glutamine, citrulline, orotic acid), protein intake, or amount of ammonia scavenging drugs have to be evaluated [44]. An exceptional clinical course has been observed so far in one of our UCD patients, the girl with citrullinemia type I. As her parents are still reluctant toward OLT, the ongoing positive effects of cell therapy in combination with conservative treatment could be demonstrated during an impressive time period of 30 months so far. She had no relevant metabolic crises after LCT. One single episode of mild hyperammonemia occurred at month 68, when her mother arbitrarily increased her protein intake because of poor weight gain (Fig. 1). Previously the longest observation time after LCT for a child with UCD had been 15 months [28,44]. In that patient, a 4-year-old girl with ASL deficiency, the Brussels group attempted to determine enzyme activity in the host liver from serial percutaneous liver biopsies. Although ASL activity could be demonstrated in the liver samples, no quantitative conclusions could be made because of the huge sampling error that must be presumed caused by an irregular distribution of infused cells throughout the liver. In our two UCD patients who underwent OLT 15 and 10 months after LCT, respectively, a stable expression of enzyme activity was found in multiple liver samples [45]. Stem cell transplantation Although it is possible to produce relatively large amounts of cryopreserved liver cells under GMP conditions [46], one of the major limitations of LCT is the scarcity of donor organs. Transplan-
tation of liver stem cells that could be expanded in vitro would therefore be most attractive for human cell transplantation programs. A simple definition of a stem cell is that such a cell can divide into a new resting stem cell and a second cell that transforms into more differentiated cells. According to Potten, a stem cell is characterized by four main features: proliferation capacity, self-renewal, the production of a large number of differentiated progeny, and the ability of regenerating tissue after injury [47]. Whereas these definitions can be easily applied to some tissues, e.g. bone marrow, there is much debate on the nature of hepatic stem cells. Obviously, there is no easily definable equivalent to hematopoietic stem cells. Fig. 2 gives an overview of different candidates for liver stem cell transplantation [48–54]. While not discussing ethical and legal issues related to embryonic stem cells (ESC), these cells are omnipotent and can be transformed into hepatocytes or hepatocyte-like cells by various protocols [49]. However, the omnipotency of ESC may implicate a serious risk for transformation and uncontrolled proliferation, as indicated by formation of teratoma in a mice following hepatic transplantation of ESC [55,56]. The risk of teratoma formation is not of concern in transplantation of pluripotent cells. Fetal liver cells (fetal hepatoblasts, fetal hepatic progenitor cells) are obtained by collagenase perfusion of fetal livers, which raises ethical questions similar to the use of ESC and restricts a possible clinical use. Several other pluripotent cell types are without these ethical implications and have therefore become the main focus in the search for hepatic stem cells suitable for transplantation. These cell types comprise hematopoietic stem cells, adipose-derived stem cells, amniotic epithelial cells and umbilical cord blood cells. Mesenchymal stem cells are bone-marrow derived, and mesenchymallike pluripotent cells could be isolated and expanded from adult livers recently [51]. Oval cells are a small cell fraction located in the canal of Hering, and play an important role in liver regeneration. They are bipotent, i.e. can differentiate into hepatocytes as well as bile duct epithelia, but their exact phenotype in men and their stability for clinical application is unclear [57]. Differentiated adult hepatocytes are able to divide in the process of liver regeneration, and may thus also be regarded as unipotent liver stem cells. Finally, very interesting results were achieved by Faehndrich and co-workers, who were able to differentiate adult monocytes into hepatocyte-like cells, so-called ‘‘Neo-Heps” [58]. A lot of experimental studies have been carried out to investigate the effects of the different cell populations in cell transplanta-
Fig. 1. Long-term metabolic stability following LCT in a girl with citrullinemia.
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Fig. 2. Stem cell populations under discussion for clinical use.
tion. Numerous markers of hepatocyte differentiation and, in the case of xenogenic transplantations, human origin of the cells were investigated [59]. However, the patterns of the investigated markers and their expression distinctly varied, making the results difficult to compare. Therefore, an expert panel recently gave recommendations for the characterization of stem/progenitor-derived hepatocyte-like cells. These recommendations specify (i) detection of genes for ESC and pluripotent cells, (ii) evaluation of protein expression, (iii) ultrastructural evaluation, (iv) functional analysis in vitro and (v) engraftment, differentiation and functional repopulation in vivo [57]. A proof of function in vivo has been achieved in stem cell transplantation for acute liver failure. Kuo et al. demonstrated increased survival rates up to 100% following xenogenic transplantation of human mesenchymal stem cells in mice treated with carbon tetrachloride. Mesenchymal stem cells were clearly more effective than in vivo differentiated hepatocyte-like cells [48]. Since fusion of transplanted stem cells with hepatocytes is well known from other animal models [60,61], it is likely that stem cells ‘‘resuscitate” dying hepatocytes by cell-fusion in acute liver failure. Therefore, the applicability of such models for the use of stem cells in metabolic diseases is at most limited. There are a number of established animal models of hepatocyte transplantation for metabolic diseases including models representing relevant human diseases such as OTC deficiency, Crigler–Najjar syndrome or Wilson’s disease [62]. In contrast to large experiences with hepatocyte transplantation in these animal models, results using stem cells are not available yet. On the other hand, first clinical applications of fetal hepatoblasts in children with biliary atresia and Crigler–Najjar syndrome, respectively, have been published recently [63,64]. This discrepancy between lack of preclinical data and first ambitious therapeutic attempts in children underlines the need for a well-defined staged approach from bench to bedside, as recently suggested by an expert panel [57].
Conclusions A transfer of enzyme activity by transplantation of cells or liver tissue seems to be an appropriate and logical strategy in severe hepatic-based metabolic diseases such as urea cycle disorders. Each of the three concepts discussed above—liver transplantation, liver cell transplantation, and stem cell transplantation—has important special aspects, its Pros and Cons and different future perspectives. LT has now been established as the first and only definitive cure for UCDs. Unlike 20 years ago, the 5-year survival rate for children after LT for metabolic disease is about 90%. These figures are the best in the whole field of solid organ transplantation. Since every metabolic crisis results in further neurologic damage, it is important to perform LT as early as possible. Unfortunately, LT in neonates and small infants is technically challenging and still has a high complication rate, especially because of the relatively largefor-size grafts commonly used in split LT. LCT is much less invasive than LT, and can be performed as a bedside procedure. Nevertheless, it should still be regarded an experiment al therapy with only about 100 patients treated during the last 25 years. Such an experimental therapy should be restricted to diseases that (i) have a poor prognosis under conventional therapy, (ii) are caused by an enzyme defect that is mainly expressed in the liver, (iii) have shown good results in preclinical models and (iv) have been successfully treated by LT. UCDs are therefore very suitable model diseases. Safety and efficacy data from individual therapeutic attempts are encouraging, and a first multicenter prospective study on LCT in neonatal UCD (SELICA 2 study) has recently started in Germany. The development of suitable in vivo monitoring devices (stable isotopes) will determine whether LCT can only be used to bridge patients until LT or whether LCT can also develop into a realistic option for middleand long-term therapy.
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Although the use of stem cells could overcome the scarcity of donor hepatocytes, clinical applications are not established yet. One of the main obstacles is the heterogeneity of the stem and precursor cells under investigation. A focus is laid on pluripotent adult cells that can be derived from different sources such as bone marrow, cord blood, amnion and discarded liver tissue. After cell transplantation, various markers of differentiation into hepatocyte-like cells can be demonstrated. First promising results from acute liver failure have to be discussed under the aspect of cell-fusion, and are therefore of limited use for the design of application in human metabolic disease. It will be important to await which cell populations can be successfully applied in animal models of metabolic diseases, which is the next important step on the road to clinical application.
[20]
[21]
[22]
[23]
[24]
Conflict of interest statement
[25]
Jochen Meyburg is scientific consultant for Cytonet GmbH, Georg F. Hoffmann is member of the advisory board.
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Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects Jochen Meyburg *, Georg F. Hoffmann Department of General Pediatrics, University Children’s Hospital, Heidelberg, Germany
a r t i c l e
i n f o
Article history: Received 7 October 2009 Received in revised form 13 January 2010 Accepted 13 January 2010 Available online 29 January 2010 Keywords: Hepatocyte transplantation Ornithine transcarbamylase deficiency Carbamoylphosphate synthase deficiency Citrullinemia
s u m m a r y Despite advances in pharmacological therapy of urea cycle disorders (UCDs), the overall long-term prognosis is poor, especially for neonatal manifestations. Transplantation of liver tissue or isolated cells appears suitable for transfer of the missing enzyme. Liver transplantation (LT) for UCDs has an excellent 5-year survival rate of approximately 90% and is the only way to completely cure the disease. However, major neurological damage can only be prevented if the operation is performed during the first months of life. Unfortunately, such early LTs have a substantial risk for peri- and postoperative complications, mostly caused by a relatively large liver graft. Liver cell transplantation (LCT) is less invasive than LT, but has still to be regarded as an experimental therapy with about 100 patients treated since its first use in 1993. UCDs are a model disease for LCT, because of the poor prognosis, mainly hepatic enzyme defects, and excellent outcome after LT. So far, 10 children underwent LCT for UCDs with very few technical complications and encouraging clinical results. A first prospective study on its use in severe neonatal UCDs has recently started. However, availability of hepatocytes is limited by the scarcity of donor livers; therefore the use of stem cells is under investigation. Several different cell types may be regarded as liver stem cells, and in vivo transformation into hepatocyte-like cells has been shown in animal studies. However, a clear proof of principle in animal models of human metabolic disease is still missing, which is the prerequisite for clinical application in humans. Ó 2010 Elsevier Inc. All rights reserved.
Introduction The prognosis of urea cycle disorders (UCDs) has improved with the introduction of alternative pathway medication. Data from a large US therapeutic trial show that the frequency of metabolic crises could be substantially reduced by the addition of phenylbutyrate to the treatment of UCDs [1]. However, the long-term prognosis under pharmacological and dietary therapy is still poor, especially for neonatal UCDs [2–4]. Besides high mortality rates, neurological sequelae cause serious morbidity in the surviving children [5]. Whereas gene therapy is tempting, its potential use in UCDs is no longer under clinical investigation following the death of a study subject [6]. Transplantation of liver tissue or liver cells may be a suitable substitute. Transplantation medicine is rapidly evolving. Whereas liver transplantation (LT) was regarded experimental in the 1980s, it is now an important successful long-term therapeutic alternative to conventional therapy. Besides LT, cell-based therapies have been developed over the last years and are under investigation. The aim of this review is to give an overview about the
* Corresponding author. Address: Department of General Pediatrics, University Children’s Hospital, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany. Fax: +49 6221 565626. E-mail address: [email protected] (J. Meyburg). 1096-7192/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2010.01.011
impact of these techniques on the treatment of UCDs and an outlook about their future use in a multidisciplinary approach.
Liver transplantation An overview of published studies on liver transplantation for UCDs is given in Table 1. First case reports at the end of the 1980s demonstrate that liver transplantation could permanently normalize elevated ammonia levels in patients with UCDs [7,8]. Until 1996, about 20 successful transplantations were reported. However, these individual case reports are hardly comparable with respect to long-term clinical outcome, and there is always a tendency to publish primarily successful cases (ascertainment bias). An evaluation of 16 LT in 4 US transplant centers between 1986 and 1996 was published by Whitington et al. [9]. Of the 16 patients (8 children and 2 adult females with OTCD, 3 CPSD, 3 citrullinemia), 14 (87%) were alive at the end of the study after a maximum observation period of 6 years. One patient had died from immediate postoperative complications, another from aspiration pneumonia. No metabolic decompensations occurred during the observation period. Leonard and McKiernan collected more recent data published in 2004 [10]. Based on the literature and personal communications, they report on a total of 59 patients (32 OTCD, 18 citrullinemia, 6 CPSD, 2 ASLD, 1 argininemia). Also in this larger patient cohort,
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Table 1 Selected studies on LT for UCDs. Number of patients
Diagnosis
Age at LT
Type of LT
Authors
Outcome
About 20
Various UCDs
Various
OLT
Various 1987–1996
16
Various
OLT
Whitington et al. [9]
Various
OLT
Leonard et al. [10]
3
8 OTCD children 2 OTCD adults 3 CPSD 3 Citrullinemia 32 OTCD 18 Citrullinemia 6 CPSD 2 ASLD 1 Argininemia OTCD girls
Good Ascertainment bias? 2/16 died Hyperammonemic crises ceased Slight neurological improvement in 3 patients 4/59 died No protein restriction Hospital admissions reduced
APOLT
Kasahara et al. [18]
Good No protein restriction
2
Citrullinemia type II
APOLT
Yazaki et al. [20]
Good
13
7 Citrullinemia type II 6 OTCD girls Citrullinemia type I
2½ years 3 years 5½ years 32 years 43 years Various
8 OLT 5 APOLT LRLT
Morioka et al. [19]
Good
Ban et al. [22]
Good despite transplantation of only 8% calculated enzyme activity
59
1
6 years
a very high survival rate (55/59 patients, 93%) was found. Two patients died from immediate postoperative problems, another two from aspiration pneumonia later (the latter two children were severely handicapped). Quality of life substantially improved in all surviving children. Discontinuation/normalization of diet and reduction of hospital admissions were considered most important. Recent and comprehensive data can be obtained from the UNOS Organ Procurement and Transplant Network Database. Between 1988 and 2004 a total of 113 patients underwent LT for UCDs in the US Overall 5-year patient survival was excellent with 86% (OTCD: 86.2%, CPSD: 100%, citrullinemia: 100%, ASLD/argininemia 88.9%, unspecified UCD: 60%). Deaths after LT were attributed to infection, multiorgan failure, primary non-function of the graft, brain death, and recurrence of disease (no further information available) [11]. Due to the nearly exclusive hepatic expression especially of the proximal urea cycle, the success of LT for UCDs is not surprising. Only small amounts of defective enzymes that are localized in kidney and gut are not replenished by LT, and LT for UCDs may thus be regarded as a gene-respective enzyme replacement therapy. An open question is however the physiological importance of substantial cerebral expression of the distal urea cycle enzymes, especially argininosuccinate lyase and arginase. Therefore, reduced (OTCD and CPSD) or still elevated (citrullinemia) concentrations of citrulline may still be observed after LT in the systemic circulation [8,12]. However, there is convincing evidence that further neurological impairment can be prevented by LT [9], and that even neurological improvement could be observed in individual cases [13,14]. This concept does not refer to the rare cases of UCDs presenting as acute liver failure. Teufel et al. 2009 reported a previously healthy 3-year old girl presenting for the first time with fulminant liver failure. After the diagnosis of OTCD was made, emergency treatment including hemodialysis was started, but liver failure could not be controlled. Her condition dramatically improved after emergency LT three days after admission, and she is healthy two years thereafter [15]. UCDs with neonatal onset, i.e. OTCD, CPS1D, and citrullinemia, usually have a dramatic initial presentation, and very poor longterm prognosis [2–4]. Currently only early LT can prevent severe brain damage and opens the chance for a reasonable to good outcome. In the early series of LT for UCDs, patient’s ages at the time of transplantation have not been reported [9,16]. However, it can be assumed that the majority was older than 12 months of age,
since LT was only performed exceptionally in infancy due to the high rate of complications at that time. In the small series reported by Maestri et al., 2 of 3 patients were already profoundly retarded at the time of LT [16]. More patients were collected by Whitington et al. and classified by a custom neurological scale [9]. They documented severe neurological impairment (no social interaction, no ambulation, no communication) in 3 of 14 patients, moderate impairment (limited social interaction, bipedal ambulation, and limited communication) in 5 of 14 patients, and mild to moderate impairment (definite social interaction, fair ambulation, and some use of language) in 5 of 14 patients. Only one child in this series was mildly impaired, and two adult female patients were within the normal spectrum of neurologic and psychologic abilities. Following LT, neurological deterioration ceased in all surviving patients, and a slight improvement was noted in 3 of 12 children. Developmental outcome after early LT was prospectively investigated by McBride et al. [17]. They evaluated three children (age at LT 5, 11 and 3 months, respectively) and one female (partial OTC child transplanted in early childhood) with the Griffiths Mental Developmental Scales. After LT, only mild to moderate psychomotor delay (average overall score 66.7, normal range 100 ± 10.8) was found. Although this was only a small series of patients, these seem to favour the concept of early LT. Special considerations have to be made for female OTCD patients. Because the disease is X-chromosomal recessively inherited, all affected girls can pass on the defected gene as conductors, but some may themselves develop severe progressive symptoms often starting in early adulthood. For these patients, auxiliary partial orthotopic liver transplantation (APOLT) appears conceptually an attractive therapeutic option [18,19]. APOLT has also been successfully performed in adult patients with citrullinemia type II [19,20]. Although small patient cohorts indicate that OLT might be superior to APOLT [19], recent results in children with non-cirrhotic metabolic diseases indicate good long-term results similar to OLT [21]. Because the concept of brain death is not established in Japan, liver transplantations are only performed as living-related liver transplantations (LRLT). A total of 13 patients that underwent LRLT for a UCD at the Kyoto transplant center are described by Morioka et al. [19]. Long-term patient and graft survival in their series are excellent, approaching 90% after 10 years, compared to about 75– 80% in non-UCD patients. However, the patients in this series consisted of adults with citrullinemia type II and girls with OTCD, both with a better prognosis than neonatal onset UCDs. In inherited
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metabolic diseases and LRLT the question of heterozygote donors arises. Ban and Sugiyama report on a 6-year-old girl with citrullinemia type I in whom liver transplantation was indicated because of recurrent metabolic decompensations. The only suitable living donor was her mother who was heterozygous for the disease. Ammonia levels normalized after LRLT and a normal diet could be established stepwise. The transplanted left liver lobe of the mother had a volume of 42% of the whole liver, the activity of argininosuccinate synthase had been determined to be only 20% of controls. From this case it can be calculated that only about 10% of enzyme activity had been transplanted to the child, apparently enough to normalize metabolic function [22]. However, possible differences between in vitro and in vivo enzyme activity could also have played a role.
Liver cell transplantation At the present time, 27 patients have been published who received liver cells for the treatment of inborn errors of metabolism whereof 10 patients suffered from UCD (Table 2). The first infusion was done in 1997 by a group from Pittsburgh. A 5-year-old boy with OTCD initially showed marked improvement of his laboratory parameters. Pathological levels of ammonia and glutamine normalized within 48 h. However, he experienced a severe metabolic decompensation four weeks after the transplantation following a protocol liver biopsy. He subsequently died after 2 weeks from pneumonia [23]. Since then an additional 9 children with different UCDs have been treated with LCT. A modest response to hepatocyte transplantation was seen in a male neonate with prenatal diagnosis of OTCD. Laboratory parameters as well as protein intolerance improved only slightly. The authors speculate that insufficient immunosuppression might have caused a rejection of the transplanted cells [24]. Another boy with the prenatal diagnosis of OTCD received hepatocytes in London immediately after birth using an umbilical vein access. After transplantation, he tolerated a normal protein supply, and no metabolic crises were observed. Because of uncertainties about the long-term stability after LCT, he received an auxiliary liver graft after 7 months and is doing well since then [25,26]. Two UCD patients were treated by the Brussels group. A 14month-old boy with OTCD had already been listed for OLT, and liver cell therapy was offered to stabilize the child until an organ was available. The patient’s ammonia levels decreased significantly and urea production increased after cell transplantation, which was repeated after 5 months. Four weeks after the last transfusion, a suitable organ became available for liver transplantation [27]. The other child was a 3-year-old girl with ASLD. Eight months after transplantation, the amount of transplanted cells (male donor) was estimated to be about 5% in several liver biopsies using FISH to detect chimeric hepatocytes with Y chromosomes [28]. A further LCT in citrullinemia has been reported anecdotally [29]. After two
applications of liver cells citrulline and ammonia dropped, but no further details of this case are available. Finally, a small series of four children with different UCDs was recently treated in our cell transplantation program [30]. The first patient, a boy with CPS1D, suffered from a very unstable clinical course from birth over the first two months before LCT was started to stabilize the child until LT later on. His ammonia levels normalized and no further metabolic crises occurred. According to the parents’ wishes, he received a full-organ transplantation 15 months after LCT. A 3-year-old girl with citrullinemia was evaluated for liver transplantation because of frequent crises and psychomotor delay, but the parents were objective to surgery. She underwent LCT and has remained metabolically stable and free of crises now 30 months hence. Finally, two boys with OTCD were treated shortly after birth. In one of these boys, the defect was already known prenatally; therefore LCT took place on the first day of life. Although his ammonia and glutamine levels improved and his urinary excretion of orotic acid normalized after LCT, he died from a fatal metabolic decompensation during an infection at the age of 4 months. The second boy was treated after neonatal manifestation and stabilization of the OTCD. Paralleled by significant improvement of ammonia, glutamine and urinary orotic acid excretion, he remained free of crises for 10 months, until the parents opted for a whole liver graft. During cell application, two possible complications have been observed in animal studies on LCT: portal vein thrombosis and shunting of liver cells into the systemic circulation resulting in pulmonary embolism. Since it has been shown that these events are highly dose-dependent, fractionated application of liver cells in multiple sessions over several days is used nowadays in most centers involved in human LCT. Thorough monitoring of the cell applications is mandatory to detect early changes in the portal venous circulation and to discontinue the infusion if necessary. The flow in the portal vein can be easily quantified by measuring the maximum flow velocity by Doppler ultrasound. Congruent with observations in animal studies, some authors found a transient decrease of portal vein flow in therapeutic attempts in humans [31,32], while others only report the absence of gross changes in flow velocity [27,28]. In animal models it has been shown that the pressure in the portal vein is inversely related to portal vein flow [33,34]. Moreover, the increase of portal vein pressure was directly related to the amount of cells given [34]. Published data on portal vein pressure in human LCT is available for 18 patients so far. Portal vein pressure temporarily increased during cell application in 5 of 6 adults [32,35] and 11 of 12 children [23,24,26,31,36–40]. The extent of the pressure increase was between 50 and 500%. In all patients, portal vein pressure almost or completely returned to baseline values within hours after cell infusions. Shunting of liver cells through the sinusoids into the systemic circulation seems to be a rare phenomenon even in animal models of LCT [34,41,42]. In human LCT, pulmonary shunting of hepatocytes was suspected
Table 2 Published experience of LCT in children with UCDs. Authors
Center
Diagnosis
Age at LCT
Observation period
Outcome
Strom et al. [23] Horslen et al. [24] Mitry et al. [25,26] Stephenne et al. [27] Stephenne et al. [28] Lee et al. [29] Meyburg et al. [30] Meyburg et al. [30] Meyburg et al. [30] Meyburg et al. [30]
Pittsburgh Omaha London Brussels Brussels Seoul Heidelberg Heidelberg Hannover Padua
OTCD OTCD OTCD OTCD ASLD Citrullinemia CPS1D Citrullinemia OTCD OTCD
5 years 1 day 1 day 14 months 3 years N.A. 2 months 3 years 1 day 9 days
6 weeks 6 months 7 months 6 months 15 months N.A. 15 months 30 months 4 months 10 months
Died OLT OLT OLT OLT N.A. OLT No crises yet Died OLT
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in two adult patients with acute liver failure and proven in one of them at autopsy [43]. However, both subjects received huge doses of liver cells in those pioneer days of human LCT, about 50–100 times higher than foreseen in actual pediatric protocols. No further pulmonary complications have been reported since. Besides safety considerations, the key issue in human LCT is the question of long-term efficacy. However, in contrast to animal studies where the transplanted cells can be labelled and manipulated in many ways, and the animals can be sacrificed to study their livers and the cells, quantification of therapeutic access is still a major obstacle in human LCT, especially for urea cycle disorders. Objective parameters like survival rates or frequency and extent of metabolic crises are almost impossible to assess due to the very low patient numbers that could be expected even in international multicenter studies. Therefore, surrogate parameters such as biochemical markers (ammonia, glutamine, citrulline, orotic acid), protein intake, or amount of ammonia scavenging drugs have to be evaluated [44]. An exceptional clinical course has been observed so far in one of our UCD patients, the girl with citrullinemia type I. As her parents are still reluctant toward OLT, the ongoing positive effects of cell therapy in combination with conservative treatment could be demonstrated during an impressive time period of 30 months so far. She had no relevant metabolic crises after LCT. One single episode of mild hyperammonemia occurred at month 68, when her mother arbitrarily increased her protein intake because of poor weight gain (Fig. 1). Previously the longest observation time after LCT for a child with UCD had been 15 months [28,44]. In that patient, a 4-year-old girl with ASL deficiency, the Brussels group attempted to determine enzyme activity in the host liver from serial percutaneous liver biopsies. Although ASL activity could be demonstrated in the liver samples, no quantitative conclusions could be made because of the huge sampling error that must be presumed caused by an irregular distribution of infused cells throughout the liver. In our two UCD patients who underwent OLT 15 and 10 months after LCT, respectively, a stable expression of enzyme activity was found in multiple liver samples [45]. Stem cell transplantation Although it is possible to produce relatively large amounts of cryopreserved liver cells under GMP conditions [46], one of the major limitations of LCT is the scarcity of donor organs. Transplan-
tation of liver stem cells that could be expanded in vitro would therefore be most attractive for human cell transplantation programs. A simple definition of a stem cell is that such a cell can divide into a new resting stem cell and a second cell that transforms into more differentiated cells. According to Potten, a stem cell is characterized by four main features: proliferation capacity, self-renewal, the production of a large number of differentiated progeny, and the ability of regenerating tissue after injury [47]. Whereas these definitions can be easily applied to some tissues, e.g. bone marrow, there is much debate on the nature of hepatic stem cells. Obviously, there is no easily definable equivalent to hematopoietic stem cells. Fig. 2 gives an overview of different candidates for liver stem cell transplantation [48–54]. While not discussing ethical and legal issues related to embryonic stem cells (ESC), these cells are omnipotent and can be transformed into hepatocytes or hepatocyte-like cells by various protocols [49]. However, the omnipotency of ESC may implicate a serious risk for transformation and uncontrolled proliferation, as indicated by formation of teratoma in a mice following hepatic transplantation of ESC [55,56]. The risk of teratoma formation is not of concern in transplantation of pluripotent cells. Fetal liver cells (fetal hepatoblasts, fetal hepatic progenitor cells) are obtained by collagenase perfusion of fetal livers, which raises ethical questions similar to the use of ESC and restricts a possible clinical use. Several other pluripotent cell types are without these ethical implications and have therefore become the main focus in the search for hepatic stem cells suitable for transplantation. These cell types comprise hematopoietic stem cells, adipose-derived stem cells, amniotic epithelial cells and umbilical cord blood cells. Mesenchymal stem cells are bone-marrow derived, and mesenchymallike pluripotent cells could be isolated and expanded from adult livers recently [51]. Oval cells are a small cell fraction located in the canal of Hering, and play an important role in liver regeneration. They are bipotent, i.e. can differentiate into hepatocytes as well as bile duct epithelia, but their exact phenotype in men and their stability for clinical application is unclear [57]. Differentiated adult hepatocytes are able to divide in the process of liver regeneration, and may thus also be regarded as unipotent liver stem cells. Finally, very interesting results were achieved by Faehndrich and co-workers, who were able to differentiate adult monocytes into hepatocyte-like cells, so-called ‘‘Neo-Heps” [58]. A lot of experimental studies have been carried out to investigate the effects of the different cell populations in cell transplanta-
Fig. 1. Long-term metabolic stability following LCT in a girl with citrullinemia.
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Fig. 2. Stem cell populations under discussion for clinical use.
tion. Numerous markers of hepatocyte differentiation and, in the case of xenogenic transplantations, human origin of the cells were investigated [59]. However, the patterns of the investigated markers and their expression distinctly varied, making the results difficult to compare. Therefore, an expert panel recently gave recommendations for the characterization of stem/progenitor-derived hepatocyte-like cells. These recommendations specify (i) detection of genes for ESC and pluripotent cells, (ii) evaluation of protein expression, (iii) ultrastructural evaluation, (iv) functional analysis in vitro and (v) engraftment, differentiation and functional repopulation in vivo [57]. A proof of function in vivo has been achieved in stem cell transplantation for acute liver failure. Kuo et al. demonstrated increased survival rates up to 100% following xenogenic transplantation of human mesenchymal stem cells in mice treated with carbon tetrachloride. Mesenchymal stem cells were clearly more effective than in vivo differentiated hepatocyte-like cells [48]. Since fusion of transplanted stem cells with hepatocytes is well known from other animal models [60,61], it is likely that stem cells ‘‘resuscitate” dying hepatocytes by cell-fusion in acute liver failure. Therefore, the applicability of such models for the use of stem cells in metabolic diseases is at most limited. There are a number of established animal models of hepatocyte transplantation for metabolic diseases including models representing relevant human diseases such as OTC deficiency, Crigler–Najjar syndrome or Wilson’s disease [62]. In contrast to large experiences with hepatocyte transplantation in these animal models, results using stem cells are not available yet. On the other hand, first clinical applications of fetal hepatoblasts in children with biliary atresia and Crigler–Najjar syndrome, respectively, have been published recently [63,64]. This discrepancy between lack of preclinical data and first ambitious therapeutic attempts in children underlines the need for a well-defined staged approach from bench to bedside, as recently suggested by an expert panel [57].
Conclusions A transfer of enzyme activity by transplantation of cells or liver tissue seems to be an appropriate and logical strategy in severe hepatic-based metabolic diseases such as urea cycle disorders. Each of the three concepts discussed above—liver transplantation, liver cell transplantation, and stem cell transplantation—has important special aspects, its Pros and Cons and different future perspectives. LT has now been established as the first and only definitive cure for UCDs. Unlike 20 years ago, the 5-year survival rate for children after LT for metabolic disease is about 90%. These figures are the best in the whole field of solid organ transplantation. Since every metabolic crisis results in further neurologic damage, it is important to perform LT as early as possible. Unfortunately, LT in neonates and small infants is technically challenging and still has a high complication rate, especially because of the relatively largefor-size grafts commonly used in split LT. LCT is much less invasive than LT, and can be performed as a bedside procedure. Nevertheless, it should still be regarded an experiment al therapy with only about 100 patients treated during the last 25 years. Such an experimental therapy should be restricted to diseases that (i) have a poor prognosis under conventional therapy, (ii) are caused by an enzyme defect that is mainly expressed in the liver, (iii) have shown good results in preclinical models and (iv) have been successfully treated by LT. UCDs are therefore very suitable model diseases. Safety and efficacy data from individual therapeutic attempts are encouraging, and a first multicenter prospective study on LCT in neonatal UCD (SELICA 2 study) has recently started in Germany. The development of suitable in vivo monitoring devices (stable isotopes) will determine whether LCT can only be used to bridge patients until LT or whether LCT can also develop into a realistic option for middleand long-term therapy.
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Although the use of stem cells could overcome the scarcity of donor hepatocytes, clinical applications are not established yet. One of the main obstacles is the heterogeneity of the stem and precursor cells under investigation. A focus is laid on pluripotent adult cells that can be derived from different sources such as bone marrow, cord blood, amnion and discarded liver tissue. After cell transplantation, various markers of differentiation into hepatocyte-like cells can be demonstrated. First promising results from acute liver failure have to be discussed under the aspect of cell-fusion, and are therefore of limited use for the design of application in human metabolic disease. It will be important to await which cell populations can be successfully applied in animal models of metabolic diseases, which is the next important step on the road to clinical application.
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Conflict of interest statement
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Jochen Meyburg is scientific consultant for Cytonet GmbH, Georg F. Hoffmann is member of the advisory board.
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