Infusion Of Allogeneic Mesenchymal Stem Cells Research Articles

P9.34: Application of Mesenchymal Stem Cells for the Treatment of Liver Graft Dysfunction Caused by Chronic Rejection. Case Report

Background: Development of immunosuppressive therapy (IST) complications after liver transplantation (LT) requires its minimization. Decrease of immunosuppression in the long-term period after transplantation in 8% of patients is accompanied with the development of chronic rejection (CR). Objective: The aim of this report was to demonstrate the successful treatment of liver transplant CR with mesenchymal stem cells (MSCs) in patient with acute kidney injury (AKI) and IST minimizing. Results: Patient with unresectable liver alveococcosis underwent LT. After surgery patient received a three-component IST, which after six months was de-escalated to tacrolimus monotherapy (Tac). A year after the operation graft dysfunction developed, which was accompanied by a maximum increase of AST up to 511 U/l and ALT up to 507 U/l, GGTP up to 1753 U/l and ALP up to 474 U/l. IST was escalated: pulse therapy with glucocorticosteroids was performed twice; mycophenolate mofetil, mTOR inhibitors, intravenous immunoglobulin were added. Thrice performed puncture liver biopsy demonstrated the chronicity of the alloimmune conflict. Developed AKI in the process of anti-rejection therapy required decreasing of Tac, which led to increase of cytolysis and cholestasis. Infusion of allogeneic MSCs with a total dose of 8 x 106 cells per kg led to normalization of laboratory blood tests. The Tac concentration was 0.8 ng/ml; kidney function recovered: urea level was 7.1 mmol/l, creatinine - 80 µmol/l, GFR - 25 ml/min. Application of MSCs formed immunotolerance: the suppressor subpopulation of T-regulatory CD3+CD4+CD25highCD127- lymphocytes increased and effector CD3+CD8+naïve T-lymphocytes, antigen-presenting myeloid dendritic cells, and antibodies-producing CD19+ naïve B-lymphocytes decreased. Conclusions: MSCs can be used in CR as an effective alternative IST that can replace the immunosuppressive effect of basic immunosuppressants.

Mesenchymal stem cells in fibrotic diseases-the two sides of the same coin.

Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials.

Effect of Stem Cell Infusion Therapy on Sexual Function in Women with Type 2 Diabetes and Metabolic Syndrome: Post-Hoc Analysis of Randomized Controlled Trials

ABSTRACT Introduction There is a growing interest in restorative therapies for sexual function, yet there exists a paucity of human research into potential therapeutic applications of stem cell therapy (SCT). Mesenchymal Stem Cells (MSCs) and their effect on sexual function have not yet been explored in women with Type 2 Diabetes Mellitus (DM) and Metabolic Syndrome (MetS). Objective To determine the safety and efficacy of intravenous mesenchymal stem cell infusion therapy on sexual function in women with DM or MetS. Methods Female participants enrolled in the ACESO (NCT02886884) and CERES (NCT03059355) clinical trials completed the Sexual Quality of Life Questionnaire-Female (SQOL-F). SQOL-F is a validated 18-item self-assessment questionnaire rated on a six-point scale ranging from “completely agree” to “completely disagree” in which higher scores reflect better sexual quality of life. Participants were enrolled in the trials based on diagnosis of DM or MetS, respectively. Intervention in both trials was peripheral intravenous infusion of allogeneic MSCs. Follow-up was for 1 year. Questionnaires were collected at baseline and 1-, 3-, 6-, and 12-months post-infusion. Participants received 20 or 100 million MSCs from either bone marrow (n=5) or umbilical cord (n=2). Results Data was pooled from 7 women who participated in the two trials; 5 were from ACESO and 2 were from CERES. Three received high dose MSCs (100 million) and four received low dose (20 million) MSCs. The women in the ACESO trial received MSCs derived from healthy allogeneic donor bone marrow, and both women in the CERES trial received umbilical cord tissue derived MSCs. Median age was 73 [IQR=55-74] years. Six of the seven (86%) had past medical history of hypertension. Median SQOL score among all women at baseline was 30 [IQR=19-50], 25 [IQR=23-36] at 1 month, 34 [IQR=19-46] at 3 months, 29 [IQR=21-32] at 6 months, and 34 [IQR=26-49] at the end of 12 months. Improvements in SQOL from baseline through follow up did not meet level of statistical significance. Limitations of this study include the absence of a placebo-control group, the small sample size, and that sexual function was not a primary endpoint of the original trials. Conclusions SQOL did not appear to improve following peripheral infusion of MSCs in women with DM or MetS, but nevertheless appears to be safe with no decline in sexual function over the following 1 year. Larger clinical trials with placebo-controls are needed to further investigate the optimal dose, source, and route administration of SCT to enact a meaningful change in sexual function in women with DM or MetS. Disclosure Yes, this is sponsored by industry/sponsor: This work was supported by National Institutes of Health Grant R01 DK130991 and Clinician Scientist Development Grant from the American Cancer Society to RR. JMH is supported by National Institutes of Health grants 1R01 HL137355, 1R01 HL107110, 1R01 HL134558, 5R01 CA136387, and 5UM1 HL113460 and Soffer Family Foundation. Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: JMH discloses a relationship with Vestion Inc. that includes equity, board membership, and consulting. Neither Longeveron, Vestion, or any other companies participated in the funding of this work. All other authors indicated no potential conflicts of interest.

Effect of Stem Cell Infusion Therapy on Sexual Function in Men and Women with Type 2 Diabetes and Metabolic Syndrome: Results from the ACESO & CERES Clinical Trials

ABSTRACT Introduction Despite growing interest in restorative therapies for sexual function, there exists a paucity of human research into potential therapeutic applications of stem cell therapy (SCT). Mesenchymal Stem Cells (MSCs) and its effects on sexual function have not yet been explored in patients with Type 2 Diabetes Mellitus (DM) and Metabolic Syndrome (MetS) Objective To determine the effect of stem cell infusion therapy on sexual function in men and women with DM or MetS. Methods We used International Index of Erectile Function (IIEF-15) collected from men and Sexual Quality of Life Questionnaire-Female (SQOL-F) collected from women enrolled in the ACESO (NCT02886884) and CERES (NCT03059355) pilot/phase I clinical trials. Participants were enrolled in the trials based on diagnosis of DM or MetS, respectively, and endothelial dysfunction - defined as Brachial Artery Flow Mediated Vasodilation (FMD) <7%. Intervention in both trials was peripheral intravenous infusion of allogeneic MSCs. Follow-up was for 1 year. Questionnaires were collected at baseline and at 1-, 3-, 6-, and 12-months post-infusion. Participants received 20 or 100 million MSCs from either bone marrow (n=21) or umbilical cord (n=6). We performed subgroup analyses evaluating dose, source, and study diseases. Descriptive and analytic statistics were used to analyze the data. Results Data was pooled from 20 men and 7 women from the two trials. Overall, 14 received 100 million MSCs and 13 received 20 million MSCs. Median age was 61 [IQR=55-73] years. Incidence of hypertension, coronary artery disease, smoking and alcohol use were similar among each trial. Erectile dysfunction (ED) was defined by an IIEF-Erectile Function (IIEF-EF) sub-domain score ≤24 at baseline (n=16). Among men with ED, median IIEF-EF score at baseline was 5 [IQR=2-17], 6 [IQR=3-17] at 1 month, 3 [IQR=2-8] at 3 months, 4 [IQR=3-13] at 6 months, and 5.5 [IQR=2-16] at the end of 12 months (p=0.8127). Subgroup analyses revealed no changes in erectile function in either treatment dose. Similar patterns were found in other IIEF sub-domains, except median sexual desire score which increased among all men from 1-3 months post-infusion, then subsided from 6-12 months (p=0.4723). SQOL-f is a validated self-assessment questionnaire rated on a six-point scale in which higher scores reflect better female sexual quality of life. Median SQOL score among all women at baseline was 30 [IQR=19-50], 25 [IQR=23-36] at 1 month, 34 [IQR=19-46] at 3 months, 29 [IQR=21-32] at 6 months, and 34 [IQR=26-49] at the end of 12 months (p=0.8866). Main limitations of this study include the small sample size, sexual function was not a primary endpoint, and the absence of a placebo comparison arm. Conclusions Neither ED or SQOL appears to have improved following peripheral infusion of MSCs in patients with DM and MetS, but nevertheless appears to be safe with no decline in sexual function over 1 year. The optimal route, source, and dose of SCT to enact a meaningful change in sexual function in different patient populations has yet to be determined and deserves further research in future larger randomized clinical trials. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Longeveron LLC

Frailty and Rejuvenation with Stem Cells: Therapeutic Opportunities and Clinical Challenges.

Frailty, one appealing target for improving successful aging of the elderly population, is a common clinical syndrome based on the accumulation of multisystemic function declines and the increase in susceptibility to stressors during biological aging. The age-dependent senescence, the frailty-related stem cell depletion, chronic inflammation, imbalance of immune homeostasis, and the reduction of multipotent stem cells collectively suggest the rational hypothesis that it is possible to (partially) cure frailty with stem cells. This systematic review has included all of the human trials of stem cell therapy for frailty from the main electronic databases and printed materials and screened the closely related reviews themed on the mechanisms of aging, frailty, and stem cells, to provide more insights in stem cell strategies for frailty, one promising method to recover health from a frail status. To date, a total of four trials about this subject have been registered on clinicaltrials.gov. The use of mesenchymal stem cells (MSCs), doses of 100 million cells, single peripheral intravenous infusion, follow-up periods of 6–12 months, and a focus primarily on safety and secondarily on efficacy are common characteristics of these studies. We conclude that intravenous infusion of allogenic MSCs is safe, well tolerated, and preliminarily effective clinically. More preclinical experiments and clinical trials are warranted to precisely elucidate the mechanism, safety, and efficacy of frailty stem cell therapy.

Safety analysis in patients with autoimmune disease receiving allogeneic mesenchymal stem cells infusion: a long-term retrospective study

ObjectiveThe aim of this study was to evaluate the safety of mesenchymal stem cell infusion in patients with autoimmune diseases.MethodsA total of 404 patients with autoimmune diseases who received mesenchymal stem cell infusion between 2007 and 2016 were included in this study. Adverse events in these patients were collected, mainly including infections and malignancies. Sources of information included hospitalization records and data from outpatient visits and each follow-up.ResultsThe mean follow-up period of all patients was 43.4 ± 25.9 months (range 1–109). Majority of stem cells were from the umbilical cord. The most common indications for mesenchymal stem cell infusion were systemic lupus erythematosus, Sjögren’s syndrome, and systemic sclerosis. The median age at infusion was 38.7 ± 15.7 years. The 5-year and 8-year survival rates were 90.4% and 88.9%, respectively. Median follow-up of survivors was 45.1 ± 25.7 months. The incidence rate of infections was 29.5% (119/404), and that of serious infections was 12.9% (52/404). Five patients (1.2%) experienced malignancies. Deaths occurred in 45 patients, and transplantation-related mortality was 0.2%. The most common causes of deaths in our study were disease relapse and complications associated with the underlying disease.ConclusionAutoimmune disease is an emerging indication for mesenchymal stem cell infusion. Our data shows that mesenchymal stem cell infusion is a safe therapy for patients with autoimmune diseases. The incidences of adverse events, whether infections or malignancies, are acceptable in these patients.Trial registrationClinaicalTrials.gov, NCT00698191. Registered 17 June 2008—Retrospectively registered

Indirect co-cultures of healthy mesenchymal stem cells restore the physiological phenotypical profile of psoriatic mesenchymal stem cells.

Psoriasis microenvironment, characterized by an imbalance between T helper type 1 (Th1)/Th17 and Th2 cytokines and also influences the mesenchymal stem cells (MSCs) phenotypical profile. MSCs from healthy donors (H-MSCs) can exert a strong paracrine effect by secreting active soluble factors, able to modulate the inflammation in the microenvironment. To evaluate the influence of H-MSCs on MSCs from psoriatic patients (PsO-MSCs), H-MSCs and PsO-MSCs were isolated and characterized. Indirect co-culture of H-MSCs with PsO-MSCs was performed; effects on proliferation and expression of cytokines linked to Th1/Th17 and Th2 pathways were assayed before and after co-culture. The results show that before co-culture, proliferation of PsO-MSCs was significantly higher than H-MSCs (P<0·05) and the levels of secreted cytokines confirmed the imbalance of Th1/Th17 versus the Th2 axis. After co-culture of H-MSCs with PsO-MSCs, healthy MSCs seem to exert a 'positive' influence on PsO-MSCs, driving the inflammatory phenotypical profile of PsO-MSCs towards a physiological pattern. The proliferation rate decreased towards values nearer to those observed in H-MSCs and the secretion of the cytokines that mostly identified the inflammatory microenvironment that characterized psoriasis, such as interleukin (IL)-6, IL-12, IL-13, IL-17A, tumour necrosis factor (TNF)-α and granulocyte-macrophage colony-stimulating factor (G-CSF), is significantly lower in co-cultured PsO-MSCs than in individually cultured PSO-MSCs (P at least <0·05). In conclusion, our preliminary results seem to provide an intriguing molecular explanation for the ever-increasing evidence of therapeutic efficacy of allogeneic MSCs infusion in psoriatic patients.

Umbilical cord-derived mesenchymal stem (stromal) cells for treatment of severe sepsis: aphase 1 clinical trial

The aim of this phase 1 clinical trial was to test the safety and feasibility of a single dose of allogeneic umbilical cord-derived mesenchymal stem cells (MSCs) in patients with severe sepsis. This is a single-center, open-label, dose-escalation phase 1 clinical trial of a single dose of intravenous MSCs in patients with severe sepsis. We enrolled 15 patients who averagely divided into low (1 × 106 cells/kg), intermediate (2 × 106 cells/kg), and high (3 × 106 cells/kg) dosing cohorts. Primary outcomes included the incidence of infusion-associated events and serious adverse events. Secondary outcomes included systemic endpoints, mortality, and inflammation biologic markers. A historical case-matched comparison group was set as the control. This study enrolled 15 patients (10 male and 5 female), with a median age of 58. Compared to those in the historical, case-matched group, neither there were infusion-associated serious events or treatment-related adverse events in any of the 15 patients in this trial, nor were there any safety or efficacy signals for serious adverse events or the measured cytokines. A single intravenous infusion of allogeneic MSCs up to a dose of 3 × 106 cells/kg was safe and well tolerated in 15 patients with severe sepsis.

Abstract 5699: Mesenchymal stem cells (MSCs) as a selective delivery vehicle for a PSA-activated protoxin for advanced prostate cancer

Abstract Circulating bone marrow-derived Mesenchymal Stem Cells (MSCs) can differentiate into cells of the mesoderm lineage and have an innate tropism for tumor tissue in response to the inflammatory microenvironment present in malignant lesions. MSCs have been detected in the perivascular space of many tumors, including prostate. MSCs are inherently non-immunogenic, which prevents allogeneic MSCs from being rejected by host defense mechanisms. This immune-privileged status, together with their oncotropic properties, makes possible the infusion of allogeneic MSCs into patients for therapeutic purposes. PRX302 is a PSA-activated aerolysin-based protoxin that forms membrane pores and leads to necrosis by a proliferation-independent mechanism at low picomolar concentrations. Active PSA is bound to inhibitors, such as A2M, in the plasma, and therefore, is only present in an active form at sites of local and metastatic prostate cancer. Consequently, PRX302 will only be converted to a toxic form in the tumor microenvironment and thereby, limit off-target toxicity. Based upon this rationale we hypothesize that MSCs can be used as a cell-based targeting vehicle to selectively deliver therapeutic agents, such as PRX302, to primary and metastatic sites of prostate cancer, and thus spare host toxicity. We have demonstrated that fluorescently-labeled MSCs “home” to sites of prostate cancer in nude mice bearing castration-resistant CWR-22RH xenografts and a significant fraction are localized to the perivascular space. This co-localization with the tumor vasculature suggests that a MSC-delivered cytotoxin would have profound anti-tumor efficacy through effects on both cancer and endothelial cells. Furthermore, we have confirmed that MSCs and stromal cells derived from human prostate cancers (PrCSCs) in men older than 50 (&amp;gt;10 tested), but not those isolated from normal prostates in men under 30 (&amp;gt;7 tested), can differentiate into adipocytes, osteoblasts, and chondrocytes under the appropriate conditions. Furthermore, these PrCSCs are positive for CD90, CD73, CD105, and FAP, but do not express CD34, CD45, CD11b, CD19, or HLA-DR, which is consistent with the hMSC phenotype and suggests that MSCs migrate to cancerous prostates in the human as well. Importantly, PRX302 binds with low nanomolar affinity to GPI-anchor proteins, which are highly expressed on the surface of all mammalian cells. Using PIG-A-targeted zinc finger nucleases (ZFNs) to knockout GPI-anchor synthesis, we have demonstrated that GPI-anchor-deficient MSCs retain their tumor homing properties. Therefore, MSCs can be genetically modified to endogenously express PRX302 from the PIG-A locus as a ‘safe harbor’ and prevent self-sterilization due to protoxin secretion. The therapeutic efficacy and host toxicity of these PRX302-expressing MSCs will be evaluated against a series of human prostate cancer xenograft models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5699. doi:1538-7445.AM2012-5699

Abstract B21: Mesenchymal stem cells (MSCs) as a selective delivery vehicle for a PSA-activated protoxin for advanced prostate cancer

Abstract Circulating bone marrow-derived mesenchymal stem cells (MSCs) can differentiate into cells of the mesoderm lineage and have an innate tropism for tumor tissue in response to the inflammatory microenvironment present in malignant lesions. We have demonstrated that endogenous MSCs migrate to sites of prostate cancer with many of these cells located in the perivascular space similar to observations in multiple other tumor types. MSCs are inherently non-immunogenic, which prevents rejection of allogeneic MSCs by host defense mechanisms. This immune-privileged status, together with their oncotropic properties, makes possible the infusion of allogeneic MSCs into patients for therapeutic purposes. Currently, MSCs are being tested in numerous FDA-approved clinical trials for a variety of human diseases and have been safely administered to thousands of patients. PRX302 is a PSA-activated aerolysin-based protoxin that forms membrane pores and leads to necrosis by a proliferationindependent mechanism at low picomolar concentrations. Active PSA is bound to inhibitors in the plasma, and therefore, is only active at sites of local and metastatic prostate cancer. Consequently, PRX302 will only be converted to a toxic form in the tumor microenvironment and thereby, limit off-target toxicity. Based upon this rationale we hypothesize that allogeneic MSCs can be used as a cell-based targeting vehicle to selectively deliver therapeutic agents, such as PRX302, to sites of prostate cancer, and thus spare host toxicity. To achieve optimal delivery of therapeutic concentrations, we are genetically engineering MSCs to endogenously express and secrete the protoxin from a defined genomic locus, or “safe harbor”, using zinc finger nucleases (ZFNs). ZFNs are hybrid proteins generated by fusing the sequence-specific DNA-binding domain of zinc-finger proteins to the non-specific endonuclease domain of the Fok1 restriction enzyme. The nuclease is fused to either the sense or antisense sequence-specific DNA-binding domain to create an obligate heterodimer at the safe harbor gene, which results in a double strand break. When combined with a third vector containing a gene of interest (PRX302) flanked by linkers encoding a complementary sequence to the “safe harbor” gene, homologous recombination occurs. Importantly, PRX302 binds with low nanomolar affinity to GPI-anchor proteins, which are highly expressed on the surface of all mammalian cells. PIG-A is the first enzyme in GPI-anchor biosynthesis. Using PIGA-targeted ZFNs, we have demonstrated that GPI-anchor-deficient MSCs retain their tumor homing properties. Therefore, MSCs can be genetically modified to endogenously express PRX302 from the PIG-A locus as a “safe harbor” and prevent self-sterilization due to protoxin secretion. The therapeutic efficacy and host toxicity of these PRX302-expressing MSCs are initially being evaluated in preclinical proof-of-principle studies against a series of human prostate cancer xenograft models. Translation of gene therapy strategies into the clinic has been slow due to legitimate concerns surrounding their safety, largely as a result of random vector insertion, which can be alleviated by the targeted insertion of genes into “safe harbors” using ZFNs. Additionally, clinical translation of this approach will be further expedited due to the fact that PRX302 has already been given safely to more than 120 patients and has undergone extensive toxicology profiling during its clinical development as a local therapy for symptomatic BPH, for which it is currently entering phase III trials. Therefore, we propose that a systemic delivery platform for PRX302 can be created through the use of allogeneic MSCs as a vehicle for the selective delivery of PRX302 to sites of local and metastatic prostate cancer. Citation Format: W. Nathaniel Brennen, Samuel R. Denmeade, John T. Isaacs. Mesenchymal stem cells (MSCs) as a selective delivery vehicle for a PSA-activated protoxin for advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B21.

Cotransplantation of HLA-Identical Mesenchymal Stem Cells and Hematopoietic Stem Cells in Chinese Patients with Hematologic Diseases.

Background: Mesenchymal stem cells(MSCs) can be isolated from bone-marrow and expanded ex-vivo, may support hematopoietic reconstruction and mitigate graft-versus-host disease (GVHD) in hematopoietic stem cells transplantation (HSCT). We hope to explore the feasibility and safety of cotransplantation culture-expanded MSCs and hematopoietic stem cells (HSCs) from the same human leucocyte antigen (HLA)-identical sibling donor in patients with hematologic diseases.Methods: Bone marrow mononuclear cells from healthy donors were cultured and expanded ex-vivo. Immunophenotype, karyotye, immunosuppressive property of the harvested MSCs were characterized. Patients were cotransplanted with HSCs and MSCs from the same donor. Hematopoietic reconstruction, complications and clinical outcomes after transplantation in these patients were observed.Results: (1.77±0.40)×106/kg (donor's weight) MSCs were successfully expanded from 23.6±5.96ml bone marrow samples. They had normal karyotype and were CD73, CD90, CD105 positive and CD34, CD45, HLA-DR negative. They can inhibit mixed lymphocyte reactions (MLRs). Twelve patients were undergoing cotransplantation. No adverse response was observed during and after the infusion of allogenic MSCs. Hematopoietic reconstruction were rapid. Two patients developed grade II∼IV acute GVHD. Two patients developed systermatic chronic GVHD. Four patients suffered from cytomegalovirus (CMV) infection but were cured at last. Till now, seven patients have been alive for 29∼57 months and five patients died.Conclusion: MSCs identified by immunophenotype analysis can be isolated from human bone marrow, expanded effectively by culture. Their quality and quantity are suitable for clinical use. It is safe and feasible to cotransplant patients with allogenic culture-expanded MSCs and HSCs.

Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation (HSCT) with Mesenchymal Stem Cells (MSC) Infusion for Treatment of Metachromatic Leukodystrophy (MLD): A Case Report.

Background: Patients (pts) with MLD have neurological and musculo-skeletal defects with a limited survival. HSCT has been reported as an effective treatment to stabilize or improve defects associated with this disease. Koç and colleagues reported that donor allogeneic MSC infusion is safe and may be associated with reversal of the disease pathophysiology in some tissues (Bone Marrow transplant, 2002). We decide thus to perform a non myeloablative familial HSCT in adult pt with a symptomatic MLD in order to evaluate the safety and the benefit allogeneic HSCT with MSC infusion in a patient with MLD. An informed consent was obtained from the pt.Patient: a 23 years old women who presented an adult form of MLD for three years was admitted in our department. The most important symptoms associated with the disease were dizziness, proximal weakness of the lower limbs, difficulty to walk, disorder of the memory and urinary incontinence. The reduced intensity conditioning was preferred to decrease the morbidity and mortality of the procedure. MSC were isolated and amplified from the BM-mononuclear cells of the HSC donor. MSC expansion was made in a commercial serum-free medium (UltraCulture, Cambrex, Walkersville, MD) supplemented with a serum substitute (Ultroser, Pall Biosepra, Cergy-Saint-Christophe, France) as previously reported by our group (Eur J Haematol, 2006). Ex vivo expanded allogeneic MSC were intravenously infused at the dose of 1×106 MSC/kg of recipient body weight. The conditioning regimen of the HSCT consisted in Fludarabine and ATG combination and 5× 106 CD34 cells were infused concomitantly with 1.106 MSC cells. We did not observed any immediate or delayed side effects after the MSC infusion. The patient did not presented any complications after the HSCT. At day 8 of the transplantation she had an normal hematological recovery. The platelet nadir was 72.000/mm3 and she did not need any transfusion. With regards of her neurological status, since 22 months the patient had no new deterioration and we observed a stabilisation of the clinical manifestations.Conclusions: This case report suggests the feasibility and the potential efficacy of reduced intensity conditioning allogeneic HSCT with MSC infusion for patient with MLD. A larger trial is required to confirm this observation.