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Thread: ADLD Leukodystrophy questions

  1. #1

    ADLD Leukodystrophy questions

    Wise, this person emailed me and asked that I post-

    Since there is no formal protocol for ADLD Leukodystrophy patients, we do not want to take a “silver bullet” / “all eggs in one basket” approach to treatment. So, we look to address the symptoms and, if possible, some root-causes to make an effort to slow, pause, or reverse the effects of the disease. Below are some of the ideas we’ve thought of, in order of our belief in the promise to make a difference. Understanding that this is all hypothetical, we would appreciate your feedback:

    Nerve Growth Factor – Research indicates that this factor causes axonal elongation and branching and that expression of this factor is related to myelin repair. Apparently, certain types of mushrooms (product link) have been known to help promote NGF levels (research link) and enhance myelination (research link). What is your opinion around this? Is this something worth pursuing as a supplement?

    Transforming Growth Factor Alpha (TGF-a) - Research (research link) indicates that Transforming Growth Factor alpha can help with astrogliosis. It apparently is a factor that helps naturally-produced adult stem cells naturally differentiate (research link). In fact, it plays such a role in this that there’s even been talk that it can completely reverse the effects of stroke (article link) Our understanding is that one natural way to get TGF-alpha is through bovine colostrum. Nancy has taken a bovine colostrum supplement for the last couple months, and she continues to take it today. Do you believe that this is a worthwhile investment in time and money? Should we look into getting TGF-a injections?

    Brain-derived Neurotrophic Factor – Research indicates that this factor helps increase neuron electrical activity and differentiation as well as neurogenesis (article link). Would this increased activity help get signals further down the partially-demyelinated nerve pathways? Is this something we can test to see what levels exist in Nancy currently? Is there an injectable/consumable food or supplement that could help increase this factor?

    ACH Inhibitors – Research indicates that ACHI drugs may aid in myelin integrity (research link). What is your opinion on this? Is it worth looking into further?

    LMNB1 Antibody – Our understanding is that ADLD is caused by over-expression / duplication of the LMNB1 protein (research link). We are aware of the existence of a LMNB1 antibody (product link). Should we keep our eye on the research around this? Is it something that could make a difference? Even a short-term reduction of over-expression might help the body re-grow myelin enough to make a difference in Nancy’s quality of life…

    We as a family greatly appreciate your time.

    Regards,

    Dan

  2. #2
    Super Moderator Sue Pendleton's Avatar
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    Is this about Adenoleukodystrophy? I've never heard of it showing up in females. As far as the BDNF I know of no known resource for this outside of certain laboratories and currently I know of no clinical trials using it in humans.

    As for the mushrooms, even some of the sciene articles added to the commercial selling of these mushrooms adds several subspecies of the mushroom together. In many mushroom types this is a dangerous practice. If you read the right side on the following page you'ss see that even established hunters can't always be sure of which type of Lion's Mane they have collected. http://www.mushroomexpert.com/hericium_erinaceus.html Does the person see an expert in this type of medicine and how much of what substances in the mushroom is condered a therapeutic dose. A generalized suggested daily dose tells us nothing.
    Last edited by Sue Pendleton; 08-17-2011 at 02:15 PM. Reason: Adding a link.
    Courage doesn't always roar. Sometimes courage is the quiet voice at the end of the day saying, "I will try again tomorrow."

    Disclaimer: Answers, suggestions, and/or comments do not constitute medical advice expressed or implied and are based solely on my experiences as a SCI patient. Please consult your attending physician for medical advise and treatment. In the event of a medical emergency please call 911.

  3. #3
    Leukodystrophies are disorders that interfere with myelin formation in the brain, spinal cord, and peripheral nerves. Several genes control myelin formation, production, and metabolism. Leuko indicates white (referring to white matter) and dystrophy indicates malformation. Categories of leukodystrophies include:
    • adrenoleukodystrophy, adrenomyeloneuropathy
    • metachromatic leukodystrophy
    • hereditary CNS demyelinating disease
    - Krabbe’s disease
    - Pelizaeus-Merzbacher disease
    - Canavan disease
    - Leukoencephalopathy or child ataxia w/central hypomyelination (CACH)

    Leukodystrophies often manifest during childhood. Progessive loss of body tone, gait, speech, motor control, vision, hearing, and behavior occurs with apparent slowdown of mental and physical development. The timing and rate of the decline varies depending on the genetic condition. For example, Krabbe’s disease is due to a mutation of the gene GalC on chromosome 14, causing a deficiency of the enzyme galactocerebrosidase with resultant buildup of unmetabolized lipids that interferes with demyelination. Babies with Krabbe’s disease are often normal at birth but develop seizures at 3-6 months with slowing mental and physical development, as well as other evidence of demyelination. The babies usually die by age 2.

    Adrenoleukodystrophy (ALD) is a condition where there is significant loss of white matter associated with adrenal gland atrophy. The most common form is an X-linked recessive condition that affects mostly males but may affect 1 of 5 females with the gene. Any male child showing up with adrenal gland deficiency should be suspected of having ALD. Diagnosis can be made from accumulation of long-chain fatty acids usually made by age 1 and death is common by age 12. Autosomal dominant forms of ALD include the Zellweger and Refsum diseases. A milder form of ALD is adrenomyeloneuropathy (AMN), which is associated with mostly spinal cord dysfunction, including limb weakness.

    Many leukodystrophies are associated with abnormalities of fatty acid metabolism. One of the very first effective treatments of this condition is a diet low in long-chain fatty acids (described in Lorenzo’s oil). Metachromatic leukodystrophy are due to a deficiency of arylsulfatase A, leading to buildup of fatty acids in cells. Many of the early treatments of leukodystrophies emphasized dietary restrictions. Dietary therapies are effective only for some forms of leukodystrophies and also do not typically reverse the neurological changes.

    In 2005, Escolar, et al. [1] from Duke University stunned the world when they reported that they were able to cure Krabbe’s disease in children when they transplanted umbilical cord blood cells shortly after birth. The treatment did not reverse the condition but prevented progression. Joanne Kurtzberg, who heads the group at Duke, believes that even earlier treatment with stem cell transplants in utero will be more effective. Umbilical cord blood transplants are attractive because they often will engraft despite mismatch of as many as 2 of 6 HLA and are more readily available than bone marrow.

    In theory, bone marrow transplants should also work. Lin, et al. [2] reported successful bone marrow transplant from a paternal source to a child with adrenoleukodystrophy and correction of very long chain fatty acid accumulation but failure of the therapy to arrest neurological deterioration. Meulman, et al. [3] transplanted hematopoietic stem cell as well as mesenchymal stem cells into a 23-year old women with dramatic stabilization of all neurological symptoms. One group transplanted allogeneic mesenchymal stem cells and were unable to find any beneficial effects of such cells on an adult patient [4].

    Neural stem cell transplants are a logical source of cells to replace oligodendroglial progenitor cells that make myelin for the central nervous system. The cells should be from an allogeneic source (i.e. from another individual of the same species) or be genetically modified to eliminate the defective gene. Several allogeneic sources of neural stem cells may soon be available, including autologous stem cells that have been genetically modified to eliminate the genetic abnormality, HLA-matched umbilical cord blood, placental, and other sources of allogeneic cells. Animal studies indicate that oligodendroglial precursor cells transplanted into animals with metachromatic leukodystrophy failed to generate oligodendroglia but nevertheless reduced brain dysfunction [5].

    Many groups have reported direct lentiviral gene therapy in animal models [6, 7] but such gene therapy have not yet been tried in clinical trials. In November 2009, Auberg, et al., from Paris reported the first successful gene therapy X-linked ALD, by removing bone marrow cells from two boys with the disease and using a lentivirus to deliver the normal gene into the cells and then transplanted the genetically modified cells into two patients with ALD. The patients were followed for 2 years and the treatment effects seemed to be holding through this period. Biffi, et al [8] transplanted gene-corrected hematopoietic stem cells in mice to metachromatic leukodystrophy. They are currently carrying out hematopoietic stem cell transplants to treat patients with metachromatic leukodystrophy.

    The cholesterol lower drug lovastatin has been reported to reduce accumulation of fatty acids and other byproducts of leukodystrophic conditions [9]. However, a double-blind randomized placebo-controlled trial showed that lovastatin does not lower tissue levels of very long chain fatty acid and was not associated with any objective clinical improvement [10]; lovastatin is not recommended at the present for treating leukodystrophies [11].

    In conclusion, there does not seem to be any rationale for the use of growth factors such as NGF, BDNF, and TGF-alpha for the treatment of leukodystrophy. This is a genetic disorder that causes demyelination. It is not clear that growth factors will improve the ability of the cells to produce abnormal myelin and that stimulating them may aggravate the situation. Likewise, drugs aimed at clearing at long-chain fatty acid may help but have not yet been shown to have clinical benefit. The most promising therapies have been transplantation of hematopoietic or neural stem cells.


    References

    1. Escolar ML, Poe MD, Provenzale JM, Richards KC, Allison J, Wood S, Wenger DA, Pietryga D, Wall D, Champagne M, Morse R, Krivit W and Kurtzberg J (2005). Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. The New England journal of medicine 352: 2069-81. Program for Neurodevelopmental Function in Rare Disorders, Clinical Center for the Study of Development and Learning, University of North Carolina at Chapel Hill, Chapel Hill 27599-7255, USA. maria.escolar@cdl.unc.edu. BACKGROUND: Infantile Krabbe's disease produces progressive neurologic deterioration and death in early childhood. We hypothesized that transplantation of umbilical-cord blood from unrelated donors before the development of symptoms would favorably alter the natural history of the disease among newborns in whom the disease was diagnosed because of a family history. We compared the outcomes among these newborns with the outcomes among infants who underwent transplantation after the development of symptoms and with the outcomes in an untreated cohort of affected children. METHODS: Eleven asymptomatic newborns (age range, 12 to 44 days) and 14 symptomatic infants (age range, 142 to 352 days) with infantile Krabbe's disease underwent transplantation of umbilical-cord blood from unrelated donors after myeloablative chemotherapy. Engraftment, survival, and neurodevelopmental function were evaluated longitudinally for four months to six years. RESULTS: The rates of donor-cell engraftment and survival were 100 percent and 100 percent, respectively, among the asymptomatic newborns (median follow-up, 3.0 years) and 100 percent and 43 percent, respectively, among the symptomatic infants (median follow-up, 3.4 years). Surviving patients showed durable engraftment of donor-derived hematopoietic cells with restoration of normal blood galactocerebrosidase levels. Infants who underwent transplantation before the development of symptoms showed progressive central myelination and continued gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills, but a few had mild-to-moderate delays in expressive language and mild-to-severe delays in gross motor function. Children who underwent transplantation after the onset of symptoms had minimal neurologic improvement. CONCLUSIONS: Transplantation of umbilical-cord blood from unrelated donors in newborns with infantile Krabbe's disease favorably altered the natural history of the disease. Transplantation in babies after symptoms had developed did not result in substantive neurologic improvement.

    2. Lin HC, Lin KH and Wang PJ (1998). Transplantation for adrenoleukodystrophy with HLA-A and B nonidentical paternal marrow: report of one case. Zhonghua Minguo xiao er ke yi xue hui za zhi [Journal]. Zhonghua Minguo xiao er ke yi xue hui 39: 260-3. Department of Pediatrics, En Chu Kong Hospital, San-Shia, Taipei, Taiwan, R.O.C. We report the result of allogeneic bone marrow transplantation (BMT) in a 14-year-old boy who was neurologically severely involved with the childhood form of adrenoleukodystrophy (ALD) and received marrow from his HLA-A and B nonidentical, MLC-nonreactive paternal donor without T-cell depletion processing. Bone marrow transplantation corrected the excess content of very long chain fatty acid in plasma but did not arrest the deterioration of the neurological status during 3.5-year post-transplant follow-up period. Since partially matched or unrelated donors have been applied to clinical BMT successfully with current new techniques, ALD patients will have a better prognosis when they are transplanted in status of mild and early involvement. Our first experience may be helpful in more trials of BMT for genetic leukodystrophy in Taiwan.

    3. Meuleman N, Vanhaelen G, Tondreau T, Lewalle P, Kwan J, Bennani J, Martiat P, Lagneaux L and Bron D (2008). Reduced intensity conditioning haematopoietic stem cell transplantation with mesenchymal stromal cells infusion for the treatment of metachromatic leukodystrophy: a case report. Haematologica 93: e11-3. Department of Clinical and Experimental Hematology, Institut Jules Bordet, Universite Libre de Bruxelles (ULB), Bruxelles, Belgium. nathalie.meuleman@bordet.be. We report the case of a 23-year-old woman who presented with an adult form of metachromatic leukodystrophy (MLD) evolving over one year with a progressive neurological deterioration. A non-myeloablative matched related haematopoietic stem cell transplantation (HSCT) with concomitant mesenchymal stromal cells (MSCs) infusion was performed. Engraftment occurred rapidly with no significant toxicity or side effects following the MSC infusion. At a follow up of 40 months, the patient had a stabilisation of all neurological manifestations of her disease. This case report suggests the feasibility and the potential efficacy of reduced intensity conditioning (RIC) allogeneic HSCT combined with MSC infusion for patients with the adult form of MLD.

    4. Smith NJ, Marcus RE, Sahakian BJ, Kapur N and Cox TM (2010). Haematopoietic stem cell transplantation does not retard disease progression in the psycho-cognitive variant of late-onset metachromatic leukodystrophy. Journal of inherited metabolic disease Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Box 157, Cambridge, UK, CB2 0QQ, njcs3@medschl.cam.ac.uk. Haematopoietic stem cell transplantation has an unproven role in the management of late-onset metachromatic leukodystrophy: theoretically justified through the engraftment of enzyme-replete haematopoietic progenitors and restoration of capacity for sulphatide catabolism in neural tissue through enzyme recapture, the long-term outcome is unknown. The rarity of the psycho-cognitive variant and slow progression of late-onset disease impairs evaluation of treatment. We report detailed clinical and neuropsychological assessments after haematopoietic stem-cell transplantation in a patient with a late-onset psycho-cognitive form of metachromatic leukodystrophy. Cognitive decline, indistinguishable from the natural course of the disease, was serially documented over 11 years despite complete donor chimaerism and correction of leukocyte arylsulphatase A to wild type values; subtle motor deterioration was similarly noted and progressive cerebral volume loss was evident upon magnetic resonance imaging. Sensory nerve conduction deteriorated 17 months post-transplantation with apparent stabilisation at 11-year review. Haematopoietic stem-cell transplantation was ineffective for this rare attenuated variant of metachromatic leukodystrophy. In the few patients identified pre-symptomatically or with early-phase disease, clear recommendations are lacking; when transplantation is considered, umbilical cord blood grafts from enzyme-replete donors with adjunctive mesenchymal stem cell infusions from the same source may be preferable. Improved outcomes will depend on enhanced awareness and early diagnosis of the disease, so that promising interventions such as genetically modified, autologous stem cell transplantation have the best opportunity of success.

    5. Givogri MI, Bottai D, Zhu HL, Fasano S, Lamorte G, Brambilla R, Vescovi A, Wrabetz L and Bongarzone E (2008). Multipotential neural precursors transplanted into the metachromatic leukodystrophy brain fail to generate oligodendrocytes but contribute to limit brain dysfunction. Developmental neuroscience 30: 340-57. Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL , USA. mgivogri@uic.edu. Neural stem cells appear to be best suited for regenerative therapy in neurological diseases. However, the effects of high levels of potentially toxic substances such as sulfatides--which accumulate in metachromatic leukodystrophy (MLD)--on this regenerative ability are still largely unclear. To start addressing this question, in vitro and in vivo experiments were used to examine the behavior of multipotential neural precursors exposed to abnormally high levels of sulfatides. Following transplantation of dissociated neurospheres into the brain of presymptomatic MLD pups, the majority of donor-derived cells were distributed in a caudal to rostral direction, with higher numbers in the cortex. Most if not all of the donor cells acquired an astroglial phenotype. We found no evidence of oligodendrocyte or neuronal commitment of transplanted cells in long-term-treated MLD mice (e.g. up to 1.5 years of age). This was in line with our in vitro findings of sulfatides blocking oligodendrocyte formation after induction of differentiation in sulfatide-treated epidermal growth factor/fibroblast growth factor responsive neurospheres. Transplanted MLD mice showed an improved arylsulfatase A (ARSA) activity and a significant amelioration of sulfatide metabolism, neurodegeneration and motor-learning/memory deficits. Furthermore, transplanted cells were shown to act as a source of ARSA enzyme that accumulated in endogenous brain cells, indicating the occurrence of enzyme cross-correction between transplanted and host cells. These results provide a first insight into the effect of sulfatides on the stemness properties of neural stem cells and on the effects of the MLD environment on the in vivo expectations of using neural stem cells in cell therapy.

    6. Lattanzi A, Neri M, Maderna C, di Girolamo I, Martino S, Orlacchio A, Amendola M, Naldini L and Gritti A (2010). Widespread enzymatic correction of CNS tissues by a single intracerebral injection of therapeutic lentiviral vector in leukodystrophy mouse models. Human molecular genetics 19: 2208-27. San Raffaele Scientific Institute, Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, 20132 Milano, Italy. Leukodystrophies are rare diseases caused by defects in the genes coding for lysosomal enzymes that degrade several glycosphingolipids. Gene therapy for leukodystrophies requires efficient distribution of the missing enzymes in CNS tissues to prevent demyelination and neurodegeneration. In this work, we targeted the external capsule (EC), a white matter region enriched in neuronal projections, with the aim of obtaining maximal protein distribution from a single injection site. We used bidirectional (bd) lentiviral vectors (LV) (bdLV) to ensure coordinate expression of a therapeutic gene (beta-galactocerebrosidase, GALC; arylsulfatase A, ARSA) and of a reporter gene, thus monitoring simultaneously transgene distribution and enzyme reconstitution. A single EC injection of bdLV.GALC in early symptomatic twitcher mice (a murine model of globoid cell leukodystrophy) resulted in rapid and robust expression of a functional GALC protein in the telencephalon, cerebellum, brainstem and spinal cord. This led to global rescue of enzymatic activity, significant reduction of tissue storage and decrease of activated astroglia and microglia. Widespread protein distribution and complete metabolic correction were also observed after EC injection of bdLV.ARSA in a mouse model of metachromatic leukodystrophy. Our data indicated axonal transport, distribution through cerebrospinal fluid flow and cross-correction as the mechanisms contributing to widespread bioavailability of GALC and ARSA proteins in CNS tissues. LV-mediated gene delivery of lysosomal enzymes by targeting highly interconnected CNS regions is a potentially effective strategy that, combined with a treatment able to target the PNS and peripheral organs, may provide significant therapeutic benefit to patients affected by leukodystrophies.

    7. Capotondo A, Cesani M, Pepe S, Fasano S, Gregori S, Tononi L, Venneri MA, Brambilla R, Quattrini A, Ballabio A, Cosma MP, Naldini L and Biffi A (2007). Safety of arylsulfatase A overexpression for gene therapy of metachromatic leukodystrophy. Human gene therapy 18: 821-36. San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy. Successful gene therapy approaches for metachromatic leukodystrophy (MLD), based either on hematopoietic stem/progenitor cells (HSPCs) or direct central nervous system (CNS) gene transfer, highlighted a requirement for high levels of arylsulfatase A (ARSA) expression to achieve correction of disease manifestations in the mouse model. Full assessment of the safety of ARSA expression above physiological levels thus represents a prerequisite for clinical translation of these approaches. Here, using lentiviral vectors (LVs), we generated two relevant models for the stringent evaluation of the consequences of ARSA overexpression in transduced cells. We first demonstrated that ARSA overexpression in human HSPCs does not affect their clonogenic and multilineage differentiation capacities in clonogenic assays and in a neonatal hematochimeric mouse model. Further, we studied ARSA overexpression in all body tissues by generating transgenic mice overexpressing the ARSA enzyme by LV up to 15-fold above the normal range and carrying multiple copies of LV in their genome. Characterization of these mice demonstrated the safety of ARSA overexpression in two main gene therapy targets, HSPCs and neurons, with maintenance of the complex functions of the hematopoietic and nervous system in the presence of supraphysiological enzyme levels. The activity of other sulfatases dependent on the same common activator, sulfatase-modifying factor-1 (SUMF1), was tested in ARSA-overexpressing HSPCs and in transgenic mice, excluding the occurrence of saturation phenomena. Overall, these data indicate that from the perspective of clinical translation, therapeutic levels of ARSA overexpression can be safely achieved. Further, they demonstrate an experimental platform for the preclinical assessment of the safety of new gene therapy approaches.

    8. Biffi A, Capotondo A, Fasano S, del Carro U, Marchesini S, Azuma H, Malaguti MC, Amadio S, Brambilla R, Grompe M, Bordignon C, Quattrini A and Naldini L (2006). Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. The Journal of clinical investigation 116: 3070-82. San Raffaele Telethon Institute for Gene Therapy, Vita-Salute San Raffaele University, Milan, Italy. biffi.alessandra@hsr.it. Metachromatic leukodystrophy (MLD) is a demyelinating lysosomal storage disorder for which new treatments are urgently needed. We previously showed that transplantation of gene-corrected hematopoietic stem progenitor cells (HSPCs) in presymptomatic myeloablated MLD mice prevented disease manifestations. Here we show that HSC gene therapy can reverse neurological deficits and neuropathological damage in affected mice, thus correcting an overt neurological disease. The efficacy of gene therapy was dependent on and proportional to arylsulfatase A (ARSA) overexpression in the microglia progeny of transplanted HSPCs. We demonstrate a widespread enzyme distribution from these cells through the CNS and a robust cross-correction of neurons and glia in vivo. Conversely, a peripheral source of enzyme, established by transplanting ARSA-overexpressing hepatocytes from transgenic donors, failed to effectively deliver the enzyme to the CNS. These results indicate that the recruitment of gene-modified, enzyme-overexpressing microglia makes the enzyme bioavailable to the brain and makes therapeutic efficacy and disease correction attainable. Overall, our data provide a strong rationale for implementing HSPC gene therapy in MLD patients.

    9. Weinhofer I, Forss-Petter S, Zigman M and Berger J (2003). Cholesterol regulates ABCD2 gene expression: implications for X-linked adrenoleukodstrophy. Advances in experimental medicine and biology 544: 331-2. Brain Research Institute, University of Vienna, Spitalgasse 4 A-1090 Vienna, Austria. isabelle.weinhofer@univie.ac.at.

    10. Engelen M, Ofman R, Dijkgraaf MG, Hijzen M, van der Wardt LA, van Geel BM, de Visser M, Wanders RJ, Poll-The BT and Kemp S (2010). Lovastatin in X-linked adrenoleukodystrophy. The New England journal of medicine 362: 276-7.

    11. Berger J, Pujol A, Aubourg P and Forss-Petter S (2010). Current and future pharmacological treatment strategies in X-linked adrenoleukodystrophy. Brain pathology 20: 845-56. Center for Brain Research, Medical University of Vienna, Vienna, Austria. johannes.berger@meduniwien.ac.at. Mutations in the ABCD1 gene cause the clinical spectrum of the neurometabolic disorder X-linked adrenoleukodystrophy/adrenomyeloneuropathy (X-ALD/AMN). Currently, the most efficient therapeutic opportunity for patients with the cerebral form of X-ALD is hematopoietic stem cell transplantation and possibly gene therapy of autologous hematopoietic stem cells. Both treatments, however, are only accessible to a subset of X-ALD patients, mainly because of the lack of markers that can predict the onset of cerebral demyelination. Moreover, for female or male X-ALD patients with AMN, currently only unsatisfying therapeutic opportunities are available. Thus, this review focuses on current and urgently needed future pharmacological therapies. The treatment of adrenal and gonadal insufficiency is well established, whereas applications of immunomodulatory and immunosuppressive drugs have failed to prevent progression of cerebral neuroinflammation. The use of Lorenzo's oil and the inefficacy of lovastatin to normalize very-long-chain fatty acids in clinical trials as well as currently experimental and therefore possible future therapeutic strategies are reviewed. The latter include pharmacological gene therapy mediated by targeted upregulation of ABCD2, the closest homolog of ABCD1, antioxidative drug treatment, small molecule histone deacetylase inhibitors such as butyrates and valproic acid, and other neuroprotective attempts.

  4. #4

    Autosomal Dominant Leukodystrophy

    Autosomal Dominant Leukodystrophy (ADLD). Recent studies have identified overexpression of lamin B1 mutations as one cause of familial ADLD [1, 2]. Duplication of the Lamin B1 gene is responsible for myelin loss in ADLD [3, 4]. While it may seem reasonable to use antibodies to treat for excessive production of a protein, it is important to emphasize that this excessive protein is intracellular and not usually reachable by antibodies and, even if they could, the antibodies do not prevent the protein production. Antibody therapies are typically very expensive and there is no easy way of delivering antibodies into the central nervous system.

    References

    1. Schuster J, Sundblom J, Thuresson AC, Hassin-Baer S, Klopstock T, Dichgans M, Cohen OS, Raininko R, Melberg A and Dahl N (2011). Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms. Neurogenetics 12: 65-72. Department of Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University and University Hospital, SE-751 85, Uppsala, Sweden. Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.

    2. Brussino A, Vaula G, Cagnoli C, Panza E, Seri M, Di Gregorio E, Scappaticci S, Camanini S, Daniele D, Bradac GB, Pinessi L, Cavalieri S, Grosso E, Migone N and Brusco A (2010). A family with autosomal dominant leukodystrophy linked to 5q23.2-q23.3 without lamin B1 mutations. European journal of neurology : the official journal of the European Federation of Neurological Societies 17: 541-9. Department of Genetics, Biology and Biochemistry, University of Torino, and SCDU.Medical Genetics, AOU San Giovanni Battista, Torino, Italy. BACKGROUND AND PURPOSE: Duplications of lamin B1 (LMNB1) at 5q23 are implicated in adult-onset autosomal dominant leukodystrophy (ADLD) having been described in six families with diverse ethnic background but with a homogeneous phenotype. In a large Italian family, we recently identified a variant form of ADLD characterized clinically by absence of the autonomic dysfunction at onset described in ADLD and, on MRI, by milder cerebellar involvement with sparing of hemispheric white matter. Aim of this study was to investigate the genetic basis of this variant form of ADLD. METHODS: We carried out a genome-wide linkage analysis using microsatellite markers, and the genes in the candidate region were screened for point mutations. LMNB1 was also screened for deletions/duplications by real-time PCR, multiplex ligation-dependent probe amplification and Southern blot. RESULTS: We mapped the variant ADLD locus to 5q23.2-q23.3, a genomic region containing 11 genes including LMNB1. Neither gene copy-number defects nor point mutations in the LMNB1 gene were found. We also excluded point mutations in the coding exons of the other ten genes in the candidate region. However, expression of lamin B1 evaluated in lymphoblastoid cells was higher in patients than in healthy controls, and was similar to the lamin B1 expression levels found in a patient with LMNB1 duplication. CONCLUSIONS: This observation suggests that a mutation in an LMNB1 regulatory sequence underlies the variant ADLD phenotype. Thus, adult forms of ADLD linked to 5q23 appear to be more heterogeneous clinically and genetically than previously thought.

    3. Lin ST and Fu YH (2009). miR-23 regulation of lamin B1 is crucial for oligodendrocyte development and myelination. Disease models & mechanisms 2: 178-88. Department of Neurology, University of California San Francisco, 94158, USA. Duplication of the gene encoding lamin B1 (LMNB1) with increased mRNA and protein levels has been shown to cause severe myelin loss in the brains of adult-onset autosomal dominant leukodystrophy patients. Similar to many neurodegenerative disorders, patients with adult-onset autosomal dominant leukodystrophy are phenotypically normal until adulthood and the defect is specific to the central nervous system despite the ubiquitous expression pattern of lamin B1. We set out to dissect the molecular mechanisms underlying this demyelinating phenotype. Increased lamin B1 expression results in disturbances of inner nuclear membrane proteins, chromatin organization and nuclear pore transport in vitro. It also leads to premature arrest of oligodendrocyte differentiation, which might be caused by reduced transcription of myelin genes and by mislocalization of myelin proteins. We identified the microRNA miR-23 as a negative regulator of lamin B1 that can ameliorate the consequences of excessive lamin B1 at the cellular level. Our results indicate that regulation of lamin B1 is important for myelin maintenance and that miR-23 contributes to this process, at least in part, by downregulating lamin B1, therefore establishing novel functions of lamin B1 and miR-23 in the regulation of oligodendroglia development and myelin formation in vitro.

    4. Meijer IA, Simoes-Lopes AA, Laurent S, Katz T, St-Onge J, Verlaan DJ, Dupre N, Thibault M, Mathurin J, Bouchard JP and Rouleau GA (2008). A novel duplication confirms the involvement of 5q23.2 in autosomal dominant leukodystrophy. Archives of neurology 65: 1496-501. Centre of Excellence in Neuromics, Centre Hospitalier de l'Universite de Montreal and Ste-Justine Hospital, Montreal, Canada. OBJECTIVE: To identify the underlying locus and disease-causing mutation for adult-onset autosomal dominant leukodystrophy (ADLD). DESIGN: Previously, an adult-onset ADLD locus on chromosome 5q23 was mapped between markers D5S1495 and CTT/CCT15. This region contains 13 known and putative candidate genes. A 2-point linkage analysis confirmed linkage of a large multigenerational French Canadian family to chromosome 5q23. In addition, screening of the 13 genes within the candidate interval as well as 5 neighboring genes was completed, followed by comparative genomic hybridization. SUBJECTS: A multigenerational French Canadian family with ADLD mimicking progressive multiple sclerosis was identified and studied. Eight affected family members were available for the study and presented with autonomic dysfunction as well as upper motorneuron signs affecting gait. RESULTS: The thorough candidate gene approach did not identify any mutation. Consequently, a whole-chromosome comparative genomic hybridization for chromosome 5 identified a 280-kilobase duplication within the chromosomal band 5q23.2 in 2 affected individuals. This duplication contains 3 genes: LMNB1, FLJ36242, and MARCH3. CONCLUSION: We have identified a novel duplication on chromosomal band 5q23.2 in a French Canadian family with ADLD that supports the implication of duplicated LMNB1 as the disease-causing mutation. However, additional functional studies of lamin B1 overexpression are necessary to elucidate the involvement of lamin B1 in myelination and in degenerative disorders such as ADLD and multiple sclerosis.

  5. #5
    Quote Originally Posted by Wise Young View Post
    In 2005, Escolar, et al. [1] from Duke University stunned the world when they reported that they were able to cure Krabbe’s disease in children when they transplanted umbilical cord blood cells shortly after birth. The treatment did not reverse the condition but prevented progression. Joanne Kurtzberg, who heads the group at Duke, believes that even earlier treatment with stem cell transplants in utero will be more effective. Umbilical cord blood transplants are attractive because they often will engraft despite mismatch of as many as 2 of 6 HLA and are more readily available than bone marrow.

    In theory, bone marrow transplants should also work. Lin, et al. [2] reported successful bone marrow transplant from a paternal source to a child with adrenoleukodystrophy and correction of very long chain fatty acid accumulation but failure of the therapy to arrest neurological deterioration. Meulman, et al. [3] transplanted hematopoietic stem cell as well as mesenchymal stem cells into a 23-year old women with dramatic stabilization of all neurological symptoms. One group transplanted allogeneic mesenchymal stem cells and were unable to find any beneficial effects of such cells on an adult patient [4].

    1]Neural stem cell transplants are a logical source of cells to replace oligodendroglial progenitor cells that make myelin for the central nervous system. The cells should be from an allogeneic source (i.e. from another individual of the same species) or be genetically modified to eliminate the defective gene. Several allogeneic sources of neural stem cells may soon be available, including autologous stem cells that have been genetically modified to eliminate the genetic abnormality, HLA-matched umbilical cord blood, placental, and other sources of allogeneic cells. Animal studies indicate that oligodendroglial precursor cells transplanted into animals with metachromatic leukodystrophy failed to generate oligodendroglia but nevertheless reduced brain dysfunction [5].

    2] Many groups have reported direct lentiviral gene therapy in animal models [6, 7] but such gene therapy have not yet been tried in clinical trials. In November 2009, Auberg, et al., from Paris reported the first successful gene therapy X-linked ALD, by removing bone marrow cells from two boys with the disease and using a lentivirus to deliver the normal gene into the cells and then transplanted the genetically modified cells into two patients with ALD. The patients were followed for 2 years and the treatment effects seemed to be holding through this period. Biffi, et al [8] transplanted gene-corrected hematopoietic stem cells in mice to metachromatic leukodystrophy. They are currently carrying out hematopoietic stem cell transplants to treat patients with metachromatic leukodystrophy.

    The cholesterol lower drug lovastatin has been reported to reduce accumulation of fatty acids and other byproducts of leukodystrophic conditions [9]. However, a double-blind randomized placebo-controlled trial showed that lovastatin does not lower tissue levels of very long chain fatty acid and was not associated with any objective clinical improvement [10]; lovastatin is not recommended at the present for treating leukodystrophies [11].

    In conclusion, there does not seem to be any rationale for the use of growth factors such as NGF, BDNF, and TGF-alpha for the treatment of leukodystrophy. This is a genetic disorder that causes demyelination. It is not clear that growth factors will improve the ability of the cells to produce abnormal myelin and that stimulating them may aggravate the situation. Likewise, drugs aimed at clearing at long-chain fatty acid may help but have not yet been shown to have clinical benefit. 3]The most promising therapies have been transplantation of hematopoietic or neural stem cells.
    s.
    Please advise on the following questions;
    1] Stem cell transplant seems to be the most promising for treating this condition. you state that allogeneic sources of stem cells may soon be available. Please advise as to how, who, and where do we contact to stay on top of the most recent innovations and findings in order to participate in trials of any kind?

    2]You reference gene therapy and hematopoietic stem cell therapy being applied today for other leukodystrophies. Are there sources or clinics we can contact to participate in these therapies for ADLD?

    3] Are there clinics or centers anywhere in the world today that are applying these types of therapies that we should consider?

    Thank You

  6. #6

    Response to question

    Maybe I missed it but has there been any response to the last question from Needinfo?

    Thanks

  7. #7
    Quote Originally Posted by needinfo View Post
    Please advise on the following questions;
    1] Stem cell transplant seems to be the most promising for treating this condition. you state that allogeneic sources of stem cells may soon be available. Please advise as to how, who, and where do we contact to stay on top of the most recent innovations and findings in order to participate in trials of any kind?

    2]You reference gene therapy and hematopoietic stem cell therapy being applied today for other leukodystrophies. Are there sources or clinics we can contact to participate in these therapies for ADLD?

    3] Are there clinics or centers anywhere in the world today that are applying these types of therapies that we should consider?

    Thank You
    Needinfo,

    May I suggest that you look up this information up yourself. You can easily do searches with Google Scholar on the studies that I have cited, identify the top scientists and clinicians who are doing the research (the address and email addresses of the authors of the papers are listed with each article), and read the articles. If a person in your family has ADLD, you should know all the top clinics that are doing research and taking care of people with ADLD. I would be glad to answer specific questions about the studies and what I have posted.

    Wise.

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