Bone Marrow Transplantation in Hurler syndrome

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Bone Marrow Transplantation in Hurler syndrome
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Transplanted tissue

• Bone Marrow
• Immature cells - stem cells
• White blood cells
• Red blood cells
• Platelets
• Peripheral blood stem cells
• Umbilical cord stem cells

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Tissue typing or matching

• Human leukocyte-associated antigens (HLA)
• 25 chance of sibling match
• 30-40 chance HLA matched sib or parent
• Unrelated donors - 6 HLA and minor antigens

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Bone Marrow Harvest

• Under anaesthesia
• Large needle into pelvis gt sternum
• Blood and bone removed from sample
• Cryopreservation
• Donor side effects
• Local tenderness
• few days to 3-4 wks full recovery

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Peripheral Stem Cell Harvest

• Stem cells stimulated by Granulocyte colony
  stimulating factor, G-CSF
• Blood removed via large vein
• Machine separates the stem cells
• Blood minus stem cells is returned via a second
  canula
• Cryopreservation

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Cord Blood Collection

• Usually compatability known from prenatal testing
• Blood collected from cord after cord cut.
• Stem cells separated in laboratory
• Cryopreservation
• (3/16 chance sib matching unaffected 1/16
  matching and not affected or carrier)

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Daria and her donor, Caleb
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The transplant

• Conditioning patients own marrow obliterated
  with chemotherapy
• Marrow or Stem cell Infusion donor cells infused
  via vein
• Engraftment - donor cells enter marrow and start
  dividing 10-21 days
• Close medical supervision 3 months
• Long term follow-up

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Jack after insertion of portocath
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Infusion of Marrow
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Complications of BMT

• Death
• Side effects of chemotherapeutic drugs (Nausea,
  vomiting, fatigue, loss of appetite, mouth
  ulcers, hair loss and skin reaction)
• Infections (viral, bacterial and fungal)
• Bleeding

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Jack during Conditioning
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Complications of BMT

• Graft rejection
• Acute graft versus host disease, GVHD (Skin rash
  liver disease gastrointestinal disturbance
  fever oedema)
• Chronic GVHD (skin, liver, eyes, mouth, lungs,
  gastrointestinal system, nervous system

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Hair like my Dad
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Complications of BMT

• Veno-occlusive disease blocking veins draining
  liver
• Lung complications infection, GVHD, drugs, fluid
• Mucositis ulceration mouth and gut
• Transfusions red cells and platelets (donors
  blood group).

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Jacks Isolation Room
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Complications of BMT

• Seizures / convulsions haemorrhage, clot, high
  blood pressure, infection, drugs
• Haemorrhagic cystitis drugs or infection
• Hypertension drugs
• Dental problems infection, loss of enamel

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Jack and his support team
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Late Complications of BMT

• Endocrine of hormone dysfunction - growth,
  puberty, energy
• Infertility
• Lung complications fibrosis
• Eye disease cataract dry eyes
• Kidney dysfunction
• Secondary malignancy

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Benefits of BMT for MPS 1H

• Maintenance of IQ
• Correction of hydrocephalus
• Improved hearing
• Normalised heart function
• Normalisation size of liver and spleen
• Survival

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Jaime post BMT
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Persisting problems after BMT for MPS 1H

• Skeletal changes
• Only partial correction corneal clouding
• Progression of retinal disease
• Heart valve changes
• Carpal tunnel syndrome

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Jaime 11yrs post BMT
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BMT - Mechanisms

• Bone marrow cells produce the microglial cells of
  the CNS
• Enzyme transfer between cells (spleen, liver,
  lung, skin )
• Release of enzyme into plasma - then taken up by
  host cell (wont cross BBB)
• Concentration gradient storage product

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Determinants of Survival GVHD

• Matched siblinggtmatched relatedgt matched
  unrelated donor
• Regime of irradiation and chemotherapy used

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Determinants of Neuropsychological Outcome

• Age lt 24 months
• IQ gt 70
• Donor not a carrier gt donor a carrier
• ? Severity of GVHD

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Psychosocial Aspects

• Limited time to decide whether or not to have BMT
• Decision period while still coming to terms with
  diagnosis
• High risk of losing child in their best years
• Disruption to family
• Outcome data lags changes in regimes

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Daria pre BMT
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The Future

• BMT ERT
• Continually improving regimes

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Jaime 11 yrs post BMT
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Animal studies - BMTMPS-IH (Hurler)

• Dog, cat and mouse
• enzyme activity CSF 7-15 donor
• Histol normal liver, kidney, brain glial cells,
  no peripheral cell vacuolation
• variable decrease neuronal vacuolation
• marked vacuolation chondrocytes