bone marrow transplantation forgdrc-cong.tums.ac.ir/images/slide/slide2/2-ghasemi.pdf · bone...

Bone marrow transplantation for the treatment of lysosomal diseases

Dr. Fariba GhasemiPediatric Endocrinologist and Metabolism Institute of Endocrinology and Metabolism

Research and Training Center

Lysosomal storage disorders

Lysosomes are cellular organelles responsible for degradation of cellular metabolites.

They are composed of a limiting external membrane containing intraluminal vesicles.

The lysosomes are estimated to contain :

50–60 soluble acidic hydrolases,

215 integral membrane proteins,

55 membrane-associated proteins.

Dysfunction in any of these components may cause lysosomal deficits, leading to accumulation of undegraded metabolites and ultimately disease.

Cinzia Maria Bellettato.Maurizio Scarpa,2010.SSIEM and springer

Lysosome

Lysosomal storage disease

Lysosomal storage diseases (LSDs) are a group of more than 50 inherited metabolic

diseases that are due to the absence or reduced activity of a specific lysosomal hydrolase

or other proteins relevant for normal function of the endosomal/lysosomal (E/L) system .

Two thirds of them involve CNS .

In the past two decades, knowledge about LSDs has grown considerably. From the genetic

point of view, all known LSDs have been characterized.

Cinzia Maria Bellettato.Maurizio Scarpa,2010.J inherit Metab Dis.


The disease course can be highly variable, even among affected siblings in the same

family, and more often than not, clear-cut genotype–phenotype correlations have not

been established.

That such multifaceted and serious disease conditions result from simple inborn errors

of metabolism raises .

C.sagne.B.Gasnier ,2008.J inherit Metab Dis


The initial pathogenic:

accumulation of a single major substrate normally degraded by that enzyme .

the undegraded substrate accumulates inside the E/L system causing:

cell enlargement,

collapse of the normal cell functions,

and eventually cell death.

This effect has been designated as the “cytotoxicity hypothesis” and is stil often cited today to explain the pathogenesis of LSDs

Marie T.Vanier,J inherit Metab Dis ,2015

Treatment of lysosomal storage disorders:

Over the past two decades, several approaches have proven successful for the

treatment of LSDs.

Current available treatments : effective for the management of visceral manifestations,

such as reductions in organomegaly by enzyme replacement therapy (ERT) and

substrate reduction therapy (SRT) for non-neuronopathic (type 1) Gaucher disease.

ERT has been studied and subsequently authorized in the EU for

Fabry disease,

mucopolysaccharidosis (MPS) types I, II, IV and VI

Pompe disease.

Carla E. M. Holak,2014. J Inherit Metab Dis

Treatment of lysosomal storage disorders:

Several new approaches are currently investigated in pre-clinical and clinical trials. These strategies focus on :

1- improving convenience of use (oral versus intravenous therapy),

2- on reduction of toxicity (second generation SRTs).

3-new approaches include improvement of enzyme stability,

4-methods to diminish antibody responses to the infused proteins,

small molecules approaches that act as pharmacological chaperones to enhance lysosomal enzyme activity and transport, gene therapy, and intrathecal enzyme delivery

Carlos R. Ferreira et al., 2017

Hematopoietic stem cell transplantation

HSCT has been applied in several of the LSDs and serves as evidence that gene-

transfer can ameliorate disease manifestations.

The proposed mechanism is the cross-correction by normal enzyme producing donor

cells, which migrate in recipient tissues.

For the brain, the microglia cells are partially replaced by donor cells and hence deliver

enzyme to the neurons.

this process may be slow and incomplete, which limits the success for rapidly

progressive neurological disease manifestations.


Preparative regimen and anti-GVHD programs

Umbilical cord blood has become the source of choice for transplants in small infants for

many reasons.

immediate access to large numbers of UCB nucleated cells since placental harvesting

Double cord blood donors have been used when adult or juvenile patients are considered

for HSCT.

This has introduced an ability to readily provide engraftment with a lower incidence of

GVHD

William Krivit, 2004, Springer Semin Immun

Hurler disease (MPS I-H)

Decisions on selection of treatment for a patient with MPS I should be made within a

team.

This team should include at least:

a metabolic physician,

a bone marrow transplant physicians

a neuropsychologist,

all with expertise in MPS I

Minke H de Ru et al., 2011


HSCT has been most extensively studied for the severe Hurler phenotype of MPS I (MPS I-H), which is characterized by:

Cognitive decline in addition to visceral and musculoskeletal symptoms, resulting in early death.

The efficacy of HSCT in MPS I depends on :

timing of the intervention,

donor cell source

engraftment .

Mieke Aldenhoven at al., 2015

Hurler disease (MPS I-H)HSCT has been used to treat more than 500 patients with MPS I since 1981 and is typically

recommended:

for patients with Hurler syndrome under 2 years of age with normal cognition (DQ>70), as

it can prolong survival,

preserve neurocognition,

ameliorate some somatic features

due to its significant morbidity and mortality,

HSCT is reserved for the most severe form of MPS 1.

The allogenic stem cell infusion is given following conditioning with chemotherapeutic

agents to suppress the immune responses.Minke H de Ru et al., 2011

MPS type 1

Based on expert experience: the age limit for HSCT should not be set too low, as

considerable preservation of CNS functions may still be achieved in patients with MPS

I-H if a successful HSCT is done even after 2 years of age.

Development (DQ/IQ) in young patients with MPS I can be very difficult due to

symptoms of the disease, including restricted motor performance.


MPS type 1

The consensus statement on this issue was therefore formulated with caution, and

DQ/IQ is not included as a criterion in the algorithm. The algorithm cannot replace

clinician judgment, and team decisions on treatment should always be considered on

a patient by patient basis


MPS type 1

ERT is not effective in preventing neurocognitive decline in patients with MPS I-H, as the recombinant Enzyme will not cross the blood-brain barrier in sufficient quantity.

Early treatment by HSCT may preserve cognition

prevent several of the somatic manifestations.

recent advances in 1- chemotherapeutic conditioning

2- donor selection

HSCT is the preferred treatment for patients with MPS I-H.

Since phenotypic variability exists even within the severe phenotype, the previously set upper age limit of 2 years for HSCT cannot be used as a strict criterion, and a limit of ‘2.5 years’ is more justified.


MPS type 1 HSCT in patients with MPS I-H is more successful if :

performed early, before overt developmental deterioration the highest chances of better outcome in intellectual functions.

Children with MPS I and advanced CNS-disease (DQ< 70) are less likely to benefit from transplant.

a younger age is more recovery after HSCT. , younger children tend to receive favorable higher cell doses from the donor graft,

monitoring of Busulfan and shorter interval between diagnosis and transplantation

are most important positively influences the outcome

2

4

1

3


MPS type 1

worldwide consensus exists that HSCT is the first line treatment in MPS I-H patients

before the age of 2.5 years.

In any individual patient with MPS I-H/S and CNS involvement, HSCT may be

considered if there is a suitable donor.

However, at present there are no data on the efficacy of HSCT in patients with this

phenotype.


MPS type 1

Clinical trials have demonstrated that ERT is safe and effective in patients with MPS I :

wide range of ages (young children to adults)

phenotypes (severe and attenuated).

Long-term ERT effectively treats several somatic signs and symptoms of MPS I,

resulting in improved health-related quality of life.

initiation of treatment ERT early in the disease course : to prevent and/or minimize

irreversible damage at least in symptomatic patients


MPS type 1

Patients who are referred for HSCT may benefit from ERT before HSCT as this can improve the clinical condition of the patient may ameliorate the pre-transplant condition of a patient.

there is evidence that ERT does not negatively influence engraftment. initiating ERT should not delay the transplant .

there is hardly any knowledge on the natural course of the disease in patients with the intermediate phenotype.

HSCT in these patients should only be performed if the risk-benefit ratio is considered to be favorable and an optimal donor is available.



The results obtained following engraftment in Hurler patients has been successful :

Cardiac pathology, the major cause of death in most patients, has been resolved so that

myocardial function and coronary artery patency is now normal.

The enzymatic leukocyte deficiency of a-l-iduronidase has been totally corrected and

has remained at normal levels .1

2

Vision and hearing have improved considerably relative to the severe disabilities

previously noted in non-transplanted patients .3


Hurler disease (MPS I-H) The results obtained following engraftment in Hurler patients has been successful :

Significant corneal clouding regression has allowed visual acuity appropriate for sports

and school.

Cataract frequency has decreased4

5

The use of tubes for tympanoplasty as well as adenoid-tonsillar surgery and hearing

aids has decreased as Hurler patients are engrafted at an earlier stage.6


Hurler disease (MPS I-H) The results obtained following engraftment in Hurler patients has been successful :

skeletal problems (hip dysplasia, kypho-scoliosis restrictive rib cage disease) will be

ameliorated

Correction of odontoid dysplasia has prevented catastrophic problems of quadriplegia

frequently found in the non-transplanted patients 8

9

Neurocognitive gains post transplant have been observe7



Earlier diagnosis will be made possible in the near future by neonatal mass screening using dried blood spots .

the transplant is a one-time procedure, though graft failure may necessitate subsequent transplants.

ERT with laronidase (recombinant human α-Liduronidase) was approved in 2003 to treat the non-neurologic manifestations of MPS I and is the primary treatment option for patients with Hurler–Scheieand Scheie syndromes.

Laronidase is also used to treat Hurler patients who are not candidates for HSCT because of age, health status, access to transplant, or parental choice

Laronidase must be given as a weekly peripheral or central intravenous infusion and is a lifelong therapy



Other management of MPS I is symptom-based and largely

supportive, such as surgical interventions (e.g., adenotonsillectomy, hernia repair,

ventriculoperitoneal shunt, cardiac valve replacement, carpal tunnel release, spinal

decompression); physical, occupational, and speech therapies; respiratory support

(e.g., continuous positive pressure ventilation with oxygen supplementation); hearing

aids; and medications for pain and gastrointestinal disturbances


Mucopolysaccharidosis type II:

As with BMT, there are very few data on the effects on HSCT in patients with MPS II

Notable observations include a reduction in levels of a urinary marker of GAG levels

(measured as dermatan sulphate to chondroitin sulphate ratio) in one patient and

complete

resolution of skin papules and a progressive reduction in skin tightness in five boys

(aged 4-11 years) within 35 days of HSCT.

Improvement or complete resolution of hepatomegaly has been reported in patients

with mild and severe forms for MPS II following UCBT .


Mucopolysaccharidosis type II:

Urinary GAG excretion was normalised in a patient with an attenuated form of MPS II,

growth and development remained normal up to 2 years after transplantation. No other

physiological changes following UCBT have been reported.

stem cells delivered by UCBT may be able to penetrate the CNS in individuals with

MPS II, although enzyme levels were insufficient for metabolic improvement .

this approach does not preserve or improve neurological function in patients with

severe forms of MPS II if they already show signs of neurological deterioration.


Morquio A Syndrome

HSCT is very limited and not encouraging for patients with Morquio A

syndrome

ERT with recombinant human GALNS (elosulfase alfa) has recently

been approved for Morquio A syndrome, providing a systemic

treatment approach.

Elosulfase alfa has shown to be effective with a favorable safety

profile.


Morquio A syndrome

A multicenter, including 20 MorquioA patients aged 5–18 years:

Urinary KS also decreased with treatment,

with the largest decreases observed when

dosing at 2.0mg/kg/week.

Showed sustained improvements: using

a 6-min walk test (6MWT) and a 3-min

stair climb test (3MSCT), and respiratory

function using elosulfase alfa 1.0

mg/kg/week and 2.0mg/kg/week, which

persisted after approximately 2 years of

treatment .


Sanfilippo syndromes(MPS-III)

Controversy still is about the use of HSCT. Previously published data clearly indicate that final

intellectual outcome has been failed .

the data shows that three patients temporarily improved in the first years after transplant.

DQ scores increased slightly, but in subsequent years they failed to maintain cognitive ability and

became severely intellectually deficient ( DQ scores below 10).

use of umbilical cord blood has a more potent effect on gaining entrance into the brain and being

more effective than other sources of donor cells for these and other patients is lacking at present.

Alternative therapies include enzyme replacement , which in the future could be combined with

HSCT.


Hunters disease

The effect of HSCT has been negligible at present using past modalities of donor

selection and type.

Sly disease (MPS VII) Two patients with Sly disease have been transplanted and, following engraftment, are

in remission from signs and symptoms.

a 12-year-old child has been reported who has responded similarly


Maroteaux-Lamy syndrome(MPS VI)

The patient treated with HSCT at the University of Minnesota had MPS VI . She came to

us with severe sleep apnea and cardiac failure.

After transplant she continued to work as a computer technologist for many years.

The skeletal abnormalities have persisted and the restrictive rib cage causes

respiratory compromise.


Niemann-Pick A

NP A due to a severe sphingomyelinase deficiency causes:

severe early neuropathic disease and death within the first year of life .

complete engraftment in two patients as measured by leukocyte enzyme activity and

DNA analysis.

. Despite this positive effect, the accumulation of lipids noted in the marrow and the

liver increased. The conclusion: the corrected enzyme can not be transplanted out of

the hematopoietic cells and endocytosed in adjacent cells.

Carla E. M. Holak, 2014. J Inherit Metab Dis

Niemann-Pick B

Niemann-Pick (NP) B disease is due to a partial deficiency of sphingomyelinase.

A clinical presentation of NP B consists of hepatosplenomegaly and severe pulmonary

disease, leading to death within the first several years.

Kloetzel in Chicago has been able to engraft such a patient and has successfully

converted this fatal disease to a long-term remission for several years without signs or

symptoms of disease at present

Purkinje cells in the cerebellum were reconstituted following engraftment.

Ami J. Shah et al., 2005, Journal of the American Academy of Pediatrics

Wolmans disease

Wolmans disease is an autosomally inherited recessive disease resulting in extreme deficiency of lysosomal acid lipase .

The clinical characteristics : severe failure to thrive,

hepatosplenomegaly

calcification of adrenal glands.

The onset is shortly after birth and death occurs by 1 year of age.

Two patients who have been successfully engrafted and have shown normalcy of lysosomal acid lipase have had no signs or symptoms of disease in the subsequent 7 years and 2 years follow-up


Wolman disease

Neonatal screening has been started in Australia

therefore anticipate that when this neonatal screening program becomes more widely

used neonatal identification of Wolmans disease will be enhanced.

In the future, treatment with synthetic acid lipase could be the first step in the treatment

of Wolmans disease. The use of such enzyme could be followed by HSCT to secure a

continuous amount of normal enzyme to all tissues involved


Gauchers disease

Gauchers disease type I has been effectively treated by enzyme therapy. However,

enzyme therapy has failed consistently to produce any effect on the CNS in either type II

(infantile) or type III (Norbottnian-Swedish) disease . Conversely, there have been

important clinical observations presented in these latter two types showing that, after

successful engraftmente ,there is reduction of signs.

However, the success and safety of ERT has led to almost complete disappearance of

HSCT for Gaucher disease, despite its positive outcomes. HSCT has been made to

reconsider this procedure, because of the increased safety of the conditioning regimens

as well as minimization of the risk for graft versus host disease


Globoid cell leukodystrophy (Krabbes disease)

Eight early-onset GLD patients have been transplanted within the first month of life. All of them had a family history of prior siblings affected by this disease which always results in rapid CNS deterioration within months of birth and death within a year.

After the present pregnancy became known and the fetus diagnosed via amniocentesis as having galactocerebrosidase enzymatic deficiency, At birth, the diagnosis was confirmed by enzymatic and mutation analysis, and preparations were made for HSCT in the neonatal period. None of the infants had the overt signs and symptoms of the avalanche of CNS catastrophes and deaths. Their developmental milestones are good . MRI anisotropic studies indicated a resolution of signal intensity

Specific neonatal screening programs for GLD to prevent misdiagnosis and provide optimal care and treatment are underway .



HSCT has also produced variable success rates .

late onset, especially adult onset cases with Krabbes disease are rare,

most of the HSCTs have been performed in patients with the classical infantile form.

Timing of HSCT has shown that in these patients neonates had better neurologic

outcome and developmental gains than babies with early symptomatic disease.

Mieke Aldenhoven at al., 2015


Despite early HSCT, all children developed deficits in gross motor function.

Reversal of the CNS deterioration has occurred following engraftment from HSCT. This

is quite dramatic of both the late onset form and the early-infantile type

all late-onset GLD patients who are symptomatic should be given the opportunity for a

normal life by use of HSCT. if the patient is asymptomatic with a galactocerebosidase

deficiency only, the clinical course should be followed carefully without intervention



The initial late-onset GLD patient was transplanted at 11 years of age and is now fully

recuperated at the age of 24 years with continuous enzymatic normalcy.

In the beginning she had: failing vision, Optic atrophy school performance was

diminished, Hand tremors, ataxia, positive Romberg, decreased vibratory and positional

sensation in the legs and hypothenar muscle atrophy were present. The incoordination

and stumbling were no longer evident 1 year after transplantation.


Metachromatic leukodystrophy

Metachromatic leukodystrophy is:

an autosomal recessive genetic disease

deficiencyof arylsulfatas

Sulfatide accumulation causes damage to the myelin, profound CNS deterioration

always leading to early death.



HSCT has been performed for more than two decades in patients with MLD.

Patients with late-infantile onset seemed to have little benefit of HSCT, but with the current

use of cord blood as stem cell source and improved conditioning regimens, there is

accumulating evidence that in asymptomatic or minimally affected patients cognitive decline

may be halted by HSCT, even in some early juvenile cases



The results from HSCT engraftment :

The adult form has a very small amount of enzyme found in all cells. Subsequent to

engraftment the survival curve of transplanted is statistically better than those non-

transplanted .

The juvenile group has similar benefits.

late-infantile onset disease deteriorates at such a rapid pace that transplant/engraftment

process has been disappointing but there have been some exceptions



Failure or even stabilized quality of life despite full engraftment in juvenile and adult

forms of metachromatic leukodystrophy is common.

There is continued loss of nerve conduction in the peripheral nerves, leading to

increasing difficulty in walking. Stool and urine incontinence is frequent.

This loss of quality of life occurs despite complete and continuous engraftment with

normalcy of enzymatic activity Normalcy of enzyme activity and decreased to normal

levels of sulfatides in the urine and cerebrospinal fluid following successful

engraftment after HSCT.


I-cell disease (mucolipidosis II)

There is a defect in the ability of cells and their lysosomes to hold on to these

constitutively formed enzymes in the cell.

This is due to failure to add a 6-mannose phosphate unit to the basic enzyme.

The deficient enzyme is a phosphotransferease.

Subsequent to full engraftment, have followed three patients and have observed

continued neurocognitive development and prevention of cardiopulmonary

complications in a long term follow-up.


Fucosidosis

when transplantation is performed in the neonatal period, the neurological disease and

its pathology does not occur and the enzyme is present in the CNS. Clinically, a patient

was successfully engrafted at Denver Children’s Hospital .


Farbers disease Ceramidase deficiency has been effectively cured by HSCT .

The initial manifestation of Farber’s disease is the accumulation of ceramide deposits

throughout the body.

Recognition of this disorder before CNS deterioration is critical for success


Conclusions

Twenty-five years ago, there was no treatment for these disorders.

Now the increase in understanding of their pathophysiology and genetics has

dramatically changed

the outlook for quality of life for these patients We are now probably “at the end of the

beginning” and embarking daily on new endeavors.

To hope that more progress will be accomplished in the next quarter of century

Many Thanks for Your Attention

دل و جان باش و ��ان باش، ار��ھار گو�و�تای �سا باغ و �ھاران �ه ��ان �ن و

سا�. ا. ه

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