HSCT for High Risk Inherited Inborn Errors

Hematopoietic stem cell transplantation has proven effective therapy for individuals with
adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy
(GLD, or Krabbe disease). However, for patients with advanced or rapidly progressive disease,
the morbidity and mortality with transplantation is unacceptably high. Unfortunately, there
are no viable alternative therapeutic options for these patients; if transplantation is not
performed the patients are sent home to die. Our group at Minnesota has developed a new
protocol incorporating transplantation using a reduced intensity conditioning regimen
designed to decrease toxicity associated with the transplant procedure. This regimen will
make use of the drug clofarabine, which has lympholytic and immune suppressive properties
without the neurologic toxicity observed in the related compound, fludarabine, commonly used
for transplantation. In addition, several agents providing anti-oxidant and anti-inflammatory
properties will be used to assist in the stabilization of the disease processes. This revised
transplant protocol will test the following: 1) the ability to achieve engraftment with the
reduced intensity protocol, 2) the mortality associated with transplant by day 100, 3)
patient outcomes, based on differential neurologic, neuropsychologic, imaging and biologic
evaluations prior to transplantation and at designated points after transplantation (day 100,
6 months, 1, 2 and 5 years). Additional biologic studies will include pharmacokinetics of
clofarabine and mycophenolate mofetil (MMF), develop experience in kinetics of
N-acetylcysteine, and evaluate biologic markers of oxidative status during transplantation.
In addition, for patients undergoing lumbar puncture studies, cerebrospinal fluid (CSF) will
be requested for determinations of biologic parameters.

Inclusion Criteria:

- Adrenoleukodystrophy: Patients from 0-55 years of age diagnosed with ALD as determined
by very long chain fatty acid testing will be eligible for this protocol if they have
evidence of cerebral or cerebellar disease based on MRI testing, AND they are
determined high risk for any of the following reasons:

1. Age >18 years

2. MRI score >10

3. Evidence of aggressive disease that in the judgment of the Inherited Metabolic
and Storage Disease group is sufficiently concerning to consider transplantation
with a reduced intensity regimen instead of a standard full preparative regimen.

- Metachromatic Leukodystrophy: Patients from 0-55 years of age diagnosed with MLD as
determined by determinations of arylsulfatase A testing will be eligible for this
protocol IF they are determined high risk for any of the following reasons:

1. Age >18 years

2. Symptomatic disease, as based on neurologic examination, or evidence of
deterioration based on subsequent neuropsychologic evaluations.

3. Evidence of aggressive disease such as rapidly changing MRI determinations that
in the judgment of the Inherited Metabolic and Storage Disease group is
sufficiently concerning to consider transplantation with a reduced intensity
regimen instead of a standard full preparative regimen.

- Globoid Cell Leukodystrophy: Patients from 0-55 years of age diagnosed with GLD as
determined by determinations of galactocerebrosidase testing will be eligible for this
protocol IF they are determined high risk for any of the following reasons:

1. Age >18 years

2. Symptomatic disease, as based on neurologic examination, or evidence of
deterioration based on subsequent neuropsychologic evaluations.

3. Evidence of aggressive disease such as rapidly changing MRI determinations that
in the judgment of the Inherited Metabolic and Storage Disease group is
sufficiently concerning to consider transplantation with a reduced intensity
regimen instead of a standard full preparative regimen.

- Patients with GM1 gangliosidosis, Tay Sachs disease, Sanfilippo syndrome, Wolman
disease or Sandhoff disease or other inherited metabolic diseases including but not
limited to I-cell disease (mucolipidosis II) who are determined to be sufficiently
advanced or high risk based on the following reasons:

1. Symptomatic disease, as based on neurologic examination, or evidence of
deterioration based on subsequent neuropsychologic evaluations.

2. Evidence of an expected poor outcome based on genetic testing or a prior family
history of aggressive disease.

3. Other metabolic disorders, including but not limited to I-cell disease, that are
deemed to be high-risk for a poor outcome with a standard transplant regimen due
to anticipated toxicity based on experience gained at the University of Minnesota
or other centers.

Exclusion criteria:

- Major organ dysfunction.

- Advanced Disease Exclusion: Following evaluation, if a consensus of the members of the
Inherited Metabolic and Storage Disease Program is that a patient is too advanced to
benefit in a measurable and meaningful way from transplant, this will be communicated
to the family, and transplant will not be offered. Measures to assist in those
determinations may include: neurologic/neurocognitive functions such as activities of
daily living, motor function, vision, hearing, interaction with environment,
toileting, swallowing, or other standardized measures