MNGIE AHSCT Safety Study
| Status: | Recruiting |
|---|---|
| Conditions: | Neurology |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 5 - 55 |
| Updated: | 4/13/2015 |
| Start Date: | November 2014 |
| End Date: | November 2019 |
| Contact: | Kristin M. Englestad |
| Email: | ke4@columbia.edu |
| Phone: | 212-305-6834 |
Allogeneic Hemapoietic Stem Cell Transplant (AHSCT) for Mitochondrial NeuroGastrointestinal Encephalomyopathy (MNGIE): a Phase I Safety Study
The purpose of this study is to find out if a stem cell transplant is safe for patients with
a very rare disease. The stem cell transplant is called AHSCT (for "allogeneic hematopoetic
stem cell transplantation"). The rare disease is called MNGIE (for "Mitochondrial
NeuroGastroIntestinal Encephalomyopathy").
MNGIE is a rare, severe genetic disease. It usually begins to affect patients in their late
teenage years. Major symptoms are gastrointestinal (difficulty swallowing, diarrhea,
abdominal pain, inability to eat normal size meals), weight loss, droopy eyelids, reduced
ability to move eyes, numbness, tingling, and weakness in the hands and feet due to nerve
damage. MNGIE is progressive. Patients generally die in early adulthood, at an average age
of 38 years. The disease occurs when a person inherits two DNA mutations in the TYMP gene
that produces the protein thymidine phosphorylase (TP). Low levels of TP activity, or no TP
activity, cause toxic accumulations of thymidine (Thd) and deoxyuridine (dUrd). These toxic
accumulations prevent the mitochondria, the energy producing parts of the cell, from
producing enough energy. When this happens, the symptoms of MNGIE develop.
Our overall clinical hypothesis is that replacing TP enzyme in MNGIE patients by AHSCT will
benefit the patients by eliminating the toxic metabolites Thd and dUrd. We have collaborated
with a group of international experts colleagues to develop the best AHSCT procedures to
treat MNGIE patients safely, but the safety of these procedure has not yet been established.
In this study, we plan to perform AHSCT on at least 3 and at most 12 patients with confirmed
MNGIE. We will evaluate mortality, the success of the transplant, biochemical parameters,
gastrointestinal function, and nerve functions. If the study shows that AHSCT for MNGIE is
sufficiently safe, we plan to follow it with another study comparing AHSCT to standard of
care (SOC) in MNGIE.
a very rare disease. The stem cell transplant is called AHSCT (for "allogeneic hematopoetic
stem cell transplantation"). The rare disease is called MNGIE (for "Mitochondrial
NeuroGastroIntestinal Encephalomyopathy").
MNGIE is a rare, severe genetic disease. It usually begins to affect patients in their late
teenage years. Major symptoms are gastrointestinal (difficulty swallowing, diarrhea,
abdominal pain, inability to eat normal size meals), weight loss, droopy eyelids, reduced
ability to move eyes, numbness, tingling, and weakness in the hands and feet due to nerve
damage. MNGIE is progressive. Patients generally die in early adulthood, at an average age
of 38 years. The disease occurs when a person inherits two DNA mutations in the TYMP gene
that produces the protein thymidine phosphorylase (TP). Low levels of TP activity, or no TP
activity, cause toxic accumulations of thymidine (Thd) and deoxyuridine (dUrd). These toxic
accumulations prevent the mitochondria, the energy producing parts of the cell, from
producing enough energy. When this happens, the symptoms of MNGIE develop.
Our overall clinical hypothesis is that replacing TP enzyme in MNGIE patients by AHSCT will
benefit the patients by eliminating the toxic metabolites Thd and dUrd. We have collaborated
with a group of international experts colleagues to develop the best AHSCT procedures to
treat MNGIE patients safely, but the safety of these procedure has not yet been established.
In this study, we plan to perform AHSCT on at least 3 and at most 12 patients with confirmed
MNGIE. We will evaluate mortality, the success of the transplant, biochemical parameters,
gastrointestinal function, and nerve functions. If the study shows that AHSCT for MNGIE is
sufficiently safe, we plan to follow it with another study comparing AHSCT to standard of
care (SOC) in MNGIE.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive
disorder characterized by: 1) ptosis and progressive external ophthalmoplegia; 2) peripheral
neuropathy; 3) severe gastrointestinal dysmotility; 4) cachexia; 5) leukoencephalopathy; and
6) laboratory evidence of mitochondrial dysfunction including somatic mutations of
mitochondrial DNA (mtDNA).
In 1999, the H Houston Merritt Center, under the direction of Drs. Hirano and DiMauro,
identified mutations in the (TYMP) gene encoding thymidine phosphorylase (TP) as the cause
of MNGIE. Normally, TP breaks down thymidine, a building block of DNA, to thymine and
ribose. TP also catabolizes the nucleoside deoxyuridine to uracil and ribose. In MNGIE
patients, TP activity in buffy coat is very low or absent resulting in dramatically elevated
levels of plasma thymidine and deoxyuridine. We have hypothesized that the elevated levels
of thymidine and deoxyuridine cause imbalances of mitochondrial nucleotide pools that, in
turn, produce mtDNA abnormalities. Consequently, treatments that reduce the circulating
levels of the toxic nucleosides may be therapeutic for patients.
Our preliminary studies of MNGIE indicate that therapies to eliminate the toxic levels of
thymidine and deoxyuridine from patients will be effective treatments for the disease1, 2.
We have demonstrated that hemodialysis can transiently eliminate these nucleosides from
blood, but was not effective as a long-term treatment in one patient3. To catabolize
nucleosides, we have administered platelets (which contain abundant TP) to two patients4. In
both individuals, plasma thymidine levels were reduced for 24-48 hours. The transient
effects of platelet infusions suggest that permanent TP replacement therapy through AHSCT
should be an effective treatment for MNGIE. While AHSCT will not restore total body TP
levels to normal, our analyses of asymptomatic TYMP mutation carriers show that 30-50% of
normal TP activity is sufficient to prevent MNGIE. Is it noteworthy that after successful
AHSCT in MNGIE patients, median buffy coat TP activity was 697 nmol/h/mg protein, range
262-1285.
AHSCT has been successfully applied to other rare metabolic diseases caused by enzyme
deficiencies. For example, over 200 bone marrow transplantations in patients with Hurler
syndrome have resulted in resolution of the enlarged liver and spleen, improved cardiac
function, reversibility of airway obstruction, and, in some cases, stabilization of
neurological deterioration. In general, AHSCT in patients with lysosomal storage diseases
leads to improvement of visceral organs with variable effects on neurological symptoms.
Furthermore, AHSCT appears to be effective in purine nucleoside phosphorylase (PNP)
deficiency, a disease that biochemically parallels MNGIE because loss-of-function mutations
in the PNP gene lead to accumulations of purine nucleosides. The disease presents with
immunological and neurological dysfunction and AHSCT can restore the immune system and may
stabilize neurological functions. Based on positive results in other metabolic disorders,
assessment of AHSCT therapy for MNGIE is merited.
disorder characterized by: 1) ptosis and progressive external ophthalmoplegia; 2) peripheral
neuropathy; 3) severe gastrointestinal dysmotility; 4) cachexia; 5) leukoencephalopathy; and
6) laboratory evidence of mitochondrial dysfunction including somatic mutations of
mitochondrial DNA (mtDNA).
In 1999, the H Houston Merritt Center, under the direction of Drs. Hirano and DiMauro,
identified mutations in the (TYMP) gene encoding thymidine phosphorylase (TP) as the cause
of MNGIE. Normally, TP breaks down thymidine, a building block of DNA, to thymine and
ribose. TP also catabolizes the nucleoside deoxyuridine to uracil and ribose. In MNGIE
patients, TP activity in buffy coat is very low or absent resulting in dramatically elevated
levels of plasma thymidine and deoxyuridine. We have hypothesized that the elevated levels
of thymidine and deoxyuridine cause imbalances of mitochondrial nucleotide pools that, in
turn, produce mtDNA abnormalities. Consequently, treatments that reduce the circulating
levels of the toxic nucleosides may be therapeutic for patients.
Our preliminary studies of MNGIE indicate that therapies to eliminate the toxic levels of
thymidine and deoxyuridine from patients will be effective treatments for the disease1, 2.
We have demonstrated that hemodialysis can transiently eliminate these nucleosides from
blood, but was not effective as a long-term treatment in one patient3. To catabolize
nucleosides, we have administered platelets (which contain abundant TP) to two patients4. In
both individuals, plasma thymidine levels were reduced for 24-48 hours. The transient
effects of platelet infusions suggest that permanent TP replacement therapy through AHSCT
should be an effective treatment for MNGIE. While AHSCT will not restore total body TP
levels to normal, our analyses of asymptomatic TYMP mutation carriers show that 30-50% of
normal TP activity is sufficient to prevent MNGIE. Is it noteworthy that after successful
AHSCT in MNGIE patients, median buffy coat TP activity was 697 nmol/h/mg protein, range
262-1285.
AHSCT has been successfully applied to other rare metabolic diseases caused by enzyme
deficiencies. For example, over 200 bone marrow transplantations in patients with Hurler
syndrome have resulted in resolution of the enlarged liver and spleen, improved cardiac
function, reversibility of airway obstruction, and, in some cases, stabilization of
neurological deterioration. In general, AHSCT in patients with lysosomal storage diseases
leads to improvement of visceral organs with variable effects on neurological symptoms.
Furthermore, AHSCT appears to be effective in purine nucleoside phosphorylase (PNP)
deficiency, a disease that biochemically parallels MNGIE because loss-of-function mutations
in the PNP gene lead to accumulations of purine nucleosides. The disease presents with
immunological and neurological dysfunction and AHSCT can restore the immune system and may
stabilize neurological functions. Based on positive results in other metabolic disorders,
assessment of AHSCT therapy for MNGIE is merited.
Inclusion Criteria:
1. Laboratory-confirmed MNGIE: thymidine phosphorylase (TP) defect (a and/or b):
1. Homozygous or compound heterozygous mutations in the TYMP gene, and/or
2. TP enzyme activity of <20% of normal,
3. Increased plasma thymidine (Thd)> 3 micromole/L, or
4. Increased plasma deoxyuridine (dUrd)> 7.5 micromole/L
2. Age at least 5 (5th birthday or later) on day that study consent is obtained and no
greater than 55 years on day of transplant.
3. Karnofsky performance status ≥50%/Lansky score>40%
4. Patient is ambulatory.
5. Availability of an human leukocyte antigen (HLA)-10/10 related or unrelated 10/10
HLA-matched donor.
6. Insurance coverage of the AHSCT and related care.
7. Agreement of investigators that AHSCT is appropriate after discussion at Adult or
Pediatric SCT Conference. Pediatric patients are defined as those under the age of 18
years.
8. Informed consent: Patients or their legal guardians must be aware of the nature of
the disease process and must willingly give consent after being informed of the
procedure, its experimental nature, alternatives, potential benefits, side-effects,
risks, and discomforts.
Exclusion Criteria:
1. Severe cognitive impairment (e.g. I.Q. <70) that prevents the patient from
participating in the treatment regimen reliably.
2. Severe psychiatric illness (i.e. depression, anxiety, etc. impairing work or
activities of daily living) that interferes with the patient's ability to comply with
treatment regimen.
3. Moderate to severe lung disease (in adults: vital capacity <50% of predicted normal,
diffusion capacity of carbon monoxide or forced expiratory volume in one second <60%
by pulmonary function tests (PFTs). In children: forced expiratory volume in one
second (FEV1), forced vital capacity (FVC), and lung diffusion capacity testing
(DLCO) corrected for hemoglobin <60% by PFTs. For children who are unable to
cooperate for PFTs: dyspnea at rest, requirement for oxygen supplement, or <90%
saturation on room air.)
4. Prior episode of peritonitis due to perforated diverticula.
5. Prior episode of intestinal pseudo-obstruction.
6. Moderate to severe hepatopathy (Liver cirrhosis on ultrasound. In adults: aspartate
aminotransferase (AST) and alanine aminotransaminase (ALT) >2x upper limit of normal
(ULN), bilirubin >2x ULN. In children: AST or ALT < 5 x upper limit of normal (ULN)
for age, total bilirubin ≥2.5mg/dL unless the increase is attributable to Gilbert
syndrome).
7. Moderate to severe diabetes mellitus
8. Moderate to severe cardiomyopathy (in adults: congestive heart failure, ejection
fraction <50%. In children: congestive heart failure, shortening fraction ≤27% by
echocardiogram, or ejection fraction ≤50% by echocardiogram).
9. Moderate to severe nephropathy (On dialysis. For adults: serum creatinine>2x ULN. For
children, creatinine clearance or radioisotope glomerular filtration rate (GFR) 70
mL/min/1.73 m2 OR serum creatine >0.4 [age 1-6 mos], 0.5 [age 6-12 mos], 0.6 [age 1-2
yrs], 0.8 [age 2-6 yrs], 1.0 [age 6-10 yrs], 1.2 [age 10-13 yrs], 1.5 [males age
13-16 yrs], 1.4 [females age 13-16 yrs], 1.7 [males >16 yrs], 1.4 [females >16 yrs])
10. For women of childbearing potential, participant cannot be pregnant, lactating, or
plan to become pregnant over the course of the study.
11. Serious infection requiring antibiotics.
12. Known hypersensitivity to E. coli-derived products.
13. HIV disease (including HIV Ab positive).
14. Positive patient anti-donor HLA antibodies >1000 in adults.
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