MNGIE treatments

Question 1

Treatments

Answer 1

No licensed treatments

Question 2

Loads of experimental therapies available

Main strategy is to

Answer 2

 Reduce systemic thymidine and deoxyuridine
 Prevent further mtDNA damage
 Translate into clinical stabilisation

Question 3

2 experimental treatment strategies - direct removal

Answer 3

Direct removal of the elevated metabolites thymidine and deoxyuridine
Haemodialysis – removal of metabolite
 Blood removed
Clinical data - 50% reduction in plasma thymidine levels
 After 19 hours plasma thymidine levels returned to normal
 This approach would have to be done daily to work - not feasible

Peritoneal dialysis – removal of metabolite
 Filling the peritoneal cavity with dialysis solution
 Diffusion of thymidine and deoxyuridine into dialysate
 Then removed as waste

Clinical data - Found no reduction in plasma thymidine/deoxyuridine
 Metabolites detected in dialysate however

Clinical improvements:
	Cessation of vomiting
	Reduction in abdominal pain
	5kg weight gain
	Intravenous feeding no longer needed
	Patient more able to climb stairs, walk longer distances

Safety issues: catheter infections, mild peritonitis

Question 4

2 experimental treatment strategies - intro of missing enzyme

Answer 4

Introduction of the missing thymidine phosphatase enzyme TYMP
 Diffusion of plasma thymidine and deoxyuridine

Question 5

Platelet transfusion

Answer 5

 Platelets are rich source of thymidine phosphorylase
 Enter donor platelets via nucleoside transporters

Clinical data – reductions in metabolite but within a few days levels returned to normal

Safety issues: immune reactions, transmission of viral infections

Question 6

Stem cell transplantation

Answer 6

 Permanent restoration of TYMP
 Allogeneic haematopoietic – patient receives healthy stem cells from a donor
 Transplantation with matched donor

Clinical data – 63% mortality rate
 Very few met criteria 18/24 died
 Survival dependent on 10/10 donor match

The 9 who survived lived on for 8.5 years
Clinical improvements:
	Hearing
	Muscle strength 
	GI manifestations 
	BMI

This procedure only recommended for patients who had irreversible disease
And perfect matched donor

Question 7

Liver transplantation

Answer 7

 Healthy liver expresses high levels thymidine phosphorylase
 Helps with permanent restoration of enzyme activity

Clinical data:

1-3 days-post LT:
 Elimination of plasma thymidine and deoxyuridine

Patient B 400 days post LT improved:
 Quality of life and lower-limb strength

Advantages – optimal approach for rescuing TYMP
 High survival rate of 85-95%

Disadvantages
 Limited data on long term clinical outcome of treatment