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Bax. J Transl Genet Genom 2020;4:1-16 I http://dx.doi.org/10.20517/jtgg.2020.08 Page 7

investigational therapeutic strategies for the treatment of MNGIE. The therapeutic strategy common to all
the approaches investigated to date is to reduce or eliminate the pathological concentrations of thymidine
and 2’-deoxyuridine with the aim of ameliorating the intracellular deoxyribonucleoside imbalances to
prevent further mtDNA damage, and ultimately translate the metabolic correction into clinical stabilization
or improvement. Currently, there are two experimental treatment strategies. The first is the direct removal
of the elevated deoxyribonucleosides and includes haemodialysis and continuous ambulatory peritoneal
dialysis (CAPD) [11,63,74] . The second strategy is the introduction of the deficient enzyme, thymidine
[26]
phosphorylase, and includes platelet infusions , allogeneic haematopoietic stem cell transplantation
(AHSCT) [46,82,83] , erythrocyte encapsulated thymidine phosphorylase (EE-TP) [77,84] and orthotopic liver
[85]
transplant (OLT) . These are individually discussed below.
Haemodialysis
Haemodialysis was the first treatment proposed for MNGIE and the first approach employed to remove
the excess concentrations of metabolites from the circulation. Using this procedure, blood is removed
from the patient and dialysed using a semi-permeable membrane to deplete the plasma of thymidine
[11]
and 2’-deoxyuridine, before being returned back to the patient. The study of Spinazzola et al.
demonstrated a 50% reduction in the plasma metabolite levels in two patients. However, by 19 h post-
dialysis, the metabolite levels returned to pre-treatment concentration. The procedure was subsequently
used to treat three further patients between 2 and 19 months [63,86,74] . In one patient, there were long-
term reductions in the urinary excretion of thymidine and in a second patient there was a reported a
reduction in the frequency of vomiting to once every 2-3 days, as opposed to after every meal [63,74] . The
third patient demonstrated transient reductions in plasma and urine metabolite concentrations, with
the metabolites returning to baseline within 24 h of stopping the procedure. Disease progression was
also reported in this patient, as demonstrated by worsening of the score for the Ataxia Assessment scale,
[86]
and declines in the Montréal Cognitive Assessment score and nerve conduction measures . For all
three cases, 3-4 haemodialysis procedures per week were required to maintain a sustained reduction in
deoxyribonucleosides. Although no safety issues were reported in these studies, potential safety issues
associated with this procedure include hypotension, fluid over-load and infections from repeated venous
access. In addition, dialysis can be a burdensome and invasive treatment, and may reduce the patient’s
quality of life.

CAPD
CAPD involves the filling of the peritoneal cavity with a dialysis solution to encourage the diffusion of
thymidine and 2’-deoxyuridine from the blood passing through the capillary network within the peritoneal
membrane, and then after several hours of exchange, draining the dialysate containing the metabolites
from the peritoneal cavity to waste [Figure 2]. This approach has been reported for the treatment of four
single cases, with patients receiving exchanges every 4-8 h, over periods of 22-36 months [74,87-89] . Although
CAPD had no reported effects on the plasma biochemical imbalances, in one study, it was shown to
remove approximately 100 µmol per day of thymidine and 2’-deoxyuridine from the peritoneal cavity [74,87] .
Clinical improvements were reported in all four patients and included reductions in vomiting, nausea
and epigastric pain; no longer requiring parenteral nutrition; improvements in appetite; increases in
body weight (ranging between 3.5 and 13 kg); slight improvement in sensorimotor polyneuropathy and
sensory ataxia; and a resolution of the numbness in peripheries. Regained abilities to perform normal daily
activities were also reported, for example climb stairs, ambulant without support and improved walking
distances [74,87,88] . Of interest, many of the clinical improvements reported were gastrointestinal in nature, and
CAPD may therefore offer an important approach to targeting the gastrointestinal symptoms of MNGIE.
In two cases, the gastrointestinal manifestations reappeared if CAPD was missed or discontinued [74,88] . A
standardised approach should be implicated in recording body weight gain as the reported increases could
be a consequence of fluid retention.