| Modality | Mechanism / rationale | Key evidence / outcomes with quantitative data | Risks / limitations | Real-world status | Suggested MAXO term(s) |
|---|---|---|---|---|---|
| Allogeneic hematopoietic stem cell transplantation (HSCT) | Replaces deficient thymidine phosphorylase (TP) via donor-derived hematopoietic cells/platelets/leukocytes, aiming to clear circulating thymidine and deoxyuridine and restore nucleoside homeostasis (pqac-00000003, pqac-00000004) | International retrospective series: 26 patients started conditioning; 24 evaluable transplants; 9/24 (37.5%) alive at last follow-up (median follow-up 1430 days), and 7/24 (29%) survived >2 years with reported clinical improvements; biochemical correction can be achieved, but short-term intestinal pathology may not improve (pqac-00000003, pqac-00000004) | High transplant-related mortality; one mismatch in unrelated donor noted to increase mortality risk by ~9%; benefit appears greatest before advanced irreversible GI damage; intestinal neuropathology/Cajal cell loss may persist (pqac-00000004) | Clinical practice in selected centers for carefully chosen patients |  |
| Liver transplantation (orthotopic LT) | Liver is a major systemic source of TP; graft supplies TP and lowers toxic plasma nucleosides, potentially with lower procedure-related mortality than HSCT (pqac-00000016, pqac-00000019) | Case series of 4 additional patients: plasma thymidine nearly normalized in all and remained low on follow-up; example pediatric case had pre-LT thymidine 25.61 umol/L and deoxyuridine 25.9 umol/L, dropping to near-normal after LT; another case had TP 6 nmol/mg/h pre-LT with thymidine 6.63 umol/L and deoxyuridine 11.17 umol/L, falling post-LT to 1.01 and 0.59 umol/L; reported thymidine reductions >20x, 11x, 8x, and 24x across four patients; symptom stabilization in all, with some improvements in intestinal function, mobility, cardiac function, and weight gain; no patient died in this series (pqac-00000016, pqac-00000017, pqac-00000018, pqac-00000019, pqac-00000020) | Surgical and immunosuppression risks; complications reported included CMV viremia, pneumonia, bacteremia, thrombosis, rejection/immunosuppression-related diarrhea, hypertension, diabetes, hypertriglyceridemia, GI bleeding; some neurologic deficits and GI dysmotility may stabilize rather than reverse (pqac-00000017, pqac-00000018) | Clinical practice in limited expert centers; increasingly considered for suitable patients |  |
| Erythrocyte-encapsulated thymidine phosphorylase (EE-TP) | Autologous erythrocytes are loaded ex vivo with TP; circulating loaded RBCs metabolize thymidine/deoxyuridine taken up via nucleoside transporters, extending enzyme exposure while reducing free-enzyme immunogenicity (pqac-00000023, pqac-00000026) | Open-label study in 3 adults: dose levels 4, 9, 18, 29, 47, and 108 U/kg every 4 weeks; Patient 1 received 31 cycles over 28 months, Patient 2 received 79 cycles over 76 months, Patient 3 escalated to 108 U/kg every 4 weeks; doses >=4 U/kg reduced urinary nucleosides in all patients; higher doses produced better plasma reductions, often below diagnostic thresholds within cycle; Patient 1 plasma thymidine fell from 10 to 2-6 umol/L and deoxyuridine from 20 to 3-13 umol/L; urinary thymidine/deoxyuridine fell from 73/118 umol/24h to 0-41/0-49 umol/24h; Patient 3 had plasma thymidine/deoxyuridine fall from 12/19 umol/L to <4/2 umol/L by ~60 days; clinical gains included weight gain, improved SF-36, improved gait/balance/fine finger function, and MRC score increase from 56 to 74 in one patient; 51Cr-labelled cells showed mean RBC life 108 days and half-life 32 days (pqac-00000021, pqac-00000022, pqac-00000024, pqac-00000025, pqac-00000026) | Repeated lifelong infusions likely required; infusion reactions occurred in 2/3 patients; one patient developed progressive disease despite treatment and later died after cessation; biomarker rebound may occur; manufacturing/logistics are complex; phase 2 trial was withdrawn for commercial reasons before enrollment (pqac-00000022, pqac-00000024, pqac-00000027, pqac-00000033) | Investigational / compassionate-use; no approved therapy identified in evidence |  |
| Hemodialysis / continuous ambulatory peritoneal dialysis (CAPD) | Physical removal of circulating toxic nucleosides from blood/peritoneal compartment to transiently reduce thymidine/deoxyuridine burden (pqac-00000003, pqac-00000004) | Hemodialysis reported to transiently lower serum/urine nucleosides but without CSF or neurological benefit after 1 year; CAPD protocol reported for 22 months with 1000 mL exchanges, giving transient clinical benefit with relapse by ~15 months; reviews conclude nucleosides rapidly reaccumulate after dialysis (pqac-00000003, pqac-00000004) | Transient effect only; poor durability because metabolites reaccumulate quickly; limited impact on neurologic disease or advanced tissue pathology (pqac-00000003, pqac-00000004) | Supportive / temporizing measure, not definitive disease-modifying therapy |  |
| Platelet infusions | Platelets are TP-rich and can transiently restore circulating TP activity, lowering nucleosides short-term (pqac-00000003, pqac-00000004) | Reported to produce transient TP restoration and short-lived reductions in nucleosides; considered proof-of-principle that enzyme replacement from blood components can work, but not durable enough as long-term standalone treatment (pqac-00000003, pqac-00000004) | Very short-lived benefit; repeated transfusions would be needed; not a durable correction strategy (pqac-00000003, pqac-00000004) | Experimental / occasional bridge strategy rather than standard long-term care |  |
| Gene therapy (preclinical: hematopoietic stem cell gene therapy / AAV approaches) | Restores TYMP/TP activity using genetically modified cells or viral vectors; intended to provide sustained endogenous TP and normalize nucleoside levels without allogeneic donor risks (pqac-00000005, pqac-00000006) | Preclinical studies in Tymp-/- Upp1-/- mouse models showed efficacy/safety for hematopoietic stem cell gene therapy, and reviews describe AAV-based and lentiviral approaches as promising emerging strategies; no human efficacy trial results in provided evidence; 2024-2025 literature also notes ongoing interest in liver-directed/AAV concepts (pqac-00000005, pqac-00000006, pqac-00000008) | Preclinical only in provided evidence; translational hurdles include vector delivery, conditioning requirements, durability, and safety; no clinical outcome data yet in provided context (pqac-00000005, pqac-00000006, pqac-00000008) | Preclinical / investigational |  |


*Table: This table summarizes disease-modifying and investigational treatment strategies for MNGIE, including mechanisms, quantitative outcomes, limitations, and current clinical status. It is useful for comparing which approaches have real-world clinical use versus those that remain experimental.*