Intraventricular pentosan polysulfate (PPS) infusion for human prion disease

Key facts

• In prion-infected transgenic mice a four-week intraventricular infusion started 10 days after inoculation lengthened survival by 141 percent, and by 71 percent when started at day 35.
• The dose response in mice was bell-shaped, and subcutaneous dosing gave no significant benefit, which is why the route into the ventricle was chosen for patients.
• Safety limits in animals: doses up to 230 ug/kg/day were without notable toxicity for two months in mice, rats and dogs, while 345 and 460 ug/kg/day caused seizures and haematoma around the cannula in dogs.
• A single Oxford-treated vCJD patient received an escalating infusion (1 to 32 ug/kg/day) from December 2003, about 19 months after onset, and survived 51 months from onset against a natural-history median of 13 months; progression was not stopped.
• The UK observational series covered seven patients, tolerated 11 to 110 ug/kg/day over six months, had frequent catheter complications, and showed stable or minimally worse status in three of the four followed for the full period.
• In Japan, Fukuoka University treated 11 patients from 2004 (six sporadic, three genetic, two iatrogenic CJD); mean survival after starting was 24.2 months (range 4 to 49), most had subdural effusion on CT, and the authors reported no apparent clinical improvement.
• A review counted catheter-related complications in 10 of the 11 Japanese patients and noted that both series were uncontrolled, so survival comparisons with historical cases cannot show efficacy.
• UK surveillance data cited in 2014 list five vCJD patients treated with intraventricular PPS who survived 16, 45, 84, 105 and 114 months, against a mean vCJD survival of about 17 months and a longest untreated survival of 40 months.
• Autopsy of the patient who survived 105 months showed typical severe vCJD changes, so the infusion had not prevented neuronal loss or PrP deposition in the brain.
• A separate early vCJD patient treated soon after diagnosis died 5 months after starting PPS, with recurrent catheter-related subdural fluid collections and no definite benefit (search summary only).
• The first cerebroventricular PPS use in vCJD was published in the Journal of Infection in 2005 by Todd, Morrow, Doh-ura and colleagues (citation seen via search only).

Timeline

1. 2003Oxford vCJD patient starts continuous intraventricular PPS; reported in 2007 with 31 months of treatment.
2. 2004Doh-ura and colleagues publish the mouse and animal-safety work on intraventricular PPS in the Journal of Virology.
3. 2004Fukuoka University begins treating prion disease patients with intraventricular PPS.
4. 2005Todd et al. report cerebroventricular PPS in vCJD (J Infect).
5. 2006Whittle, Knight and Will report an unsuccessful early-treated vCJD case (online publication date from a search summary).
6. 2007Parry et al. published online, case with 51-month survival.
7. 2008UK observational series (Bone et al.) and an accompanying editorial by Pocchiari and colleagues appear in European Journal of Neurology.
8. 2009Tsuboi, Doh-ura and Yamada publish the 11-patient Japanese series.
9. 2014Newman et al. publish autopsy findings and the five-patient UK survival data online.