Ignite Creation Date:
2024-05-05 @ 11:59 PM
Last Modification Date:
2024-10-26 @ 10:43 AM
Study NCT ID:
NCT01465100
Status:
TERMINATED
Last Update Posted:
2023-08-16
First Post:
2011-10-20
Brief Title:
Liver Cell Transplant for Phenylketonuria
Sponsor:
Ira Fox
Organization:
University of Pittsburgh
Study Overview
Official Title:
Hepatocyte Transplantation for Phenylketonuria
Status:
TERMINATED
Status Verified Date:
2023-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Study was funded by NIH grant grant funding ended in June 2023 without enrollment of additional subjects the only subject enrolled was in 2011
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Human phenylketonuria PKU results from phenylalanine hydroxylase PAH deficiency and represents one of the most common and extensively studied single-gene Mendelian disorders in humans Unfortunately optimum clinical outcome demands lifelong dietary restriction through adherence to an unpalatable and expensive artificial diet Challenges in maintaining traditional therapy lead to increasing phenylalanine Phe levels in patients as they approach adulthood with an incumbent severe burden of psychosocial and intellectual difficulties The recent introduction of the new medication Sapropterin for treatment of PKU has improved Phe control and dietary tolerance in some patients but at enormous cost to patients and insurers for the FDA designated orphan product Thus there is an unmet need for novel therapies to correct PKU PAH is almost exclusively expressed in the liver in humans The main objective of the current proposal is to examine the safety and efficacy of hepatocyte transplantation in patients with PKU
Detailed Description:
Hepatocytes from more than one donor may be required to provide sufficient numbers of cells for transplantation to correct the disease process We have previously estimated that the hepatic mass of a recipient approaches 4 x 10 to the 9th power hepatocyteskg However this is just an estimate and the true mass may be twice this number Our goal is to attempt to infuse at least 2x10 to the 8th power cellskg Once it has been determined that IND release criteria for the hepatocytes has been met the patient will then receive Intensity-Modulated Radiation Therapy IMRT and the hepatocyte transplant will begin
Preparative Liver Irradiation A portion of the right hepatic lobe comprising between 35-50 of the entire liver volume will be irradiated to a dose of 10 Gy in a single fraction using a linear accelerator-based stereotactic radiosurgery system with intensity-modulated radiation therapy planning IMRT Respiratory gating will be used to further increase the accuracy of delivering the dose to a specified volume and limiting the exposure to adjacent tissues After hepatic irradiation the right or main portal vein will be occluded transiently 0-90 min to provide a compensatory mitotic signal to donor hepatocytes Transient portal vein occlusion or embolization has been shown in primates to provide the appropriate mitotic signals necessary for donor cell proliferation At that time donor hepatocytes will be transplanted into the irradiated portion of the recipients liver
The number of infusions from each donor liver will depend on the tolerance of the patient to infusion avoidance of portal vein thrombosis and portal vein to systemic venous system shunting and viability of donor hepatocytes The hepatocytes from each donor liver will be given over three to four infusions every 6 to 8 hours until the cells are no longer viable approximately twenty-four hours after initial preparation Ideally the infusion catheter will be maintained just outside the portal circulation in the umbilical vein remnant so the patient can be potentially discharged from the hospital until the next donor liver is available Since we do not yet know from our experience the number of cells needed for transplant in order to improve function so that a metabolic disease is cured we will continue to infuse hepatocytes as donors become available until reaching the goal volume of hepatocytes and until viability of cells has expired Using hepatocytes from multiple donors will help to ensure that an adequate number of cells is infused while maintaining portal pressure in the normal rangePhe levels will be collected once a week by the subject using a capillary blood sample on a newborn screening filter paper and mailed to CHP Phe levels will also be collected in a venous sample monthly During months when a Follow-Up Visit is scheduled both a venous and capillary sample will be collected
Subjects will receive careful dietary observation post-transplant through the UPMC Childrens Hospital of Pittsburgh Division of Medical Genetics research dietician Three-day diet records will be completed once a month for six months then every three months thereafter Diet should remain unchanged throughout the study unless directed by study staff
Subjects will undergo a repeat neuropsychological assessment at 6 12 and 24 months post-transplant Visits 4 and 6 and the End of Study Visit which will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure
Isotopic monitoring of whole body Phe oxidation will be performed at every follow-up visit following the final hepatocyte infusion An additional Phe oxidation test may also be completed in the event of suspected graft rejection
Liver biopsies will be performed at 3 and 12 months post-transplant to assess for the presence of donor hepatocytes and may be completed in the event of suspected graft rejection
Preparative Liver Irradiation A portion of the right hepatic lobe comprising between 35-50 of the entire liver volume will be irradiated to a dose of 10 Gy in a single fraction using a linear accelerator-based stereotactic radiosurgery system with intensity-modulated radiation therapy planning IMRT Respiratory gating will be used to further increase the accuracy of delivering the dose to a specified volume and limiting the exposure to adjacent tissues After hepatic irradiation the right or main portal vein will be occluded transiently 0-90 min to provide a compensatory mitotic signal to donor hepatocytes Transient portal vein occlusion or embolization has been shown in primates to provide the appropriate mitotic signals necessary for donor cell proliferation At that time donor hepatocytes will be transplanted into the irradiated portion of the recipients liver
The number of infusions from each donor liver will depend on the tolerance of the patient to infusion avoidance of portal vein thrombosis and portal vein to systemic venous system shunting and viability of donor hepatocytes The hepatocytes from each donor liver will be given over three to four infusions every 6 to 8 hours until the cells are no longer viable approximately twenty-four hours after initial preparation Ideally the infusion catheter will be maintained just outside the portal circulation in the umbilical vein remnant so the patient can be potentially discharged from the hospital until the next donor liver is available Since we do not yet know from our experience the number of cells needed for transplant in order to improve function so that a metabolic disease is cured we will continue to infuse hepatocytes as donors become available until reaching the goal volume of hepatocytes and until viability of cells has expired Using hepatocytes from multiple donors will help to ensure that an adequate number of cells is infused while maintaining portal pressure in the normal rangePhe levels will be collected once a week by the subject using a capillary blood sample on a newborn screening filter paper and mailed to CHP Phe levels will also be collected in a venous sample monthly During months when a Follow-Up Visit is scheduled both a venous and capillary sample will be collected
Subjects will receive careful dietary observation post-transplant through the UPMC Childrens Hospital of Pittsburgh Division of Medical Genetics research dietician Three-day diet records will be completed once a month for six months then every three months thereafter Diet should remain unchanged throughout the study unless directed by study staff
Subjects will undergo a repeat neuropsychological assessment at 6 12 and 24 months post-transplant Visits 4 and 6 and the End of Study Visit which will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure
Isotopic monitoring of whole body Phe oxidation will be performed at every follow-up visit following the final hepatocyte infusion An additional Phe oxidation test may also be completed in the event of suspected graft rejection
Liver biopsies will be performed at 3 and 12 months post-transplant to assess for the presence of donor hepatocytes and may be completed in the event of suspected graft rejection
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None