What is the mechanism of action of this treatment?

Cystinosis treatments primarily involve cysteamine, which reduces cystine accumulation in cells by converting it into compounds that can exit the lysosome, thus preventing organ damage. This is crucial for managing kidney and systemic complications. Additionally, treatments like αβdepleted-HSCT, which induce immune tolerance to prevent kidney rejection post-transplantation, are significant as they aim to minimize lifelong immunosuppression and prevent chronic rejection, enhancing the quality of life for Cystinosis patients.

What side effects are associated with this type of intervention?

Common treatments for Cystinosis include cysteamine therapy and kidney transplantation, which often necessitate immunosuppressive drugs such as cyclosporine and mycophenolate mofetil. Cysteamine can cause gastrointestinal upset, unpleasant body odor, and skin rashes. Cyclosporine may lead to serious adverse effects like nephrotoxicity, hypertension, and increased risk of infections. Mycophenolate mofetil can cause gastrointestinal disturbances, increased susceptibility to infections, and hematologic abnormalities such as anemia and leukopenia. These side effects are important considerations in the management of Cystinosis.

What prior FDA approvals exist?

The FDA has approved cysteamine (Cystagon and Procysbi) for the treatment of Cystinosis. These drugs work by reducing cystine levels in cells, thereby preventing damage to the kidneys and other organs. While these treatments focus on managing the underlying metabolic defect in Cystinosis, the αβdepleted-HSCT trial aims to induce immune tolerance to prevent kidney rejection post-transplantation, representing a different therapeutic strategy.

What other types of research exist?

Promising alternatives to αβdepleted-HSCT for Cystinosis patients include: 1) T-regulatory cell (Treg) therapy, which uses regulatory T cells to promote immune tolerance and reduce rejection risk. 2) Mesenchymal stem cell (MSC) therapy, which has immunomodulatory properties and can aid in tissue repair and immune tolerance. 3) Gene editing techniques like CRISPR-Cas9 to correct genetic defects and potentially reduce the need for immunosuppression. 4) T-cell receptor (TCR) or chimeric antigen receptor (CAR) T-cell therapies, which can be engineered to target specific immune pathways involved in rejection.

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Antibody

Stem Cell + Kidney Transplant for Renal Disease

Phase 1 & 2

Recruiting

Led By Alice Bertaina, MD

Research Sponsored by Alice Bertaina

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Chronic kidney disease (CKD) stage 3 or greater

Anticipated need for kidney transplant due to underlying genetic/immunologic disease such as SIOD, FSGS, Cystinosis, SLE, Membranoproliferative glomerulonephritis, renal vasculitis characterized by positivity of the presence of ANCA, other genetic diseases leading to kidney disease requiring KT, or patients who have rejected a previous KT regardless of the underlying disease

Must not have

Dysfunction of liver (ALT/AST > 10 times upper normal value, or direct bilirubin > 3 times upper normal value), unmanageable dysfunction of renal function while undergoing dialysis

Severe cardiovascular disease at the time of evaluation unresponsive to nutritional and dialytic support (left ventricular ejection fraction < 40%), or clinical or echocardiographic evidence of severe diastolic dysfunction

Timeline

Screening 3 weeks

Treatment Varies

Follow Up +1 year post-kt

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a special stem cell transplant followed by a kidney transplant in patients who need a new kidney. The goal is to prevent kidney rejection without lifelong medication by preparing the immune system to accept the new kidney.

Who is the study for?

This trial is for patients with certain kidney diseases needing a transplant, who have moderate to severe chronic kidney disease and can consent to the study. They must be able to use birth control if of childbearing potential and match their donor in specific genetic markers. Excluded are those with significant liver dysfunction, uncontrolled medical disorders, active infections or severe heart disease.

What is being tested?

The trial tests whether a sequence of stem cell transplantation (using αβ T-cell depletion) followed by a kidney transplant from the same donor can prevent organ rejection without lifelong immunosuppression drugs. It's an early-phase study at one center without randomization or control groups.

What are the potential side effects?

Potential side effects include reactions to medications like ATG and Rituximab, risk of infection due to immune system suppression, complications from chemotherapy agents such as Melphalan and Fludarabine, and issues related to total body irradiation.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My kidney function is moderately to severely reduced.

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I need a kidney transplant due to a specific genetic or immune disease, or because I rejected a previous transplant.

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I can make my own medical decisions or have someone legally authorized to do so for me.

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I am taking less than 0.5 mg/kg/day of steroids.

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My donor and I match for at least one allele at specific genetic markers.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My liver and kidney functions are not severely impaired.

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I have severe heart issues not improved by diet or dialysis.

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I have no serious health issues affecting my kidneys besides my primary condition.

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I have severe graft-versus-host disease from a past transplant.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ +1 year post-kt

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~+1 year post-kt

This trial's timeline: 3 weeks for screening, Varies for treatment, and +1 year post-kt for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Therapeutic immunosuppression

Secondary study objectives

Number of cases of secondary malignancies

Number of patients with acute GvHD

Number of patients with chronic GvHD

+6 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

4Treatment groups

Experimental Treatment

Group I: Cohort 2a: Conditioning Regimen BExperimental Treatment8 Interventions

If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.

Group II: Cohort 2a: Conditioning Regimen AExperimental Treatment7 Interventions

If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.

Group III: Cohort 1b: Conditioning Regimen BExperimental Treatment8 Interventions

An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.

Group IV: Cohort 1b: Conditioning Regimen AExperimental Treatment7 Interventions

An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Melphalan

2008

Completed Phase 3

~1500

Rituximab

1999

Completed Phase 4

~2990

ATG

2016

Completed Phase 4

~1070

Kidney Transplant

2013

N/A

~120

Fludarabine

2012

Completed Phase 4

~1860

Total Body Irradiation

2006

Completed Phase 3

~820

0 / 9Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Cystinosis treatments primarily involve cysteamine, which reduces cystine accumulation in cells by converting it into compounds that can exit the lysosome, thus preventing organ damage. This is crucial for managing kidney and systemic complications. Additionally, treatments like αβdepleted-HSCT, which induce immune tolerance to prevent kidney rejection post-transplantation, are significant as they aim to minimize lifelong immunosuppression and prevent chronic rejection, enhancing the quality of life for Cystinosis patients.

Elimination of acute GVHD and prolongation of rat pancreas allograft survival with DST cyclosporine, and spleen transplantation.The effect of antilymphocyte serum, fractionated donor bone marrow, and cyclosporine on renal allograft survival in mongrel dogs.Selective lymphoid irradiation and cyclosporin A in rat heart allografts.