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Study on Gene Therapy for Pyruvate Kinase Deficiency Using Autologous CD34+ Cells in Adults and Children

Verified siteRegistered drugNo placebo

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This clinical trial is focused on studying a condition known as Pyruvate Kinase Deficiency (PKD), which is an inherited disorder affecting the enzyme pyruvate kinase. This enzyme is crucial for the survival of red blood cells. The trial aims to evaluate the safety of a new treatment involving autologous CD34+ hematopoietic stem cells that have been modified with a lentiviral vector carrying a gene called the codon-optimized red cell pyruvate kinase (coRPK) gene. This treatment is a form of gene therapy, which involves altering the genes inside a person's cells to treat or stop disease.

The study will involve the infusion of these modified stem cells into both adult and pediatric participants who have been diagnosed with PKD. The main goal is to assess the safety and any potential side effects of this gene therapy. Participants will receive the treatment through an intravenous infusion, which means the modified cells will be delivered directly into the bloodstream. The trial will monitor participants for any adverse reactions and evaluate how well the treatment works in helping the body produce healthy red blood cells.

In addition to the gene therapy, the study will also use other medications such as Busulfan, Filgrastim, and Plerixafor to support the treatment process. Busulfan is used as a conditioning treatment before stem cell transplantation, Filgrastim helps stimulate the production of white blood cells, and Plerixafor aids in mobilizing stem cells for collection. The trial will not only focus on the safety of the gene therapy but also observe the effects of these additional medications in the treatment process. Participants may receive a placebo as part of the study to compare the effects of the actual treatment against no active treatment. The study is expected to continue until October 2025.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Initial assessment
The trial begins with an initial assessment to confirm eligibility. This includes a diagnosis of pyruvate kinase deficiency and a confirmed mutation in the PKLR gene.
Medical records from the past two years are reviewed to ensure a history of severe or transfusion-dependent anemia.
Tests are conducted to confirm adequate heart, lung, kidney, and liver function.
Step 2
Pre-treatment preparation
Before starting the treatment, a series of medications are administered to prepare the body.
The first medication is busulfan, given as an infusion. This medication helps to prepare the bone marrow for the new cells.
Following this, filgrastim is administered through a subcutaneous injection to stimulate the production of blood cells.
Next, plerixafor is given as a subcutaneous injection to help mobilize stem cells into the bloodstream.
Step 3
Stem cell collection
Stem cells are collected from the bloodstream after the administration of filgrastim and plerixafor.
These cells are then modified in a laboratory to carry the corrected version of the gene responsible for pyruvate kinase deficiency.
Step 4
Infusion of modified cells
The modified stem cells are infused back into the body through an intravenous infusion.
This step aims to introduce the corrected gene into the body to improve red blood cell function.
Step 5
Post-infusion monitoring
After the infusion, monitoring is conducted to assess the safety and effectiveness of the treatment.
Blood tests are performed to evaluate the presence of the modified gene and to check for any adverse reactions.
The goal is to achieve stem cell engraftment within 42 days, which is confirmed by specific blood cell counts.
Step 6
Follow-up assessments
Regular follow-up assessments are scheduled to monitor long-term outcomes and any potential side effects.
These assessments include checking for antibodies against the modified gene and evaluating overall health.

Who can join the trial?

11 criteria

The patient must have a confirmed diagnosis of **Pyruvate Kinase Deficiency (PKD)**, which is a genetic condition affecting red blood cells.
The patient must have a confirmed **PKLR mutation**, which is a specific change in the gene related to PKD.
The patient must be within the following age ranges:
- For adults: 18 to 50 years old.
- For children: 8 to less than 18 years old.
- The patient must have a history of severe or transfusion-dependent **anemia**, which means having low red blood cell levels. This can be shown by:
  - At least 6 episodes of red blood cell transfusions in the past year and hemoglobin (Hb) levels below 9.5 g/dL in the last month, even after spleen removal.
  - At least 3 episodes of red blood cell transfusions per year over the past two years and Hb levels below 9.5 g/dL in the last year, even after spleen removal.
  - Hb levels below 8.0 g/dL without transfusions, documented in at least two assessments over the past 1-2 years, even after spleen removal.
  - The patient must have adequate heart, lung, kidney, and liver function.
  - The patient must have detailed medical records available, including information about transfusion needs, for at least the past two years.
  - The patient must be willing and able to read and understand the information about the study and provide consent to participate. For minors, informed assent is required.
  - Female patients who can have children must have a negative pregnancy test.

Who cannot join the trial?

10 criteria

Individuals with any other serious health condition that could interfere with the study.
Pregnant or breastfeeding women.
Individuals who have participated in another clinical trial within the last 30 days.
Individuals with a known allergy to any component of the investigational product.
Individuals with a history of drug or alcohol abuse that could affect their ability to follow the study procedures.
Individuals with a history of cancer, except for certain types of skin cancer that have been treated.
Individuals with an active infection that requires treatment.
Individuals who have received a blood transfusion within the last 3 months.
Individuals with a history of certain heart conditions.
Individuals with a history of certain lung conditions.

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Hospital Universitario Fundacion Jimenez Diaz
Verified
Madrid, Spain

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Investigated drugs

Autologous CD34+ Cells Transduced with a Lentiviral Vector Carrying the Codon Optimized Red Cell Pyruvate Kinase (coRPK) Gene are used in this trial. These are special cells taken from the patient's own body. They are modified in the laboratory using a lentiviral vector, which is a tool that helps deliver new genetic material into the cells. The new genetic material includes a gene that is optimized to help produce a protein called pyruvate kinase, which is important for red blood cell function. This therapy aims to help patients with Pyruvate Kinase Deficiency by improving the function of their red blood cells.

What is already known about the treatment

Autologous CD34+ Cells Transduced with Lentiviral Vector Carrying Codon Optimized Red Cell Pyruvate Kinase Gene – This investigational gene therapy is administered through an infusion of the patient's own CD34+ cells, which have been genetically modified using a lentiviral vector to carry a codon-optimized version of the red cell pyruvate kinase gene. Currently in Phase I clinical trials, this therapy is being studied for its safety and potential to treat pyruvate kinase deficiency, a genetic disorder affecting red blood cell survival. The therapy aims to correct the underlying enzyme deficiency by introducing a functional gene into the patient's cells, thereby improving red blood cell function. It falls under the pharmacological classification of gene therapy, representing a novel approach to treating inherited metabolic disorders.

Investigated diseases

Pyruvate Kinase Deficiency – This is an inherited metabolic disorder affecting the enzyme pyruvate kinase, which plays a crucial role in the survival of red blood cells. The deficiency leads to a reduced ability of red blood cells to maintain their energy levels, causing them to break down more quickly than normal. As a result, individuals with this condition often experience symptoms related to anemia, such as fatigue, weakness, and pale skin. The disorder is genetic, meaning it is passed down from parents to their children. It can vary in severity, with some individuals experiencing mild symptoms and others having more pronounced effects. The condition is typically diagnosed in childhood, but symptoms can appear at any age.