In 2017, CIRM funded a discovery or early stage research project for Dr. Caroline Kuo at UCLA for a hereditary immune disorder known as X-Linked Hyper IgM Syndrome. The work has gone so well that Dr. Kuo and her team are now preparing the pre-clinical work needed to launch a clinical trial.
Thanks to the success of her discovery stage project (these are intended to promote promising new technologies that could be translated to enable broad use and improve patient care), Dr. Kuo received a CIRM progression award to launch a new project for DOCK8 deficiency, a different type of Hyper IgE Syndrome. This new project will compare two gene therapy techniques as potential treatments for DOCK8 deficiency.
Hyper IgM Syndrome is a genetic disorder that occurs when there are abnormal levels of different types of antibodies (Ig) in the body. Antibodies combat infections by attaching to germs and other foreign substances, marking them for destruction. In infants with Hyper IgM Syndrome , there are normal or high levels of antibody IgM but low levels of antibodies IgG, IgA, and IgE. The low level of these antibodies make it difficult to fight off infection, resulting in frequent pneumonia, sinus infections, ear infections, and parasitic infections. Additionally, these infants have an increased risk of cancerous growths.
While X-Linked Hyper IgM Syndrome is caused by a mutation in the X gene, DOCK8 deficiency is caused by a mutation in the DOCK8 gene. More than 95% of patients with DOCK8 deficiency die by age 40.
To determine the best approach to treat DOCK8 deficiency, Dr. Kuo will compare a traditional gene therapy method with another gene therapy approach that uses CRISPR-Cas9, which work like scissors and can be directed to cut DNA at specific sites to disable, repair, or make other alterations to genes.
In a press release from UCLA, Dr. Kuo describes what inspired her to pursue this research.
“I wanted to research new treatment options for DOCK8 deficiency because I see how debilitating it can be for my patients. It’s already bad enough that my patients feel sick but then add to that visible skin infections on their hands and face that are difficult to treat, I think that’s the hardest part for a lot of the children I see. The prospect of developing a curative therapy for patients definitely brings a lot more meaning to the work.”
In addition to these awards, the Board also approved investing $15.80 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.
Before we go into more specific details of each one of these awards, here is a table summarizing these four new projects:
Ex Vivo Gene Editing of Human Hematopoietic Stem Cells for the Treatment of X-Linked Hyper IgM Syndrome
BCMA/CS1 Bispecific CAR-T Cell Therapy to Prevent Antigen Escape in Multiple Myeloma
Neural Stem cell-mediated oncolytic immunotherapy for ovarian cancer
City of Hope
Development of a human stem cell-derived inhibitory neuron therapeutic for the treatment of chronic focal epilepsy
$4.89 million was awarded to Dr. Caroline Kuo at UCLA to pursue a gene therapy approach for X-Linked Hyper IgM Syndrome (X-HIM).
X-HIM is a hereditary immune disorder
observed predominantly in males in which there are abnormal levels of different
types of antibodies in the body.
Antibodies are also known as Immunoglobulin (Ig) and they combat
infections by attaching to germs and other foreign substances, marking them for
destruction. In infants with X-HIM,
there are normal or high levels of antibody IgM but low levels of antibodies
IgG, IgA, and IgE. The low level of
these antibodies make it difficult to fight off infection, resulting in
frequent pneumonia, sinus infections, ear infections, and parasitic
infections. Additionally, these infants
have an increased risk of cancerous growths.
The gene therapy approach Dr. Kuo is
continuing to develop involves using CRISPR/Cas9 technology to modify human
blood stem cells with a functional version of the gene necessary for normal
levels of antibody production. The
ultimate goal would be to take a patient’s own blood stem cells, modify them
with the corrected gene, and reintroduce them back into the patient.
CIRM has previously funded Dr. Kuo’s earlier work related to developing this gene therapy approach for XHIM.
$3.17 million was awarded to Dr. Yvonne Chen at UCLA to develop a CAR-T cell therapy for multiple myeloma (MM).
MM is a type of blood cancer that forms in
the plasma cell, a type of white blood cell that is found in the bone marrow. An estimated 32,110 people in the United
States will be diagnosed with MM in 2019 alone.
Several treatment options are available to patients with MM, but there
is no curative therapy.
The therapy that Dr. Chen is developing will consist of a genetically-modified version of the patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells. The T cells will be modified with a protein called a chimeric antigen receptor (CAR) that will recognize BCMA and CS1, two different markers found on the surface of MM cells. These modified T cells (CAR-T cells) are then infused into the patient, where they are expected to detect and destroy BCMA and CS1 expressing MM cells.
Dr. Chen is using CAR-T cells that can detect two different markers in a separate clinical trial that you can read about in a previous blog post.
$2.87 million was awarded to Dr. Karen Aboody at City of Hope to develop an immunotherapy delivered via neural stem cells (NSCs) for treatment of ovarian cancer.
Ovarian cancer affects approximately 22,000
women per year in the United States alone.
Most ovarian cancer patients eventually develop resistance to
chemotherapy, leading to cancer progression and death, highlighting the need
for treatment of recurring ovarian cancer.
The therapy that Dr. Aboody is developing will use an established line of NSCs to deliver a virus that specifically targets these tumor cells. Once the virus has entered the tumor cell, it will continuously replicate until the cell is destroyed. The additional copies of the virus will then go on to target neighboring tumor cells. This process could potentially stimulate the body’s own immune response to fight off the cancer cells as well.
million was awarded to Dr. Cory Nicholas at Neurona Therapeutics to
develop a treatment for epilepsy.
Epilepsy affects more than 3 million people in the United States with about 150,000 newly diagnosed cases in the US every year. It results in persistent, difficult to manage, or uncontrollable seizures that can be disabling and significantly impair quality of life. Unfortunately, anti-epileptic drugs fail to manage the disease in a large portion of people with epilepsy. Approximately one-third of epilepsy patients are considered to be drug-resistant, meaning that they do not adequately respond to at least two anti-epileptic drugs.
therapy that Dr. Nicholas is developing will derive interneurons from human
embryonic stem cells (hESCs). These newly derived interneurons would then be
delivered to the brain via injection whereby the new cells are able to help
regulate aberrant brain activity and potentially eliminate or significantly
reduce the occurrence of seizures.