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.”
The Stem Cellar 
A gene in human genome consists of introns and exons. Introns are extremely common within the nuclear genome of jawed vertebrates, such as human and mice. However, intron is rare within the nuclear gene of some ekaryotic and microorganisms. During the transcription of RNA, a sequence of DNA contains the intron and exon is transcripted into primer RNA. Then, the primer RNA removes the introns by splicing. The mechanism of alternative splicing is widely used to generate multiple copies of exon from single gene. This mechanism is operated through a complex network of signaling that respond to a wide range intracellular and extracellular of signals. The final product of multiple copies of exon are later joined together to form a mature RNA. This mature RNA (mRNA) has entirely different DNA sequence from the gene in genome. This mRNA is important to translate into functioning proteins. The newly gene editing technology CRISPR-Cas 9 is considered as a faster, cheaper, more accurate and efficiency to edit the existing genome. This approach creat a small piece of RNA guide sequence to attach to a specific target of DNA sequence in a genome. A single guide RNA or chimeric RNA contains 20 base nucleotide, which are complimentary to the target DNA of interest. However, evidence reported that off-target of CRISPR-Cas 9 with 3 to 5 mismatches causes the altering of functioning gene and instability in genomic. The DOCK 8 gene is considered as a big molecular gene in DNA genome. A short sequence of guide RNA is not specific and efficient enough to bind to the target sequences of gene in genome. In addition, the sequence of gene in genome contains multiple introns and final product of mRNA has different genetic sequence from a gene in genome. Therefore, gene editing technology of CRISPR-Cas is expected to pose high risk of producing greater numbers of wrong edited target DNA sequences and resulted in genomic instability of patients.