Building hope through science: Dr. Angels Almenar-Queralt and the power of neural organoids

In a major stride forward for Kleefstra syndrome (KS) research, earlier this year IDefine announced that Dr. Angels Almenar-Queralt, an assistant professor of Pediatrics at UC San Diego, was awarded a $100,000 grant to develop cutting-edge neural organoid models of Kleefstra syndrome. This project—selected through a competitive application process—marks an exciting new phase in our effort to uncover the underlying biology of KS and chart a path toward future treatments.

Dr. Almenar-Queralt’s lab is using induced pluripotent stem cells (iPSCs), recently developed by IDefine, to construct three-dimensional organoid models that mimic early stages of human brain development. These 3D systems will allow researchers to investigate how mutations in EHMT1—the single gene whose dysfunction causes KS—impact neuronal development, communication, and function.

“Developing advanced 3D neural organoids from human iPSCs is a time-intensive but incredibly rewarding process,” says Dr. Almenar-Queralt. “Over weeks and months, these structures increase in complexity, forming layers and neural networks that help us model real brain function and dysfunction in a species-relevant context.”

From Barcelona to the frontlines of translational neuroscience

Dr. Almenar-Queralt brings more than 15 years of experience in cell biology and neurological disease modeling. Originally from Barcelona, Spain, she began her scientific journey studying the internal scaffolding of muscle cells, later shifting her focus to neurons and the sophisticated transport systems that allow them to function.

“There’s something truly awe-inspiring about how cells build and maintain their complex internal structures with such precision,” she reflects. “And that organization is fundamental to their function. That’s what drew me to cell biology—the idea that in order to cure disease, we first need a deep, foundational understanding of the cell.”

Her transition into organoid research began under the mentorship of Dr. Larry Goldstein and deepened through her collaboration at UC San Diego with Dr. Alysson Muotri, a pioneer in brain organoid modeling. Together, they’ve developed organoid models of neurodevelopmental disorders such as FOXG1 and SETD5 syndromes—efforts that directly inform her current work on KS.

Why EHMT1?

Kleefstra syndrome, caused by pathogenic variants or deletions in the gene EHMT1, offers a unique opportunity for discovery. Because KS is caused by a change to a single gene it can be isolated more cleanly in models, providing insights that could extend to other neurodevelopmental conditions with overlapping mechanisms.

“EHMT1 encodes a lysine methyltransferase that regulates gene expression—basically turning genes on or off at the right times,” explains Dr. Almenar-Queralt. “Disrupting that regulation can have far-reaching effects on brain development. Our goal is to understand exactly how and then test ways to reverse or mitigate those effects.”

Her lab’s strategy includes testing for known KS-related features like microcephaly (an unusually small head size) in the organoids, identifying disrupted molecular pathways, and screening potential therapies—ranging from gene therapy to antisense oligonucleotides (ASOs)—to see if any can “rescue” the deficits observed.

Importance of human models

For Dr. Almenar-Queralt, the use of human neural organoids is not just about innovation—it’s about precision.

“Mouse models have taught us a lot, but they can’t replicate the uniquely human aspects of early brain development,” she says. “EHMT1 expression peaks during early fetal stages, so if we want to understand its role—and how to intervene—we need human-specific models that reflect those developmental windows.”

Some of the therapies being developed today—like the gene therapy Zolgensma for spinal muscular atrophy or ASOs for Rett and Angelman syndromes—demonstrate that postnatal treatment of monogenic brain disorders is possible. Her hope is that similar approaches could emerge from this work on Kleefstra syndrome.

“If we discover that EHMT1 deficiency impairs neuronal maturation or synaptic connectivity, we can screen for tools that restore those functions,” she notes. “Ultimately, the goal is to identify targeted therapies that can improve brain function—even after birth.”

Measuring success

For Dr. Almenar-Queralt, success on this research project means identifying reliable cellular signatures of KS and using them to launch a new phase of research and therapy development.

“If we can define the molecular fingerprints of Kleefstra syndrome in organoids, we can begin to test interventions. Even a partial rescue would show that aspects of KS are modifiable—which is incredibly hopeful.”

From there, she envisions scaling the work to include more patient-derived lines, exploring more complex models like assembloids, and pursuing partnerships to translate lab discoveries into clinical pipelines.

“With support from IDefine and collaborators across UCSD, we have an ecosystem built for impact,” she says. “What’s so exciting is that we’re not just exploring biology—we’re building realistic pathways to therapies.”

A message to families

Dr. Almenar-Queralt is unequivocal about the role that families and advocacy groups like IDefine play in driving science forward:

“Your fundraising and advocacy are not just helpful—they’re essential. Many of the biggest breakthroughs in rare disease research have come because families refused to wait. With your support, we can ask bold questions, move faster, and build the foundation for change.

“This is a critical moment. The FDA is beginning to accept human-based models like organoids in therapy evaluation. That means what we build in the lab today could shape real treatments tomorrow.”

In the end, this project isn’t just about studying a gene—it’s about serving a community.

“As a scientist, I feel a deep responsibility to use my expertise not just to understand disease, but to improve lives,” Dr. Almenar-Queralt said. “Together—with researchers, families, and organizations like IDefine—we’re creating something powerful: a path to hope.”