Hope For Hypothalamic Hamartomas - April 2024

So, what exactly is a Mouse Model and what does it mean for my loved one with HH?

Mouse models are incredibly important when it comes to doing research to better understand the critical aspects of human physiology or disease. Mouse and human brains share a considerable amount of structural organization and genetic information, so scientists can easily manipulate the mouse genome to address specific questions and to build models of human diseases – such as hypothalamic hamartomas. Mouse models are also an essential tool to assess the efficacy of novel drugs. They offer hope for new therapeutic strategies for future drug development!

Hope for HH is excited to share our on-going research grants – funded by your generous donations – that are a source of hope for our community!

NEW RESEARCH FUNDED

Catherine Christian-Hinman, Ph.D.

Univ of Illinois Urbana-Champaign

Assoc. Prof of Molecular and Integrative Physiology

Faculty Member Neuroscience Program

Affiliate Faculty, Backman Institute for Advanced Science and Technology

Learn more about Dr Christian-Hinman and her lab.

Grant Title: Testing viral-genetic strategies to develop mouse models of hypothalamic hamartoma

Grant Amount: $30,000¹

^{Grant Type: Extension (previous grant)}

The basic hypothesis of Dr Christian-Hinman’s research is:

“There is no cure for HH short of surgery, and no animal models of HH have been described in any published scientific literature. The lack of an animal model of HH is a significant impediment to basic research needed to understand the causes of HH and to enable screening and testing of new therapies. Development of animal models that can be used as platforms for future studies. This is critical to increasing our understanding of HH and facilitating development of new therapeutic strategies. This research is innovative and impactful because it represents an entirely new approach to developing an animal model of HH. Importantly, by directly targeting the mouse hypothalamus, it mimics the hypothalamic tumor locations in HH. If successful, these models can be widely adopted by other labs to include not only the study of HH but also other epilepsy and neurobiology. Therefore, these studies have the potential to transform basic and translational research opportunities in HH.

The experiments proposed are centered on continued validation and testing of promoters to determine which are most effective at driving changes in the hypothalamus and cause puberty significantly earlier, a comorbidity that is commonly seen in children with HH.  First, the experiment will test different promoters to determine which show stronger efficacy in driving gene expression in hypothalamic cells and show the highest potential for inducing tumor formation. Second, it will use technology to examine expression of multiple pathway genes in the region of the injection. This research will increase understanding of whether these strategies produce valid mouse models of HH. Ultimately, this will advance progress towards development of mouse models for HH and will allow for collection of data to support an application for NIH federal grant funding.”

Stephanie Baulac, Ph.D.

Paris Brain Institute/Institut du Cerveau

Paris, France

Research Director and Group Leader

Learn more about Dr Stephanie Baulac and her lab.

Grant Title: Somatic Mosaicism in Hypothalamic Hamartoma

Grant Amount: $49,500¹

^{Grant Type: New}

The basic hypothesis of Dr Baulac’s research is:

“Research indicates that somatic mutations (alteration in DNA that occurs after conception) in the Sonic Hedgehog (Shh) signaling pathway within the brain may contribute to the development of Hypothalamic Hamartomas (HH). Shh is a signaling pathway and is necessary for the development of the front part of the brain.

Recently there was research completed on exome sequencing on DNA extracted from matched brain and blood samples obtained from 9 HH patients following epilepsy surgery. Exome sequencing is used to investigate protein-coding to uncover genetic influences on a disease. This approach enabled the identification of pathogenic mutations in 7 out of 9 individuals involving genes already recognized as contributors to the disease, such as GLI3, OFD1, and PRKACA. Additionally, they discovered a novel candidate gene in one patient, which impacts a tyrosine kinase protein and regulates AR phosphorylation (TNK2) in link with the Shh pathway. They hypothesize that a loss of TNK2 leads to Shh signaling decrease and therefore, HH.

To expand on this previous research, this study aims to validate this presumed novel HH gene and identify novel HH-causing genes. There are three aims to this study. The first aim of the proposal is to identify new or known causative HH genes by performing exome sequencing on brain and blood DNA samples in at least 3 additional HH cases. The second aim is to validate the likelihood of the TNK2 variant causing HH. They will be able to further study these in-vitro methods. The third aim is to investigate the disease by generating an HH animal model for these variants to model somatic mutations in vivo and target specifically the hypothalamus during its neurogenic phase.  They will do this via a method called in-utero electroporation. This is a technique in which an electrical field is applied to cells to increase the permeability of the cell membrane. There are no available mouse models that replicate the symptoms (e.g., seizures, behavioral alterations, hamartoma) observed in non-syndromic HH. It is, therefore, crucial to establish in vivo preclinical models to gain deeper insights into how non-syndromic HH develops.

Because HH is a rare condition with limited treatment options, it is critical to improve diagnosis and targeted therapies to enhance patient outcomes. By combining the creation of both an in-utero electroporation and genetic studies on human tissue, this study will increase our current knowledge of HH's cellular mechanisms and genetics. This knowledge has the potential to improve how we diagnose, treat, and care for individuals affected by HH, ultimately enhancing outcomes."

Both grants are for a period of one year. Stay tuned as we will share any exciting findings as they become available.

These grants are made possible by the generous donations of friends, families, and those who care about driving the research forward to make a difference for our loved ones. If you feel moved to donate and support our efforts – please click here. We appreciate you being on this journey with us!!

¹ We would like to thank Hope for HH UK for their partnership and financial contribution to both of these new research grants.

UPDATE ON FUS CLINICAL TRIAL

John Ragheb, MD

Nicklaus Children's Hospital

Chief, Department of Surgery

Director, Division of Neurosurgery

Trial ID: NCT03028246

Trial Title: Feasibility Safety Study of Benign Centrally-Located Intracranial Tumors in Pediatric and Young Adult Subjects Trial  

Recruitment Status: Recruiting

This trial is the first study in children/young adults of the safety and feasibility of high frequency (650kHz) focused ultrasound (FUS) energy using the Insightec Exblate 4000 system to treat benign brain tumors in children. The study is structured to enter 10 children/young adults in incrementally younger age groups between 8 and 22 years of age, beginning with the young adults and progressing to younger ages as safety is demonstrated. The practical limitations of the treatment system has meant that we can only treat lesions of a very limited size and brain location. As of February 2023, the study has treated 8 children/young adults at two research sites (7 at Nicklaus Children’s Hospital, Miami FL and one at Children’s National Medical Center, Washington D.C.). All the children had benign central brain tumors (6 hypothalamic hamartomas, one subependymal giant cell astrocytoma and one low grade astrocytoma). There were no significant safety events and no child suffered any procedure related neurological, behavioral or endocrine complications.  

The study, which is nearing maximum enrollment, is open to the youngest age group, 8 – 22 years old. The individuals with hypothalamic hamartomas have all shown improvement in their seizures, without the typical post-surgical or laser ablation side effects.

The planning has begun for a larger clinical trial to study the effectiveness of FUS treatment in children and to request permission from the FDA to expand the study to include children younger than 8 years of age. We hope to assemble five to ten centers with expertise in pediatric epilepsy surgery and the treatment hypothalamic hamartoma to demonstrate the effectiveness of FUS in children with gelastic epilepsy.

If you are interested in learning more and determining if you or your loved one is a candidate for this FUS clinical trial, please contact research investigator Dr John Ragheb (john.ragheb2@nicklaushealth.org).

MENTAL HEALTH 101

We've scheduled the times to accommodate our international community. Make sure to follow our Facebook page to find out when registration opens for each of thes sessions.

• Adults with HH (April 28th, 3pm EDT)
• HH Caregivers (June 2nd, 3pm EDT)
• Teens (July 14th, 3pm EDT)ly 14th, 3pm EDT)