Focus Areas
We focus on developing stem cell-based therapy and generating protective small molecules for neurological diseases. Our approach combines precision medicine, using genetic information for patient stratification, with regenerative medicine (iPSC-derived cells for therapy) and pharmaceutical intervention (small-molecule drugs) to replace and restore lost or injured nerve cells. Therapeutic programs are designed to preserve the functions of the most vulnerable cell populations in the brains of patients with neurodegenerative and neurodevelopmental disorders. A major target is apoE4-associated neurological disorders.
The Role of ApoE
ApoE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). Individuals carry one of three variants of the apoE gene: apoE2, apoE3, or apoE4.
Carriers of the apoE4 allele have an increased risk of developing AD at an earlier age-of-onset and an increased rate of progression in a gene dose-dependent manner. 65–80% of all AD patients have at least one apoE4 allele, and 20% of all AD patients are homozygous for apoE4.
Our program aim is to treat apoE4 carriers with AD and is based on the work of GABAeron’s founders, Drs. Yadong Huang and Sheng Ding from the Gladstone Institutes, and Dr. Robert W. Mahley. Their work has led to novel findings related to understanding the structure and function of apoE and recent studies in animal models of AD and in human iPSC-derived neurons. For more visit our Publications page.
– Detrimental Effects of ApoE4
GABAergic Interneuron Loss
ApoE4 causes GABAergic interneuron loss in the hippocampus, which correlates with the impairment of hippocampal network activity and the extent of learning and memory deficits.
Selective Neuron Death
ApoE4 causes the selective death of human iPSC-derived GABAergic interneurons in culture.
Autonomous Detrimental Effect
The detrimental effect of apoE4 on GABAergic interneurons is cell autonomous.
+ Breakthroughs Towards Treatment
Learning & Memory Restoration
Transplantation of mouse GABAergic interneuron progenitors into the hippocampus restores normal learning and memory in aged apoE4 knock-in (apoE4-KI) mice without or with Αβ accumulation.
Restoration by Human Progenitors
Transplantation of human iPSC-derived GABAergic interneuron progenitors into the hippocampus restores normal learning and memory in aged apoE4-KI mice.
Small Molecule Protection
Small molecules have been identified to protect neurons and to modulate sterol (cholesterol) biosynthesis in neurodevelopment.
Cell Replacement Therapy to Treat GABAergic Interneuron Dysfunction
Current Targets: Alzheimer’s Disease, Down’s Syndrome, Epilepsy
Dysfunction of GABAergic Interneurons
A prominent feature of Alzheimer’s disease (AD) is impaired GABAergic inhibitory interneuron function and an associated network hyperactivity. The loss of both the neurotransmitter GABA and the GABAergic interneurons is associated with neurological disorders, including AD and epilepsy, and psychiatric disorders, including schizophrenia and depression. Specifically, AD patients have a loss of somatostatin-positive interneurons in the hippocampus.
Cell Replacement Therapy
GABAergic inhibitory interneurons in the hippocampus are highly vulnerable to apoE4-mediated toxicity. Specifically, apoE4 expression in mice results in a decrease in GABAergic somatostatin-positive interneurons in the hilus of the hippocampus. The loss of hilar GABAergic interneurons is associated with impaired learning and altered electrical activity. The working hypothesis is that apoE4 synthesized in neurons selectively undergoes proteolysis, generating a series of neurotoxic fragments that injure or kill susceptible hippocampal interneurons. Previous studies in mice have demonstrated that the transplantation of GABAergic progenitors into the hippocampus restored the impaired learning and memory in apoE4 mice. In addition, transplantation of GABAergic interneuron progenitors has the potential to correct seizure activity in an epilepsy model. Thus, the goal of GABAeron is to use cell replacement as a treatment for neurological disorders by selectively producing human iPSC-derived GABAergic interneurons and transplanting them into the dentate gyrus of the hippocampus.
Pharmaceutical Intervention through Small Molecule Modulation of Sterol Biochemistry
Current Target: Smith-Lemli-Opitz Syndrome (SLOS)
Smith-Lemli-Opitz Syndrome
The Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder (autosomal recessive) resulting in defective cholesterol synthesis and is associated with abnormalities in neurodevelopment, cognition, and behavior along with various physical malformations. The incidence of SLOS is approximately 1/10,000 – 1/50,000 live births. The pathophysiological mechanism responsible for SLOS is a deficiency in the enzyme 7-dehydrocholesterol reductase (DHCR7) that converts 7-dehydrocholesterol (7DHC) to cholesterol. The enzyme deficiency results in an increase of 7DHC and a decrease in cholesterol. The SLOS abnormalities may result either from an increase in 7DHC that may be toxic to cells or from a reduction in cholesterol, or a combination of the two. Cholesterol plays multiple roles during central nervous system neurodevelopment and neuronal function, including synapse formation and myelination of nerve axons.
Correct Defective Cholesterol Biosynthesis
GABAeron scientists have identified small molecules that modulate the activity of several enzymes in the cholesterol biosynthesis pathway and appear to correct the defective cholesterol biosynthesis in cultured neurons and other cells from patients with SLOS. The goal is to develop a drug that would both reduce the 7DHC and increase cholesterol. Delivery of the drug soon after birth, when neurodevelopment is still occurring, could lessen or prevent the abnormalities associated with impaired cholesterol biosynthesis and could translate into normal cognitive and behavioral function. Presently there is no effective treatment for SLOS.
