# Modeling ASD-linked genetic mutations in 3D human brain organoids

> **NIH NIH R01** · HARVARD UNIVERSITY · 2021 · $517,884

## Abstract

Project summary:
 Modern genomic sequencing technologies have allowed the field to identify important genetic
polymorphisms associated with neurodevelopmental and neuropsychiatric disorders such as schizophrenia
(SCZ) and autism spectrum disorder (ASD). However, we still have a limited understanding of the cellular and
gene-expression defects associated with genetic mutation and variation in these pathologies. Finding answers
to these key questions is made difficult by the complexity of these diseases (which affect multiple cell types in
distinct brain regions), the lack of single, ideal experimental models for these specifically “human” pathologies,
and the need to investigate phenotypic abnormalities across many genetic backgrounds. Rodent models have
important limitations due to the inherent differences in the development, architecture and function of their
brains compared to humans; it is increasingly clear that work in rodents must be integrated with the use of
primate models, including models of the human brain.
 Studies using endogenous human brain tissue are complicated by practical and ethical concerns of tissue
availability, expansion and manipulation. However, recent progress has enabled the development of cellular
models of the human developing brain via the generation of 3D brain organoids, which we propose can
complement animal model systems to model basic aspects of human brain development and pathology.
Although reductionist in nature, 3D human brain organoids are amenable to genetic engineering and high-
throughput analysis, making them advantageous platforms for investigating a spectrum of genetic mutations.
These models can provide a valuable platform to link mutations in disease-associated genes with specific
abnormalities in human neurons and circuits, as well as to help identify molecular targets for intervention.
 The CHD8 gene is one of the most commonly mutated genes in sporadic ASD, producing an ASD subtype
frequently associated with macrocephaly. Although it has been demonstrated that CHD8 regulates many other
ASD risk genes, limited information is available on the cellular and molecular defects across different cell types
in CHD8 mutant human tissue. We have recently established an optimized culture system that is able to
develop healthy human brain organoids for up to 13 months, producing unusually mature organoids containing
diverse cell types that molecularly resemble their endogenous counterparts, and mature neurons that develop
dendritic spines and participate in spontaneously active networks (Quadrato et al., Nature, in press). We will
use this protocol to characterize the expression profile of ASD risk genes in individual human brain cell types
within organoids using high-throughput single-cell sequencing. In addition, we have created human brain
organoids from pluripotent stem cells engineered to carry a heterozygous null mutation in CHD8, which we
show recapitulate some of the phenotypic changes seen in patien...

## Key facts

- **NIH application ID:** 10086933
- **Project number:** 5R01MH112940-04
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Paola Arlotta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $517,884
- **Award type:** 5
- **Project period:** 2018-02-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086933

## Citation

> US National Institutes of Health, RePORTER application 10086933, Modeling ASD-linked genetic mutations in 3D human brain organoids (5R01MH112940-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10086933. Licensed CC0.

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