GnRH Therapy on Cognition in Down Syndrome

Summary

Down syndrome (DS) is the most common chromosomal disorder; with the increasing life expectancy, about 80% of DS adults reach age 65 years old. Early Alzheimer's disease (AD) is the most common cause of death within this population. DS individuals already show AD neuropathology by the age of 30, while it becomes clinically recognized in their late forties. DS subjects also exhibit olfaction defects in adulthood.

To date, there is no treatment available for the cognitive or olfactory defects in DS. The development of an effective treatment targeting cognitive dysfunction in DS adolescents/adults would be warranted.

GnRH, a decapeptide secreted by hypothalamic neurons is the pilot light of reproduction in all mammals. Pulsatile GnRH acts on the gonadotrophs via the GnRH receptor (GNRHR) in the pituitary gland to stimulate LH and FSH, which themselves will act on the gonads to produce gametes and steroids. However, GNRHR are also expressed in cerebral cortex, hippocampus, amygdala, habenula, olfactory structures, and adrenal gland, suggesting that GnRH may have a role beyond reproduction.

Recently, GnRH has been shown to be involved in the process of ageing and lifespan control. Notably, in murine models, GnRH acts as an anti-ageing factor, independent of sex hormones. While ageing is characterized by hypothalamic inflammation and diminished neurogenesis, particularly in the hypothalamus and the hippocampus, GnRH was able to promote adult neurogenesis.

The regulation of GnRH secretion is complex and involves hormonal, neuronal input, and environmental factors.

Prévot et al. recently explored cognition within the Ts65Dn model and showed an age-dependent loss of the ability to recognize new objects. Also, these mice exhibit defects in olfaction. Given the role of GnRH in anti-aging mice model, pulsatile GnRH or continuous GnRH infusion (leading to desensitization of the GNRHR) were given to the Ts65Dn mice for two weeks. Amazingly, pulsatile but not continuous GnRH therapy was able to recover cognitive and olfaction defects.

Conditions

• Down Syndrome
• Cognitive Decline
• Alzheimer Disease, Early Onset
• Olfaction Disorders

Interventions

DRUG

GnRH, gonadorelin acetate

Drug administered by a subcutaneous pump

DRUG

0.9% NaCl

Drug administered by a subcutaneous pump

Sponsors & Collaborators

• Nelly Pitteloud

  lead OTHER

Principal Investigators

• Nelly Pitteloud, MD · Endocrinology, Metabolism, Diabetology (CHUV)

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

16 Years

Max Age

50 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-08-27

Primary Completion

2028-12-31

Completion

2028-12-31

Countries

• Switzerland

Study Locations