Everyone can think that extra add-ons to the living may change the lifestyles. Is the leverage similar in life with an extra-chromosome?? The answer is, No!

Take the case of Down syndrome (DS) that has an extra copy of chromosome 21 and associated higher societal costs with physical changes and intellectual disability. Among genetic disorders, Down syndrome is the most common, complex disorder with a huge medical cost throughout the world. Down syndrome can be presented in three forms Trisomy 21, Mosaic trisomy, and Translocation. Trisomy 21–error in cell division called “nondisjunction”–results in an extra copy of chromosome 21 in every cell. In Translocation, an extra part or a whole extra chromosome 21 is attached or “trans-located” to a different chromosome rather than as a separate one. Mosaicism is diagnosed when there is a mixture of two types of cells: 46 and 47 chromosomes; those cells with 47 chromosomes contain an extra chromosome 21. Among the type-specific cases of Down syndrome, Trisomy 21 is the most common form with the maximum number of cases followed by translocation and mosaicism in the 7MM (the US, EU5 and Japan).

Down syndrome can cause complications in the child physically, cognitively, and behaviorally. It can cause a wide variety of clinical manifestations such as intellectual and developmental disabilities and other abnormalities. Down syndrome cases are further divided by Clinical Manifestations as Dementia associated with Alzheimer’s disease, congenital heart disease, gastrointestinal atresia’s, otolaryngology complication (conductive hearing loss), endocrinology dysfunction, especially thyroid defect, and others.

Down Syndrome Prevalence

Steering towards the epidemiological burden of the syndrome, the lifetime Down syndrome prevalence is increasing substantially as the global population grows. Until 2008, DS was a rare disease; however, the current prevalence rates with increased survival have changed this scenario. The total diagnosed Down syndrome prevalent population in the 7MM countries was 699,750 as per the DelveInsight assessments.

Japan’s prevalence of DS at present, approximately 22 per 10,000 births, is twice the prevalence in other 7MM countries. In Japan, the number of DS cases failed to decrease despite antenatal screening tests, most likely due to advanced maternal age. Japan had 152,698 cases of Down syndrome in 2017 and is expected to increase further.

The total Down syndrome prevalence is estimated at approximately 1 in 790 for 0–4 years and decreases with age to an estimated 1 in 1,169 for 20–24, 1 in 5,273 for 60–69, and 1 in 122,364 for those older than 80 years. Also, it was observed that the cases are slightly higher in males than in females. 

However, life expectancy for people with Down syndrome has improved noticeably in recent decades, from 26 years in 1950 to 60 years in 2010. It can be majorly attributed to early and accurate diagnosis. As per ‘The National Down Syndrome Cytogenetic Register,’ the overall diagnosis of Down syndrome has risen by 71% over the past 20 years.

Based on the DelveInsight analysis, the United States showed the highest diagnosed prevalent cases (295,492) of Down syndrome compared to EU5 and Japan. Among the European countries, Germany had the highest diagnosed prevalent population of Down syndrome, and Spain had the lowest prevalent population of 39,402 in 2017.

Down Syndrome Diagnosis and Therapeutics Market

There are different methods used for the prenatal diagnosis of Down syndrome. Ultrasound can be used as a tool for diagnosis. Invasive procedures such as amniocentesis and chorionic villus sampling have been used; however, these are associated with the risk of miscarriages. In recent years, non-invasive prenatal diagnostics came into the light, i.e., Non-invasive prenatal testing (NIPT).

Non-invasive prenatal testing (NIPT):  Bliss for the parents

In October 2011, the US launched NIPT based on the analysis of cell-free DNA (cfDNA) in maternal blood to examine the possibility of fetal Down syndrome. It emanates from the placenta, but represents the entire fetal genotype and is rapidly cleared from the maternal circulation, making it pregnancy-specific. If the fetus has Down syndrome, there will be slightly more chromosome 21-specific DNA in the maternal circulation.

NIPT has a much greater sensitivity than traditional screening methods that significantly reduce the need for invasive testing. It has a much higher detection rate, lower false-positive rate for the three most common genetic abnormalities (Trisomy 21, 13, and 18). Along with this, NIPT decreases the chances of miscarriage. However, NIPT is currently too expensive for most people in various countries, and some governments cannot afford to subsidize it. Moreover, it must be used effectively and ethically if NIPT ultimately becomes the first-tier screen.

Although, improvements in the screening process have led to a decrease in Down’s syndrome births due to a high rate of elective terminations, the effect of increasing maternal age has slightly outweighed the growth of prenatal screening followed by elective terminations, leading to an increase in the prevalence of Down syndrome in the US and Europe. Thus, the population growth of people with DS has leveled off as a consequence of elective terminations.

However, in recent years, individuals’ lives with DS have improved by the evolution of medical care and the benefits of societal changes. Various organizations support several research projects that aim to improve the prevention, diagnosis, treatment, and social integration of people with Down syndrome. There is no medical cure for Down syndrome; thus children would benefit from early medical support and developmental interventions during childhood. The current Down syndrome therapeutic market consists only of supportive care with various classes of therapies such as anti-anxiety medications, anticonvulsants, antidepressants, anti-hypertensive, antipsychotics, antispasmodics, cholesterol-lowering drugs, cholinesterase inhibitors, hormones, hypothyroid-related medications, respiratory medications, and others (e.g., pain relievers, prophylactic antibiotics, and topical ointments). All these therapies only provide symptomatic relief depending on the underlying condition.  In 2017, the Down syndrome market size in the 7MM was USD 662.9 million, wherein the United States had the highest DS market size of 377.8 compared to EU5 (the United Kingdom, Germany, Italy, France, and Spain) and Japan.

The absence of approved products in the Down syndrome market makes the treatment process more complex, and the disease is associated with numerous health problems and high health care costs. However, in the last decade, significant advances in different fields have allowed Down syndrome research to flourish, creating a time of both unparalleled opportunity with considerable challenges, and these advancements are hopeful of making remarkable changes in the future of Down syndrome.

The National Institutes of Health reports estimates that more than half of people with Down syndrome will develop Alzheimer’s disease (AD) dementia as they age. Genes such as the DYRK1A gene, APP gene, proteins α-synuclein, and others are an essential determinant of dementia risk in individuals with DS. Early-onset AD in individuals with Down syndrome is genetically analogous to AD. Therefore, amyloid-targeting drugs should be trialed in individuals with DS, preferably to prevent or delay the onset of dementia. Further, Down syndrome provides defied pathophysiology with a universal enrollment of patients in the clinical trials. Therefore, many companies are exploring various drugs to find efficient therapy for the treatment of Down syndrome, including AC Immune Therapeutics (ACI-24), Annovis (ANVS401), Alzheon (ALZ-801), Balance Therapeutics (BTD-001), Opko health/ Transition therapeutics (ELND005) considering the above factors.

AC Immune is developing the first disease-modifying liposomal therapeutic anti-Abeta vaccine–ACI-24 that specifically targets the misfolded Abeta conformer (oligomeric and fibrillary Abeta proteins)to prevent plaque accumulation and enhance plaque clearance. The vaccines derived from the SupraAntigen platform showed high selectivity for conformational targets and had favorable safety profiles due to a T-cell independent mechanism of action. It addresses Alzheimer’s disease (AD)-like symptoms for Down syndrome, with a potential preventive and therapeutic application. The company is planning to initiate phase II trials in October 2020. With the successful completion of this trial, the vaccine may reach the market by 2028 in the US and occupy a decent share in dementia associated with Down syndrome as well as Alzheimer’s disease.

Besides AC Immune, Annovis Bio is developing ANVS-401 as a combination therapy approach to inhibit the translation of multiple neurotoxic proteins such as APP/Aβ, tau/phospho-tau, and α-synuclein. The company plans to obtain human data for AD in Down syndrome and conduct a Phase III pivotal study.

Finally, the launch of therapies in this arena may change the treatment pattern and may add to the revenue generated in the Down syndrome market associated with Dementia in the near future. More awareness has led to increasing birth registries in the different parts of the world, facilitating more accurate and early diagnosis. With the hope for emerging better treatment options, Down syndrome patients can somewhat lead a more healthy and independent life.