NHP / Marmoset / Cynomolgus / On-Off Phenomenon

(Yuan, 2021 #2441) serum or plasma NfL levels in healthy individuals are about 2.5% of the levels in CSF and correlate highly with the 40-fold higher NfL concentrations in CSF with typical R values ranging from 0.6 to 0.7

			Synthesis →	Release into ECF/CSF/Blood →	In fluid (degradation in blood), half-life calculator: https://www.calculator.net/half-life-calculator.html?type=1&nt=&n0=100&t=80&t12=40&x=58&y=4						Degradation in blood
					Baseline (pre-exisisting)	¼ t½ after 1st dosing	½ t½	T½	2 t½	무한정 긴시간후	At steady state
PD +Tx	약이 NFL의 synthesis엔 무영향이고 degradation에만 영향있다는 가정.	0% neuroprotection (ie no Tx)		100	100			100		100 (0% correction)
		↓ (25%) neuroprotection		50	100			(75: 약 영향 안 받는 부분)+ 12.5 = 87.5 (12.5% correction)	(50: 약 영향안 받는 부분)+ 12.5 = 62.5 (37.5% correction)	75 (25% correction)
		↓ (50%) neuroprotection		50	100		50+35=85 (15% correction)	(50: 약 영향 받는 portion)+ 25 = 75 (25% correction)	(50: 약 영향안 받는 부분)+ 12.5 = 62.5 (37.5% correction) 즉 noticeable/meaningful change보려면 "반감기의 두배" 시간필요하구나.	50 (50% correction)
		↓ (100%) neuroprotection		0	100		84	70 (30% correction)	50 (50% correction)	25 (75% correction)	0 (100% correction)
	Baseline (normal state)			100	100			100		100	100

• Middling results article: drug achieve therapeutic concentration (eg loading dose 4w) → Target engagement (the ASO has to become active, lowering SOD1mRNA. Eg 2w) → protein turn over (half life 4w? Steady state 20w?) : overall 처음부터 여기까지 짧으면 10w, 길면 26w , to reduce aggregated SOD1 → neuronal death (nfl reduction reached 28w) → secondary molecular pathologies before patient functions better

Structure

protein aa	NCBI Ref Seq	Predicted molecular mass
Peripherin	470
Iternexin	499
NFL	543
NFM	916
NFH	1020

Neurofilaments contain three subunits: a light polypeptide (NEFL/NFL), a medium polypeptide (NEFM/NFM), and a heavy polypeptide (NEFH/NFH), with molecular weights of 68, 160, and 212 kD respectively.

NHP

TY1*

Marmoset Translation

The Marmoset Translation panel is a phylogenetic tree with branches colored green for the primate clade containing Human, Chimpanzee, Bonobo, Gorilla, Orangutan, Gibbon, Baboon, Rhe. macaque, Cyn. macaque, Vervet, Sq. monkey, Marmoset, and red for the more distant clade containing Tarsier, Bushbaby, Mouse lemur, Flying lemur, Treeshrew, Mouse. The x-axis is labelled Millions of Years Ago with ticks at 90, 80, 70, 60, 50, 40, 30, 20, 10, 0.

Cynomolgus (Macaca fascicularis)

• the life span of a Cynomolgus monkey is 25-30 years. The monkeys aging 19-31 months are considered juveniles with no sexual dimorphism and those of 32-44 months are considered adolescent (not yet sexually mature) → Their sexual maturity is achieved in four years of age for females and six years for males. The central nervous, skeletal, immune, male reproductive, and endocrine systems complete their development at approximately 5 to 9 years of age.

{Li 2023 #2727}

TABLE 1 Age-dependent organ system development in humans and CMs

column	header
Species	Human / Monkey
Neonate	< 1 month / < 1 month
1st solid food/Infant	~ 6 months / ~ 3 months
Weaning/Toddler	~ 2 years / ~ 6 months
Juvenile/Child	2 - <11 years / 1 - <3 years
Adolescent/Puberty	11 - 15 years / ~ 3 - 4 years
Mature/Adulthood	> 18 years / > 4 years

Central nerve system
Skeleton system
Immune system
Hepatobiliary system
Cardiovascular system
Kidney
Gastrointestinal tract
Pulmonary system
Hematopoietic system
Endocrine system
Reproductive - ovaries and testes

Color code (legend at bottom of figure):

• Critical development period (red)
• Active development period (orange)
• Slow growth and refinement period (cyan)
• Mature in both structures and functions (green)

On-Off Phenomenon

• occur in at least 50% of PD patients who have received levodopa for 5-10 years (Movement Disorders: A Video Atlas pp 14-15| )
• As PD advances, some patients begin experiencing wearing-off effects in which motor benefits following levodopa are reduced in duration and last less than 4 h (the “short duration response”).
• “These off periods are a time when dopamine is going low in the brain usually around 3-4 hours after a dose of levodopa, as the medication literally wears off and symptoms re-emerge or worsen. Symptoms then typically improve 15-45 minutes after the next dose is taken. This phenomenon is called ‘wearing off’ (also known as ‘early wearing off’).
• Wearing off is very individual. In some people, motor symptoms such as tremor may be the first sign, whilst for others it might be stiffness and difficulty initiating movement
• Criteria of off
  • (2018 Simuni) the minimum requirement for OFF time in the PPMI study is 6 hours compared to (js ie other studies) the hours practically defined OFF state

ake, Kentarou-san

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Uncertain Spans

location	text/status	reason
NfL table half-life cells	yellow/cyan highlighted correction percentages	Highlight overlay reduces contrast for some digits inside the cyan blocks; values were taken at the OCR-supported reading.
Structure mini table	NCBI Ref Seq / molecular mass columns	The right two columns of the structure mini table are visually empty in this photo apart from the header row; verify against the prior page if a reference accession or molecular mass is expected per row.
ake, Kentarou-san row	preceding text and table column ordering	Left edge of the bottom table is clipped, so the leftmost cell label is partial; the line ake, Kentarou-san directly above is the visible end of a name fragment from the cropped left margin.
TABLE 1 cells	per-cell color shading	The dense matrix is preserved as evidence; per-cell colors should be read from the body_tile crops rather than transcribed because individual cells are too small for reliable text-form reconstruction.