Table 2 Overview of current published IPN stem cell research and phenotypes.

CMT1A

PMP22_dup

iPSC-derived Schwann cell precursors

NA

Developmental disabilities of Schwann cells.

Shi et al., ¹⁶²

CMT1A

PMP22_dup

iPSC-derived Schwann cell precursors

Yes

Upregulation of CXCL1 and MCP-1 proteins, as well an associated infiltration of immune cells into nerve tissues.

Mukherjee-Clavin et al. ⁵⁰

CMT1A

PMP22_dup

iPSC-derived organoids

Yes

Early ultrastructural myelin alterations; increased myelin periodic line distance and hypermyelination of small axons.

Treatment? shRNA & combinatorial treatment with baclofen, naltrexone hydrochloride, and D-sorbitol

Van Lent et al. ¹⁰⁶

CMT1A

PMP22_dup

iPSC-Schwann cell precursors

Yes

Lipid metabolic abnormalities primarily associated with cholesterol and sphingolipids.

Prior et al. ⁵¹

CMT1A, CMT1B, CMT1D

PMP22_dup, MPZ^R98C, EGR2^R353G

iPSC-derived neural crest cells

NA

Glutathione-mediated detoxification gene expression pathway as common pathway behind demyelinating neuropathies.

Kitani-Morii et al., ¹⁶³

CMT1F

NEFL^A367*

iPSC-derived motor neurons

NA

Complete absence of NEFL protein.

Sainio et al., ¹⁶⁴

CMT1F

NEFL^A367*, NEFL^−/−

iPSC-derived motor neurons

Yes

Absence of NEFL protein. Also, reduced axonal caliber, decreased amplitude of miniature excitatory postsynaptic currents, reduced NEFH levels, and no compensatory increases in other filament subunits. The movement of mitochondria and to a lesser extent lysosomes was increased. Tested: Nonsense suppressor drugs did not rescue NEFL loss.

Sainio et al., ¹⁶⁵

CMT2A, CMT2E

MFN2^R364W, NEFL^N98S

iPSC-derived motor neurons

NA

Abnormal cytoskeletal and mitochondrial dynamics. Hyperexcitable and altered sodium and calcium channel kinetics.

Saporta et al. ¹⁵

CMT2A

MFN2^A383V

iPSC-derived motor neurons

NA

Global reduction in mitochondrial content and altered mitochondrial positioning. Abnormal apoptosis resistance and increased autophagy.

Treatment? RNAi/gene therapy combined approach

Rizzo et al., ¹⁶⁶; Rizzo et al. ¹⁵¹

CMT2A, CMT2E

MFN2^R94Q, NEFL^P8R

iPSC-derived motor neurons

NA

Reduced PFN2 expression

Juneja et al. ¹¹²

CMT2A, CMT2E, CMT2F, CMT2L

MFN2^R94Q, NEFL^P8R, HSPB1^G84R, HSPB1^P182L, HSPB8^K141N

iPSC-derived motor and sensory neurons

Yes

Gene-specific phenotypes and common hallmarks of axonal degeneration such as impairments in axonal transport and mitochondrial function.

Treatment? GNE-8505 (DLK-inhibitor)

Van Lent et al. ²¹

CMT2A

MFN2^R94Q

Human ESCs-derived motor neurons

Yes

Impaired mitochondrial trafficking and reduced numbers of mitochondria in distal parts of axons.

Treatment? ACY-738 (HDAC6 inhibitor)

Butler et al. ⁸⁶

CMT2B

RAB7A^V162M

iPSC-derived sensory neurons

NA

Increased lysosomal protein expression and lysosomal activity.

Romano et al. ²⁹

CMT2D

GARS1^P724H

iPSC-derived motor neurons

Yes

Deficiencies in spontaneous action potential firing and burst fire behavior. Decreased acetylated α-tubulin levels and mitochondrial movement within axons.

Treatment? Tubastatin A and CKD504 (HDAC6 inhibitors)

Smith et al., 2021¹⁶⁷

CMT2E

NEFL^N98S

iPSC-derived motor neuron spheroids

NA

NEFL deposits and increased neurofilament levels in the culture supernatant.

Treatment? PLK1 (PLKi) and CK2 inhibitor (kinase inhibitors)

Maciel et al. ⁷³

CMT2E

NEFL^N98S

iPSC-derived (inducible) motor neurons

Yes

Pathologic accumulation of NEFL protein in the cell body.

Feliciano et al. ²⁵

CMT2F

HSPB1^S135F, HSPB1^P182L

iPSC-derived motor neurons

NA

Decreased acetylation of α-tubulin and axonal movement defects of mitochondria.

Treatment? CHEMICAL X4 and CHEMICAL X9 (HDAC6 inhibitors)

Kim et al. ¹⁴⁶

CMT2F

HSPB1^P182L

iPSC-derived motor neurons

NA

Decreased autophagic flux.

Haidar et al. ⁷¹

CMT2F

HSPB1^P182L

iPSC-derived motor neurons

NA

Large, cytoplasmic aggregates.

Alderson et al. ⁷²

CMT2H

GDAP1^S194*

iPSC-derived motor neurons

NA

Lipid dysfunction, oxidative stress, and mitochondrial cristae defects.

Miressi et al. ²⁴

CMT2-AR

SORD^−/−

iPSC-derived motor neurons

NA

Increased sorbitol levels.

Treatment? AT-007 (govorestat) (Aldose reductase inhibitor)

Zhu et al. ⁶⁹

CMT2

MT-ATP6 ^m.9154C>T

iPSC-derived motor neurons

Yes

Impaired assembly of ATP synthase, disrupted mitochondrial cristae morphology, defective differentiation with high heteroplasmy, metabolic shift with lower heteroplasmy.

Kenvin et al. ⁷⁴

CMT4A

GDAP1^{(L239F/R273G)}

GDAP1^{(c.579 + 1G>A)}

iPSC-derived motor neurons

NA

Increased glutaminolysis, reduced lipid droplets, and reduced mitochondrial Ca²⁺ levels.

Wolf et al. ¹⁶⁸

CMTX6

PDK3^R158H

iPSC-derived motor neurons

Yes

Increased phosphorylation of the PDC, energy metabolism defects, and mitochondrial abnormalities.

Treatment? DCA (pan PDK inhibitor)

Perez-Siles et al. ¹⁷

dHMNX

ATP7A^T994I

iPSC-derived motor neurons

NA

Reduced ATP7A protein levels in the soma and failure to upregulate expression of ATP7A under copper-loading conditions.

Perez-Siles et al. ²⁷

dHMN

DHMN1^UBE3C-IF

iPSC-derived motor neurons

NA

Significant reduction of wild-type full-length UBE3C protein levels.

Cutrupi et al. ¹⁸

HSAN-I (HSN1)

SPTLC1^C133W

iPSCs, iPSC-derived sensory neurons, and myelinating cocultures (iPSC-SN and rat Schwann cells)

NA

Production of neurotoxic deoxysphingolipid bases (DSBs), reduced complex gangliosides, and impaired neurotrophin signaling, resulting in reduced neurite outgrowth. In HSN1 myelinating cocultures, major disruption of nodal complex proteins causing myelin breakdown.

Treatment? L-serine supplementation

Clark et al. ²⁸

HSAN-III (Familial dysautonomia)

Homozygous IKBKAP^{IVS20+6 T>C}

iPSC-derived neural crest precursors

NA

Low levels of normal IKBKAP transcript. Decreased rate of neurogenesis, and reduced migration.

Treatment? Early stage long-term kinetin

Lee et al. ¹⁴

HSAN-III

Homozygous IKBKAP^IVS20+6T>C

iPSC-derived neural crest precursors

NA

Low levels of normal IKBKAP transcript and reduced migration.

Treatment? SKF-86466

Lee et al., ¹⁶⁹

HSAN-III

Homozygous IKBKAP^IVS20+6T>C

*Severe HSAN-III patients had additional +/-mutations in LAMB4, FAT2 or KIAA1211

iPSC-derived neural crest, and sensory and autonomic-like neurons

Yes

IKBKAP missplicing, deficit in ASCL1 expression levels, and migration defects. Severe FD patient cells display impaired specification of NC derivatives, affecting autonomic and sensory neurons. Both severe and mild FD cells exhibit defects in peripheral neuron survival.

Treatment? Kinetin and SKF-86466

Zeltner et al., ¹⁷⁰

HSAN-III

Homozygous IKBKAP^IVS20+6T>C

iPSC-derived neural crest and iPSC-derived sensory neurons

Yes

Affected dense ridges in NCC generation, decrease in SOX10, affected sensory neuron generation from iPSCs.

Saito-Diaz et al. ³⁵

HSAN-III

Homozygous IKBKAP^IVS20+6T>C

iPSC-derived sensory neurons

NA

Absence of serine/arginine-rich splicing factor 6 (SRSF6) binding to an intronic splicing enhancer in intron 20

Treatment? Small molecule splice modulator, RECTAS, interacts with CDC-like kinases (CLKs) and enhances SRSF6 cellular activity

Ajiro et al., ¹⁷¹

HSAN-III

Homozygous IKBKAP^IVS20+6T>C

iPSC-derived neural crest, and sympathetic autonomic neurons

Yes

Spontaneous, intrinsic hyperactivity, defective norepinephrine autoregulatory pathway, lower NET expression.

Treatment? Dexmedetomidine, carbidopa, clozapine, flupiritine, …

Wu et al. ⁴³

HSAN-III

Homozygous IKBKAP^IVS20+6T>C

iPSC-sympathetic and parasympathetic autonomic neurons

NA

FD-parasymANS are spontaneously hyperactive and the normal crosstalk with symANS is disconnected.

Wu et al. ⁴⁴

Congenital insensitivity to pain (CIP)

Compound heterozygote SCN9A^{R830X & FS1773},

SCN9A^{R896W & c.377+5C>T}

SCN9A^−/−

iPSCs, iPSC-derived sensory neurons

Yes

Nociceptors are hypoexcitable to both threshold and suprathreshold electrical stimuli

Treatment? PF-05089771, BIIB074 (lacks specificity for Nav1.7, the protein product of SCN9A)

McDermott et al. ⁷⁰