Microbiota changes associated with ADNP deficiencies: rapid indicators for NAP (CP201) treatment of the ADNP syndrome and beyond

Kapitansky, Oxana; Giladi, Eliezer; Jaljuli, Iman; Bereswill, Stefan; Heimesaat, Markus M.; Gozes, Illana

doi:10.1007/s00702-020-02155-5

Cited by 12 publications

(8 citation statements)

References 72 publications

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“…We have previously shown sex differences in ADNP expression in the mouse and the human hippocampus [ 21 ] as well as in the mouse hypothalamus [ 103 ]. Interestingly, not only in muscles, as seen here, but also in other tissues, Adnp regulates other genes in a sexually-dependent manner in the brain [ 21 , 25 ] as well in the spleen [ 28 ], which is also reflected in differential gut microbiota expression [ 104 ]. Importantly and pertinent to our results here, Adnp [ 25 , 28 ] and NAP [ 28 ] regulate the Y-chromosome gene lysine demethylase 5d ( Kdm5d ), which may be partially linked with cardiac muscle differentiation [ 105 ].…”

Section: Discussionmentioning

confidence: 99%

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

Kapitansky

Karmon

Sragovich

et al. 2020

Cells

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Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle deficiency results in myopathy, treatable by the ADNP fragment NAP. Here, single-cell transcriptomics identified ADNP as a major constituent of the developing human muscle. ADNP transcript concentrations further predicted multiple human muscle diseases, with concentrations negatively correlated with the ADNP target interacting protein, microtubule end protein 1 (EB1). Reverting back to modeling at the single-cell level of the male mouse transcriptome, Adnp mRNA concentrations age-dependently correlated with motor disease as well as with sexual maturation gene transcripts, while Adnp expressing limb muscle cells significantly decreased with aging. Mouse Adnp heterozygous deficiency exhibited muscle microtubule reduction and myosin light chain (Myl2) deregulation coupled with motor dysfunction. CRISPR knockdown of adult gastrocnemius muscle Adnp in a Cas9 mouse resulted in treadmill (male) and gait (female) dysfunctions that were specifically ameliorated by treatment with the ADNP snippet, microtubule interacting, Myl2—regulating, NAP (CP201). Taken together, our studies provide new hope for personalized diagnosis/therapeutics in versatile myopathies.

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Section: Discussionmentioning

confidence: 99%

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

Kapitansky

Karmon

Sragovich

et al. 2020

Cells

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“…To this end, CP201 is being developed for the treatment of the ADNP syndrome. This is based on reports of CP201 administration in heterozygous (haploinsufficient) mouse models of ADNP that has shown amelioration of some cognitive abnormalities along with restoration of learning and memory, skeletal strength, and vocalization with a reduction in neurodegeneration (22,(32)(33)(34)(35)(36). This is further based on CP201 mechanism of action as illustrated below.…”

Section: Rationale For Drug Developmentmentioning

confidence: 98%

The ADNP Syndrome and CP201 (NAP) Potential and Hope

Gozes

2020

Front. Neurol.

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Activity-dependent neuroprotective protein (ADNP) syndrome, also known as Helsmoortel-Van Der Aa syndrome, is a rare condition, which is diagnosed in children exhibiting signs of autism. Specifically, the disease is suspected when a child is suffering from developmental delay and/or intellectual disability. The syndrome occurs when one of the two copies of the ADNP gene carries a pathogenic sequence variant, mostly a de novo mutation resulting in loss of normal functions. Original data showed that Adnp+/− mice suffer from learning and memory deficiencies, muscle weakness, and communication problems. Further studies showed that the ADNP microtubule-interacting fragment NAP (called here CP201) resolves, in part, Adnp deficiencies and protects against ADNP pathogenic sequence variant abnormalities. With a clean toxicology and positive human adult experience, CP201 is planned for future clinical trials in the ADNP syndrome.

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“…Indeed, in a culture model of wound healing with cells derived from the mutated-ADNP skin biopsy, NAP showed protective effects [47]. In this respect, Adnp haploinsuffient mice (Adnp +/− ) mimicked some of the skin deficient ADNP syndrome phenotype [47] and further showed distinct microbiota changes which were ameliorated by NAP treatment [48], potentially, through immune-modulatory effect. Given the gut microbiota changes towards higher loads of commensal bifidobacteria which are regarded as anti-inflammatory and probiotic bacterial species as observed in our previous NAP treatment studies applying mice harboring a murine or human gut microbiota [37,39,48], we will address the triangle relationship ("ménage à trois") between C. jejuni, host commensal gut bacteria, and host immunity in future surveys.…”

Section: Discussionmentioning

confidence: 99%

Immune-modulatory Properties of the Octapeptide NAP in Campylobacter jejuni Infected Mice Suffering from Acute Enterocolitis

et al. 2020

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Human infections with the food-borne zoonotic pathogen Campylobacter jejuni are progressively rising and constitute serious global public health and socioeconomic burdens. Hence, application of compounds with disease-alleviating properties are required to combat campylobacteriosis and post-infectious sequelae. In our preclinical intervention study applying an acute C. jejuni induced enterocolitis model, we surveyed the anti-pathogenic and immune-modulatory effects of the octapeptide NAP which is well-known for its neuroprotective and anti-inflammatory properties. Therefore, secondary abiotic IL-10−/− mice were perorally infected with C. jejuni and intraperitoneally treated with synthetic NAP from day 2 until day 5 post-infection. NAP-treatment did not affect gastrointestinal C. jejuni colonization but could alleviate clinical signs of infection that was accompanied by less pronounced apoptosis of colonic epithelial cells and enhancement of cell regenerative measures on day 6 post-infection. Moreover, NAP-treatment resulted in less distinct innate and adaptive pro-inflammatory immune responses that were not restricted to the intestinal tract but could also be observed in extra-intestinal and even systemic compartments. NAP-treatment further resulted in less frequent translocation of viable pathogens from the intestinal tract to extra-intestinal including systemic tissue sites. For the first time, we here provide evidence that NAP application constitutes a promising option to combat acute campylobacteriosis.

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Microbiota changes associated with ADNP deficiencies: rapid indicators for NAP (CP201) treatment of the ADNP syndrome and beyond

Cited by 12 publications

References 72 publications

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

The ADNP Syndrome and CP201 (NAP) Potential and Hope

Immune-modulatory Properties of the Octapeptide NAP in Campylobacter jejuni Infected Mice Suffering from Acute Enterocolitis

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