Galactosemia future or investigational therapies: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
|||
| Line 7: | Line 7: | ||
==Future or Investigational Therapies== | ==Future or Investigational Therapies== | ||
The [[therapeutic]] modalities currently being explored are: | The [[therapeutic]] modalities currently being explored are: | ||
===[[Aldose]] [[reductase]] [[inhibitors]]=== <ref name="pmid2516529">{{cite journal| author=Lou MF, Dickerson JE, Chandler ML, Brazzell RK, York BM| title=The prevention of biochemical changes in lens, retina, and nerve of galactosemic dogs by the aldose reductase inhibitor AL01576. | journal=J Ocul Pharmacol | year= 1989 | volume= 5 | issue= 3 | pages= 233-40 | pmid=2516529 | doi=10.1089/jop.1989.5.233 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2516529 }} </ref>: They prevent the conversion of [[galactose]] to [[galactitol]], a highly [[osmotically]] active substance <ref name="pmid32314655">{{cite journal| author=Timson DJ| title=Therapies for galactosemia: a patent landscape. | journal=Pharm Pat Anal | year= 2020 | volume= 9 | issue= 2 | pages= 45-51 | pmid=32314655 | doi=10.4155/ppa-2020-0004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32314655 }} </ref>. It can accumulate in the [[lens]] causing [[cataract]]<ref name="pmid10915771">{{cite journal| author=Ai Y, Zheng Z, O'Brien-Jenkins A, Bernard DJ, Wynshaw-Boris T, Ning C | display-authors=etal| title=A mouse model of galactose-induced cataracts. | journal=Hum Mol Genet | year= 2000 | volume= 9 | issue= 12 | pages= 1821-7 | pmid=10915771 | doi=10.1093/hmg/9.12.1821 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10915771 }} </ref>, in the [[brain]] causing [[cerebral]] [[edema]] and [[pseudotumor]] [[cerebri]]<ref name="pmid11174626">{{cite journal| author=Berry GT, Hunter JV, Wang Z, Dreha S, Mazur A, Brooks DG | display-authors=etal| title=In vivo evidence of brain galactitol accumulation in an infant with galactosemia and encephalopathy. | journal=J Pediatr | year= 2001 | volume= 138 | issue= 2 | pages= 260-2 | pmid=11174626 | doi=10.1067/mpd.2001.110423 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11174626 }} </ref>, and also plays a role in [[cognitive]] and [[neurological]] [[symptoms]] of [[galactosemia]]<ref name="pmid7821191">{{cite journal| author=Kamijo M, Basso M, Cherian PV, Hohman TC, Sima AA| title=Galactosemia produces ARI-preventable nodal changes similar to those of diabetic neuropathy. | journal=Diabetes Res Clin Pract | year= 1994 | volume= 25 | issue= 2 | pages= 117-29 | pmid=7821191 | doi=10.1016/0168-8227(94)90037-x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7821191 }} </ref>. However, the [[therapy]] has been investigated only on animal models (rats and dogs) till now<ref name="pmid9043821">{{cite journal| author=Obrosova I, Faller A, Burgan J, Ostrow E, Williamson JR| title=Glycolytic pathway, redox state of NAD(P)-couples and energy metabolism in lens in galactose-fed rats: effect of an aldose reductase inhibitor. | journal=Curr Eye Res | year= 1997 | volume= 16 | issue= 1 | pages= 34-43 | pmid=9043821 | doi=10.1076/ceyr.16.1.34.5113 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9043821 }} </ref>, and the effect of blocking the [[polyol]] [[pathway]] is still not exactly known. | |||
* '''[[ER]] [[stress]] reducers''': [[ER]] [[stress]] has been shown to contribute to the [[pathogenesis]] of [[galactosemia]] by altering the chemical signaling, such as the [[PI3K/Akt]] pathway<ref name="pmid17643331">{{cite journal| author=Slepak TI, Tang M, Slepak VZ, Lai K| title=Involvement of endoplasmic reticulum stress in a novel Classic Galactosemia model. | journal=Mol Genet Metab | year= 2007 | volume= 92 | issue= 1-2 | pages= 78-87 | pmid=17643331 | doi=10.1016/j.ymgme.2007.06.005 | pmc=2141683 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17643331 }} </ref>. [[Downregulation]] of this pathway has been linked to [[subfertility]] and [[cerebellar]] [[ataxia]]<ref name="pmid26773505">{{cite journal| author=Balakrishnan B, Chen W, Tang M, Huang X, Cakici DD, Siddiqi A | display-authors=etal| title=Galactose-1 phosphate uridylyltransferase (GalT) gene: A novel positive regulator of the PI3K/Akt signaling pathway in mouse fibroblasts. | journal=Biochem Biophys Res Commun | year= 2016 | volume= 470 | issue= 1 | pages= 205-212 | pmid=26773505 | doi=10.1016/j.bbrc.2016.01.036 | pmc=4728015 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26773505 }} </ref>. Hence, its reversal by administering molecules that reduce the [[ER]] [[stress]] might prove beneficial for the [[brain]] and [[reproductive]] [[organs]].Positive effects of such compounds i.e. the [[eukaryotic]] [[initiation]] factor 2-alpha inhibitors (salburinal) have already been demonstrated in mice, thus making it a valid potential [[treatment]]<ref name="pmid28844959">{{cite journal| author=Balakrishnan B, Nicholas C, Siddiqi A, Chen W, Bales E, Feng M | display-authors=etal| title=Reversal of aberrant PI3K/Akt signaling by Salubrinal in a GalT-deficient mouse model. | journal=Biochim Biophys Acta Mol Basis Dis | year= 2017 | volume= 1863 | issue= 12 | pages= 3286-3293 | pmid=28844959 | doi=10.1016/j.bbadis.2017.08.023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28844959 }} </ref>. | * '''[[ER]] [[stress]] reducers''': [[ER]] [[stress]] has been shown to contribute to the [[pathogenesis]] of [[galactosemia]] by altering the chemical signaling, such as the [[PI3K/Akt]] pathway<ref name="pmid17643331">{{cite journal| author=Slepak TI, Tang M, Slepak VZ, Lai K| title=Involvement of endoplasmic reticulum stress in a novel Classic Galactosemia model. | journal=Mol Genet Metab | year= 2007 | volume= 92 | issue= 1-2 | pages= 78-87 | pmid=17643331 | doi=10.1016/j.ymgme.2007.06.005 | pmc=2141683 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17643331 }} </ref>. [[Downregulation]] of this pathway has been linked to [[subfertility]] and [[cerebellar]] [[ataxia]]<ref name="pmid26773505">{{cite journal| author=Balakrishnan B, Chen W, Tang M, Huang X, Cakici DD, Siddiqi A | display-authors=etal| title=Galactose-1 phosphate uridylyltransferase (GalT) gene: A novel positive regulator of the PI3K/Akt signaling pathway in mouse fibroblasts. | journal=Biochem Biophys Res Commun | year= 2016 | volume= 470 | issue= 1 | pages= 205-212 | pmid=26773505 | doi=10.1016/j.bbrc.2016.01.036 | pmc=4728015 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26773505 }} </ref>. Hence, its reversal by administering molecules that reduce the [[ER]] [[stress]] might prove beneficial for the [[brain]] and [[reproductive]] [[organs]].Positive effects of such compounds i.e. the [[eukaryotic]] [[initiation]] factor 2-alpha inhibitors (salburinal) have already been demonstrated in mice, thus making it a valid potential [[treatment]]<ref name="pmid28844959">{{cite journal| author=Balakrishnan B, Nicholas C, Siddiqi A, Chen W, Bales E, Feng M | display-authors=etal| title=Reversal of aberrant PI3K/Akt signaling by Salubrinal in a GalT-deficient mouse model. | journal=Biochim Biophys Acta Mol Basis Dis | year= 2017 | volume= 1863 | issue= 12 | pages= 3286-3293 | pmid=28844959 | doi=10.1016/j.bbadis.2017.08.023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28844959 }} </ref>. | ||
Revision as of 10:37, 5 July 2022
|
Galactosemia Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Case Studies |
|
Galactosemia future or investigational therapies On the Web |
|
American Roentgen Ray Society Images of Galactosemia future or investigational therapies |
|
Galactosemia future or investigational therapies in the news |
|
Risk calculators and risk factors for Galactosemia future or investigational therapies |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]
Overview
Future or Investigational Therapies
The therapeutic modalities currently being explored are:
===Aldose reductase inhibitors=== [1]: They prevent the conversion of galactose to galactitol, a highly osmotically active substance [2]. It can accumulate in the lens causing cataract[3], in the brain causing cerebral edema and pseudotumor cerebri[4], and also plays a role in cognitive and neurological symptoms of galactosemia[5]. However, the therapy has been investigated only on animal models (rats and dogs) till now[6], and the effect of blocking the polyol pathway is still not exactly known.
- ER stress reducers: ER stress has been shown to contribute to the pathogenesis of galactosemia by altering the chemical signaling, such as the PI3K/Akt pathway[7]. Downregulation of this pathway has been linked to subfertility and cerebellar ataxia[8]. Hence, its reversal by administering molecules that reduce the ER stress might prove beneficial for the brain and reproductive organs.Positive effects of such compounds i.e. the eukaryotic initiation factor 2-alpha inhibitors (salburinal) have already been demonstrated in mice, thus making it a valid potential treatment[9].
References
- ↑ Lou MF, Dickerson JE, Chandler ML, Brazzell RK, York BM (1989). "The prevention of biochemical changes in lens, retina, and nerve of galactosemic dogs by the aldose reductase inhibitor AL01576". J Ocul Pharmacol. 5 (3): 233–40. doi:10.1089/jop.1989.5.233. PMID 2516529.
- ↑ Timson DJ (2020). "Therapies for galactosemia: a patent landscape". Pharm Pat Anal. 9 (2): 45–51. doi:10.4155/ppa-2020-0004. PMID 32314655 Check
|pmid=value (help). - ↑ Ai Y, Zheng Z, O'Brien-Jenkins A, Bernard DJ, Wynshaw-Boris T, Ning C; et al. (2000). "A mouse model of galactose-induced cataracts". Hum Mol Genet. 9 (12): 1821–7. doi:10.1093/hmg/9.12.1821. PMID 10915771.
- ↑ Berry GT, Hunter JV, Wang Z, Dreha S, Mazur A, Brooks DG; et al. (2001). "In vivo evidence of brain galactitol accumulation in an infant with galactosemia and encephalopathy". J Pediatr. 138 (2): 260–2. doi:10.1067/mpd.2001.110423. PMID 11174626.
- ↑ Kamijo M, Basso M, Cherian PV, Hohman TC, Sima AA (1994). "Galactosemia produces ARI-preventable nodal changes similar to those of diabetic neuropathy". Diabetes Res Clin Pract. 25 (2): 117–29. doi:10.1016/0168-8227(94)90037-x. PMID 7821191.
- ↑ Obrosova I, Faller A, Burgan J, Ostrow E, Williamson JR (1997). "Glycolytic pathway, redox state of NAD(P)-couples and energy metabolism in lens in galactose-fed rats: effect of an aldose reductase inhibitor". Curr Eye Res. 16 (1): 34–43. doi:10.1076/ceyr.16.1.34.5113. PMID 9043821.
- ↑ Slepak TI, Tang M, Slepak VZ, Lai K (2007). "Involvement of endoplasmic reticulum stress in a novel Classic Galactosemia model". Mol Genet Metab. 92 (1–2): 78–87. doi:10.1016/j.ymgme.2007.06.005. PMC 2141683. PMID 17643331.
- ↑ Balakrishnan B, Chen W, Tang M, Huang X, Cakici DD, Siddiqi A; et al. (2016). "Galactose-1 phosphate uridylyltransferase (GalT) gene: A novel positive regulator of the PI3K/Akt signaling pathway in mouse fibroblasts". Biochem Biophys Res Commun. 470 (1): 205–212. doi:10.1016/j.bbrc.2016.01.036. PMC 4728015. PMID 26773505.
- ↑ Balakrishnan B, Nicholas C, Siddiqi A, Chen W, Bales E, Feng M; et al. (2017). "Reversal of aberrant PI3K/Akt signaling by Salubrinal in a GalT-deficient mouse model". Biochim Biophys Acta Mol Basis Dis. 1863 (12): 3286–3293. doi:10.1016/j.bbadis.2017.08.023. PMID 28844959.