Galactosemia future or investigational therapies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]


A number of therapeutic modalities are currently being explored.

Future or Investigational Therapies

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 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].

Intravenous administration of human GALT mRNA in galactosemic mice resulted in hepatic expression of long-lasting GALT enzyme. It removed galactose-1-phosphate from liver and peripheral tissues and also significantly lowered plasma galactose. It also resulted in decreasing overall galactose sensitivity in affected pups.[10]

Chaperones are small molecules that bind to proteins and prevent their misfolding and instability[11]. Abnormal folding and aggregation of the defective emzyme has been demonstrated in almost all variants of galactosemia[12] [13] [14] [15]. Hence, pharmacological chaperones might prove to be a novel therapeutic approach to tackle galactosemia in the near future.


  1. 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.
  2. 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).
  3. 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.
  4. 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.
  5. 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.
  6. 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. PMID 9043821.
  7. 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.
  8. 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.
  9. 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.
  10. Balakrishnan B, An D, Nguyen V, DeAntonis C, Martini PGV, Lai K (2020). "Novel mRNA-Based Therapy Reduces Toxic Galactose Metabolites and Overcomes Galactose Sensitivity in a Mouse Model of Classic Galactosemia". Mol Ther. 28 (1): 304–312. doi:10.1016/j.ymthe.2019.09.018. PMC 6952165 Check |pmc= value (help). PMID 31604675.
  11. Tao YX, Conn PM (2018). "Pharmacoperones as Novel Therapeutics for Diverse Protein Conformational Diseases". Physiol Rev. 98 (2): 697–725. doi:10.1152/physrev.00029.2016. PMC 5966717. PMID 29442594.
  12. McCorvie TJ, Gleason TJ, Fridovich-Keil JL, Timson DJ (2013). "Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia". Biochim Biophys Acta. 1832 (8): 1279–93. doi:10.1016/j.bbadis.2013.04.004. PMC 3679265. PMID 23583749.
  13. Jójárt B, Szori M, Izsák R, Marsi I, László A, Csizmadia IG; et al. (2011). "The effect of a Pro²⁸Thr point mutation on the local structure and stability of human galactokinase enzyme-a theoretical study". J Mol Model. 17 (10): 2639–49. doi:10.1007/s00894-011-0958-y. PMID 21264483.
  14. McCorvie TJ, Timson DJ (2013). "In silico prediction of the effects of mutations in the human UDP-galactose 4'-epimerase gene: towards a predictive framework for type III galactosemia". Gene. 524 (2): 95–104. doi:10.1016/j.gene.2013.04.061. PMID 23644136.
  15. Iwasawa S, Kikuchi A, Wada Y, Arai-Ichinoi N, Sakamoto O, Tamiya G; et al. (2019). "The prevalence of GALM mutations that cause galactosemia: A database of functionally evaluated variants". Mol Genet Metab. 126 (4): 362–367. doi:10.1016/j.ymgme.2019.01.018. PMID 30910422.

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