Advances in stem cell and other therapies for Huntington's disease: An update.

Huntington's disease (HD) is a neurodegenerative disorder caused by an autosomal dominant mutation leading to an abnormal CAG repeat expansion. The result is the synthesis of a toxic misfolded protein, called the mutant huntingtin protein (mHTT). Most current treatments are palliative, but the latest research has expanded into multiple modalities, including stem cells, gene therapy, and even the use of 3D cell structures, called organoids. Stem cell research as a treatment for HD has included the use of various types of stem cells, such as mesenchymal stem cells, neural stem cells, embryonic stem cells, and even reprogrammed stem cells called induced pluripotent stem cells. The goal has been to develop stem cell transplant grafts that will replace the existing mutated neurons, as well as release existing trophic factors for neuronal support. Additionally, research in gene modification using CRISPR-Cas9, PRIME editing, and other forms of genetic modifications are continuing to evolve. Most recently, advancements in stem cell modeling have yielded 3D stem cell tissue models, called organoids. These organoids offer the unique opportunity to transplant a structured stem cell graft which, ideally, models normal human brain tissue more accurately. This manuscript summarizes the recent research in stem cells, genetic modifications, and organoids as a potential for treatment of HD.

Late endocrine effects of L-dopa, 5-HTP, and 6-OH-dopa administered to neonatal rats.

Neonatal rats were injected with L-dopa, 5-hydroxytryptophan (5-HTP) or 6-hydroxy-dopa (6-OH-dopa) and allowed to mature. Eye opening, vaginal opening, endocrine organ weights and pituitary hormone concentration in the serum were measured. Treatment with either the dopamine (DA) precursor or the serotonin (5-HT) precursor caused an acceleration in eye opening, a significant decrease in serum TSH (males) an elevation of serum prolactin (Prl; males), and a lowering of serum growth hormone (females). After chemical sympathectomy (6-OH-dopa) vaginal opening was delayed, thyroid weights were increased and serum TSH decreased (males). It is concluded that during the critical neonatal period overloading either of 2 of the principal monaminergic systems results in similar and persistent alterations in pituitary function. Chemical sympathectomy produced a different pattern of abnormalities.

Late endocrine effects of administering monosodium glutamate to neonatal rats.

Rats were injected with monosodium 1-glutamate (MSG) daily for the 1st 5 days of life and allowed to mature. This is known to cause selective destruction of neurons in the retina and in the arcuate nucleus of the hypothalamus. The adult animals had a significant increase in body fat without an increase in weight, a marked reduction in pituitary, thyroid, adrenal, gonadal and prostate weights. Pituitary, hypothalamic and serum thyrotropin (TSH) were significantly reduced in the males. Serum growth hormone (GH) was markedly reduced in both sexes and the serum prolactin (Prl) was increased significantly in females. FSH did not appear to be abnormal and the LH may have been increased in the males. Serum T4 was significantly reduced in females. The fertility of the females was normal, but treated males mated with normal females showed a marked reduction in fertility and, although the litter sizes of the offspring were normal, the birth weights of the pups of both sexes were significantly reduced. These persistent alterations in neuroendocrine function indicate that lesions produced by neonatal MSG treatment provide a convenient model for studying hypothalamic function.

Endocrine studies in the untreated F1 and F2 progeny of rats treated neonatally with thyroxine.

When neonatal rats are made hyperthyroid with large doses of thyroxine during the first 5 days of life, they develop hypothalamopituitary, thyroidal and gonadal abnormalities that persist through life. When female rats, which have been treated neonatally, are subsequently mated to normal males, their offspring show unexpected gonadal and thyroidal defects, such as reduced weaning weight and delayed vaginal opening and first estrus in females; males show a significant increase in relative thyroid weight and a significant decrease in ventral prostate weight. Cross-fostering was done to separate prenatal from postnatal influences. Even more surprising was the finding that when the untreated female F1 progeny were mated with normal males, the untreated F2 progeny showed more defects and to a greater degree than those present in the maternal parent.

Lifelong alterations in endocrine function resulting from brief perinatal hypothyroidism in the rat.

The late consequences of a brief period of perinatal hypothyroidism were studied in the rat by giving propylthiouracil (PTU) prenatally to the mothers and/or neonatally for 5 days to the pups. Perinatal hypothyroidism produced a delay in eye opening, a diminution in weaning weight, a delay in puberty and first estrus, and a prolongation of estrus cycles. The neo-PTU rats usually had a persistently enlarged thyroid gland associated with an elevated pituitary, hypothalamic, and serum thyroid-stimulating hormone (TSH) concentration. The metabolic clearance rate of TSH and response to luteinizing hormone-releasing hormone (LH-RH) were normal. The response to thyrotropin-releasing hormone (TRH) stimulation was significantly blunted in adult neo-PUT males, suggesting secondary or tertiary hypothyroidism. As a result of these studies, serious thought should be given to the possible consequences of antithyroid drug therapy of pregnant women, and certainly all pregnant hypothyroid women should receive full replacement therapy.

Observations on the untreated progeny of hypothyroid male rats.

The untreated progeny (F1) of hypothyroid male rats that were either radiothyroidectomized (Tx) or had the neo-T4 syndrome (an endocrine disorder produced by large doses of thyroxine (T4) injected during the neonatal period) were studied. The mother rats were all normal. The fathers never had any contact with their progeny. Unexpectedly, the progeny usually showed delayed eye opening, decreased weaning weights, and increased final body weight. The thyroid glands from F1 offspring of both Tx and neo-T4 fathers were enlarged significantly in all but F1 males of Tx fathers. The F1 of Tx fathers had significantly smaller uteri, both absolutely and relatively. The ovaries were significantly larger, whereas the testes were significantly smaller. Pituitary TSH, stalk-median eminence (SME) TSH, and serum TSH were all normal with the exception of an increase in SME TSH in F1 males born of neo-T4 fathers. The response to thyrotropin releasing hormone (TRH) stimulation of the F1 adult progeny of neo-T4 fathers was significantly blunted in the males, whereas the response was normal in offspring of Tx fathers. The mechanisms by which hypothyroid fathers caused changes in their progeny is not known.

Endocrine studies of the untreated progeny of thyroidectomized rats.

Experiments were conducted to assess late and persistent endocrine changes in the progeny of rats born and/or nursed by thyroidectomized (Tx) dams. Forty-five female rats were radiothyroidectomized several weeks before mating with normal males, and compared with the progeny of 26 control females. In all, 248 progeny were studied when adult. Tx dams had significantly reduced fertility (87% of controls), increased pup (11% versus 0) and maternal mortality (27% versus 0), and smaller litters (6.5 versus 11.8 pups/litter). It was shown that the offspring of thyroidectomized female rats had delayed eye opening (15.3 versus 14.3 days), smaller weaning (40.4 versus 54.4 g) and adult body weight (230 versus 260 g), smaller pituitary glands (12.2 versus 14.0 mg), and enlarged thyroid gland (14.2 versus 12.4 mg). Ovarian and testicular weight were decreased (73.9 versus 83.7 mg and 3.2 versus 3.6 g, respectively). The serum thyroid stimulating hormone (TSH) concentrations were increased from 53.8 to 84.4 muU/ml in the males. The pituitary TSH contents were not significantly altered, and the serum TSH response to thyrotropin releasing hormone (TRH) was normal. These persistent effects differed from the late effects of both fetal and neonatal hypothyroidism and neonatal underfeeding. Cross-fostering experiments showed that the diminished weaning weights were the result of the pups being nursed by the hypothyroid dams. The increased nursing mortality and the pituitary and thyroidal changes were the result of prenatal influences produced by the hypothyroid dams, since being nursed by a normal foster dam did not prevent them. The persistently enlarged thyroid glands and the elevated serum TSH in the male offspring of thyroidectomized dams suggested a permanent alteration in the set point of pituitary-thyroid regulation as the consequence of maternal hypothyroidism.

The late effects of neonatal hyperthyroidism upon the feedback regulation of TSH secretion in rats.

Rats made thyrotoxic with large doses of thyroxine (T4) during the neonatal period (neo-T4) show many abnormalities as adults. These usually include impaired body, pituitary and thyroid growth, diminished pituitary and serum TSH concentrations, a diminished serum T4 and a diminished response to PTU challenge and to thyrotropin-releasing hormone (TRH) stimulation. Experiments are presented which show that these rats are hypersensitive to feedback regulation by T4 in a manner similar to that seen after bilateral anterior hypothalamic lesions. They show a subnormal response to PTU challenge and an excessive suppression of serum TSH and goiter growth after T4. Pituitary TSH was less depleted in neo-T4 rats when a small dose of T4 was given daily with PTU and pituitary TSH was more sensitive to suppression by a larger dose of T4 in the neo-T4 group. There was an impaired rebound increase in pituitary TSH following a single inhibitory dose of T4 injected into the adult hypothyroid rat. Although the hypothalamic TRH content is increased in the neo-T4 rat, the circulating concentration of TRH was found to be significantly decreased, supporting the theory that the defects observed in the neo-T4 rat may be the consequence of an impaired hypothalamic secretion of TRH.

Late effects of neonatal undernutrition and overnutrition on pituitary-thyroidal and gonadal function.

Neonatal rats were underfed or overfed and then, at weaning, placed on a normal diet and allowed to mature. Although overfed rats were obese at weaning, they were of normal weight when mature. The underfed rats remained smaller all their lives. The endocrine organs did not share in this retardation, and were actually larger in several instances when expressed per 100 g body weight. Underfed rats also had delayed eye-opening, normal puberty and normal estrous cycles. Pituitary, hypothalamic and serum TSH concentrations were normal, or even increased (in the underfed females). The responses to propylthiouracil and to thyrotropin-releasing hormone (TRH) were both normal. Thus the tertiary hypothyroidism reported in underfed rats 16 days old did not persist into adult life. In all comparisons the males had higher serum TSH concentrations than females and usually had a greater response to TRH stimulation. The various persistent endocrine abnormalities resulting from neonatal thyrotoxicosis differ from those seen after neonatal caloric deprivation in all pertinent regards except that both have reduced body weights.

DDT Administered to Neonatal Rats Induces Persistent Estrus Syndrome.

In the report "DDT administered to neonatal rats induces persistent estrus syndrome" by W. L. Heinrichs et al. (13 Aug., p. 642), line 4 in the last paragraph of column 1, page 643, should read " secretion of luteinizing hormone(LH)."

DDT administered to neonatal rats induces persistent estrus syndrome.

The o,p'-isomer of the insecticide DDT when injected into neonatal female rats significantly advanced puberty, induced persistent vaginal estrus after a period of normal estrous cycles, and caused the ovaries to develop follicular cysts and a reduced number of corpora lutea. The uterotropic response to administered estradiol was reduced, and the female pattern of mating behavior was slightly disturbed. Residues of DDT in ovarian, brain, and adipose tissues of the adult animals were the same in both treated and control groups.